Entry - *300401 - PROTEOLIPID PROTEIN 1; PLP1 - OMIM
* 300401

PROTEOLIPID PROTEIN 1; PLP1


Alternative titles; symbols

PROTEOLIPID PROTEIN, MYELIN; PLP
LIPOPHILIN


Other entities represented in this entry:

DM20, INCLUDED

HGNC Approved Gene Symbol: PLP1

Cytogenetic location: Xq22.2   Genomic coordinates (GRCh38) : X:103,776,506-103,792,619 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Xq22.2 Pelizaeus-Merzbacher disease 312080 XLR 3
Spastic paraplegia 2, X-linked 312920 XLR 3

TEXT

Description

Proteolipid protein, or lipophilin, is the primary constituent of myelin in the central nervous system (CNS) (Diehl et al., 1986).


Cloning and Expression

Using a PLP-specific cDNA clone, Diehl et al. (1986) isolated the human gene encoding PLP from a human genomic library. The gene encodes a 276-amino acid polypeptide with 5 strongly hydrophobic domains that interact with the lipid bilayer as trans- and cis-membrane segments.

The 2 isoforms of the myelin proteolipid protein, PLP and DM20, are very hydrophobic integral membrane proteins that account for about half of the protein content of adult CNS myelin. The mRNAs encoding them are synthesized through alternative splicing of the primary transcript of a single gene. The nucleotide sequence of the protein-encoding regions of the PLP gene is highly conserved among all species studied. There is, for example, no amino acid difference between human, rat, and mouse PLP (Yool et al., 2000).

Dhaunchak and Nave (2007) stated that both PLP and DM20 are tetraspanins with intracellular N and C termini, 2 extracellular loops (EC1 and EC2), and an intracellular loop, which is shorter in DM20 than in full-length PLP. EC1 and EC2 interact in vivo with the opposing membrane in myelin, and EC2 contains 2 disulfide bridges.

Using quantitative RT-PCR, Lauriat et al. (2008) found that expression of both PLP and DM20 showed a linear increase with age from fetus to adulthood (up to 46 years of age) in human prefrontal cortex. Expression was also developmentally regulated in the hippocampus, with a large increase between 1 to 2 months and 1 to 2 years of age, followed by leveling off in older children and adults.


Gene Structure

Diehl et al. (1986) determined that the human PLP gene contains 7 exons and spans approximately 17 kb. Wilkins et al. (1991) reported a correction to the base sequence of the intronic region 5-prime to exon 6 of the PLP gene as published by Diehl et al. (1986); the site in question contained 3 rather than 4 thymidines.


Mapping

Using a bovine cDNA probe in Southern blot analysis of somatic cell hybrid DNA, Willard and Riordan (1985) assigned the gene to human Xq13-q22. They assigned the gene to the mouse X chromosome also.

Mattei et al. (1986) mapped PLP to Xq22 by in situ hybridization. With a panel of hybrids segregating portions of the X chromosome defined by radiation-induced breaks, Willard et al. (1987) found that PLP maps distal to PGK1 (311800) and proximal to PRPS (311850); however, PLP showed complete cosegregation with GLA (300644) to which it must be very close.


Gene Function

Swanton et al. (2005) found that endogenous Plp from porcine brains formed stable oligomers in myelin with molecular masses of approximately 40 and 60 kD, corresponding to dimers and trimers, respectively. In vitro studies with mouse Plp showed that wildtype Plp leaves the endoplasmic reticulum (ER) as a monomer and forms stable oligomers, most likely at the cell surface, after a period of over 24 hours. In contrast, various forms of mutant Plp, including A242V (300401.0019), rapidly assembled into stable oligomers resembling wildtype oligomers while still in the ER. Most of the mutant oligomers were retained in the ER. Swanton et al. (2005) postulated a gain-of-function effect of mutant PLP in which the oligomers may overwhelm ER degradation machinery or may be toxic to the cell.

Quaking (QKI; 609590) proteins bind RNA and regulate RNA splicing, intracellular localization, stability, and translation. Using quantitative RT-PCR, Lauriat et al. (2008) found that expression of Plp1 was reduced in brains of qk(e5) mice, which show decreased expression of all 3 Qki isoforms. Lauriat et al. (2008) concluded that QKI may be required for PLP1 expression.

Myelin rafts in oligodendrocytes are specialized membrane domains that are enriched in cholesterol and galactosylceramide. PLP associates with myelin rafts during biosynthesis and is transported with rafts to the plasma membrane. Using baby hamster kidney (BHK) cells and primary mouse oligodendrocytes, Simons et al. (2002) showed that overexpressed wildtype Plp accumulated in the endosomal/lysosomal compartment and sequestered cholesterol there, rather than accompanying myelin rafts to the plasma membrane. Endosomal/lysosomal accumulation of Plp and cholesterol led to an increase in the amount of detergent-insoluble cholesterol and Plp and to missorting of myelin raft markers. Immunohistochemical analysis showed 10-fold increased colocalization of Plp and the lysosomal marker Lamp1 (153330) in sagittal brain sections of transgenic mice overexpressing Plp compared with wildtype mice. Simons et al. (2002) concluded that overexpression of PLP results in endosomal/lysosomal accumulation of cholesterol and PLP and mistrafficking of raft components, leading to perturbed myelination and reduced viability of oligodendrocytes.


Molecular Genetics

Willard et al. (1987) investigated the structure of the PLP gene in 9 boys with Pelizaeus-Merzbacher disease (PMD; 312080), using a PLP cDNA and genomic probes upstream from and within the PLP gene. One of the 9 samples showed an abnormal Southern blotting pattern consistent with a defect in the PLP gene.

Cremers et al. (1987) found an insertional translocation into the proximal long arm of the X chromosome in a boy who showed findings typical of PMD at autopsy. Duplication of Xq21-q22 was identified using a large number of X-specific and several X-Y-specific probes. There appeared to be 2 intact copies of the PLP gene present. The duplication was apparently due to a de novo mutation, because the mother had a normal female karyotype. The duplication must have resulted from interaction between the 2 maternal X chromosomes during the first meiotic division, as evidenced by the presence of 2 distinguishable alleles at 2 of the marker loci studied.

In a family in which 4 males had classic manifestations of PMD, Pratt et al. (1992) found a C-to-G transversion at nucleotide 193 of exon 3. The change should not result in an amino acid change in the protein but did cause the loss of a HaeIII restriction site which was concordant with the disease in the family. The change was not found in 110 unrelated X chromosomes. No other sequence defect was found in the PLP exons of the affected males, and the cause of disease in this family remained unknown. Trofatter et al. (1991) reported a silent mutation in exon 4 that caused gain of an AhaII restriction site. Unlike the HaeIII variant, the AhaII polymorphism was frequent (0.26) in the normal population.

Hodes et al. (1993) provided an extensive review of the proteolipid protein, which included a tabulation of 36 allelic variants found to be associated with disease. These included point mutations in all 7 of the exons, primarily within exons 3, 4, and 5. In addition, there was 1 mutation in the 3-prime untranslated region, 4 duplications, 1 complete deletion, and a rearrangement. They found that about 30% of patients with the diagnosis of Pelizaeus-Merzbacher disease had a mutation in the coding portion of the proteolipid protein gene. Although the mutations were generally recessive, some mutations were frequently expressed in females.

Using the candidate gene approach, Saugier-Veber et al. (1994) showed that the mutation in the form of X-linked spastic paraplegia that maps to Xq22 (SPG2; 312920) is due to mutation in the PLP gene (see 300401.0012). The his139-to-tyr mutation found in SPG2 resulted in mutant PLP but normal DM20.

Inoue et al. (1996) examined 5 families with PMD without exonic mutations in the PLP gene, using comparative multiplex PCR as a semiquantitative assay of gene dosage. PLP gene duplications were identified in 4 families and confirmed in 3 families by densitometric RFLP analysis. PMD may thus be caused by duplication or deletion of the PLP gene (Raskind et al., 1991), as well as by point mutations. This situation is similar to that in Charcot-Marie-Tooth disease type 1a (CMT1A; 118220), which may be caused by duplication, deletion, or point mutation in the PMP22 gene (601097). Inoue et al. (1996) suggested that since the homologous myelin protein gene PMP22 is duplicated in the majority of patients with CMT1A, PLP gene overdosage may be an important genetic abnormality in PMD and affect myelin formation.

Duplication of the PLP1 gene is responsible for PMD in most patients, whereas deletion of PLP1 is infrequent. Inoue et al. (2002) studied genomic mechanisms for these submicroscopic chromosomal rearrangements. They identified 3 families with PLP1 deletions (including 1 family described by Raskind et al. (1991)) that arose by 3 distinct processes. In 1 family, PLP1 deletion resulted from a maternal balanced submicroscopic insertional translocation of the entire PLP1 gene to the telomere of chromosome 19. PLP1 on the 19q telomere was probably inactive by virtue of a position effect, because a healthy male sib carried the same der(19) chromosome along with a normal X chromosome. Genomic mapping of the deleted segments revealed that the deletions were smaller than most of the PLP1 duplications and involved only 2 other genes. Inoue et al. (2002) hypothesized that a deletion is infrequent because only the smaller deletions can avoid causing either infertility or lethality. Analyses of the DNA sequence flanking the deletion breakpoints revealed Alu-Alu recombination in the family with translocation. In the other 2 families, no homologous sequence flanking the breakpoints was found, but distal breakpoints were embedded in novel low-copy repeats, suggesting the potential involvement of genome architecture in stimulating these rearrangements. In 1 family, junction sequences revealed a complex recombination event. The data suggested that PLP1 deletions are likely caused by nonhomologous end joining.

Hodes et al. (1999) pointed out that 4 codons of the PLP molecule are known in which more than 1 amino acid substitution has been identified: valine-165 to glutamate or glycine, leucine-45 to proline or arginine, aspartate-202 to asparagine or histidine, and leucine-223 to isoleucine or proline.

Mimault et al. (1999) investigated 82 strictly selected sporadic cases of PMD and found PLP mutations in 77%. Complete PLP gene duplication was the most frequent abnormality (62%), whereas point mutations in coding or splice site regions of the gene were involved less frequently (38%). In the case of the 22 point mutations, 68% of mothers were heterozygous for the mutation, a value identical to the two-thirds of carrier mothers that would be expected if there was an equal mutation rate in male and female germ cells. In sharp contrast, among the 34 duplicated cases, 91% of mothers were carriers, a value significantly in favor of a male bias, with an estimation of the male/female mutation frequency (k) of 9.3. Moreover, Mimault et al. (1999) observed de novo mutations between parental and grandparental generations in 17 three-generation families, which allowed a direct estimate of the k value (k of 11). Again, a significant male mutation imbalance was observed only for the duplications. The mechanism responsible for this strong male bias in the duplications may involve an unequal sister chromatid exchange, since 2 deletion events, responsible for mild clinical manifestations, had been reported in PLP-related disorders.

Hodes et al. (2000) described 2 families in which males affected with PMD had a copy of the PLP gene on the short arm of the X chromosome, in addition to a normal copy on Xq22. In the first family, the extra copy was first detected by the presence of heterozygosity of the AhaII dimorphism within the PLP gene. FISH analysis showed an additional copy of PLP on Xp22.1, although no chromosomal rearrangements could be detected by standard karyotype analysis. Another 3 affected males from the family had similar findings. In a second unrelated family with signs of PMD, cytogenetic analysis showed a pericentric inversion of the X chromosome. In the inverted X chromosome carried by several affected family members, FISH showed PLP signals at Xp11.4 and Xq22. The authors noted that Woodward et al. (1998) had reported a family in which affected members had an extra copy of the PLP gene detected at Xq26 in a chromosome with an otherwise normal banding pattern. The identification of 3 separate families in which PLP is duplicated at a noncontiguous site suggested that such duplications could be a relatively common but previously undetected cause of genetic disorders.

Hobson et al. (2000) identified 4 novel mutation in noncoding regions of the PLP1 gene in 5 patients with PMD from 4 families. Three of the mutations, 2 point mutations and 1 deletion (300401.0023-300401.0025), involved the splice donor site of intron 3, which is involved in alternative splicing of PLP and DM20. The fourth mutation (300401.0022) resulted in skipping of exon 6. Female carriers of the mutations, who were mildly symptomatic or asymptomatic, were detected in 3 of the 4 families.

Yool et al. (2000) reviewed the mechanisms of PLP mutations in human disease and in animal models.

Lee et al. (2006) reported a patient with a mild form of SPG2. Although there were no mutations, duplications, or deletions in the PLP1 gene, detailed molecular analysis detected a small duplication of less than 150 kb approximately 136 kb downstream of the PLP1 gene in the patient and his unaffected mother. Lee et al. (2006) suggested that the duplication resulted in silencing of the PLP1 gene by position effect since the patient's relatively mild phenotype resembled that seen with PLP1-null mutations.

Dhaunchak and Nave (2007) found that most PMD-associated mutations mapping to EC2 of PLP/DM20 interfered with formation of correct intramolecular disulfide bridges in transfected oligodendrocytes, leading to abnormal protein crosslinks, ER retention, and activation of the unfolded protein response. Surface expression of mutant PLP/DM20 was restored and the unfolded protein response was reverted by removal of 2 cysteines. Dhaunchak and Nave (2007) concluded that covalent protein crosslinks are the cause, rather than the consequence, of ER retention.


Genotype/Phenotype Correlations

Cailloux et al. (2000) investigated 52 PMD and 28 SPG families without large PLP duplications or deletions by PCR amplification and sequencing of the 7 coding regions and splice sites of the PLP1 gene. Abnormalities were identified in 29 (56%) of the PMD and 4 (14%) of the SPG cases. Of the 33 mutations detected, 23 were missense mutations, 3 were deletion/insertions with frameshifts, and 7 were splice site mutations. Clinical severity was found to be correlated with the nature of the mutation. The severe forms of PMD were most frequently associated with missense mutations in exons 2 and 4, leading to amino acid changes at positions highly conserved in other DM proteins. The mild forms of PMD were frequently caused by mutations, resulting in the production of truncated proteins or by missense mutations. The mutations mostly affected exon 5, leading to the substitution of amino acids only partly conserved in the extracytoplasmic C-D loop. SPG was associated with splice site mutations or changes in the PLP-specific B-C loop.

Carrier females with the submicroscopic duplication in the PLP gene that causes PMD are usually asymptomatic. Inoue et al. (2001) described 2 unrelated female patients who presented with mild PMD or spastic paraplegia. In 1 patient, clinical features as well as cranial magnetic resonance imaging and brainstem auditory evoked potential results improved dramatically over a 10-year period. The other patient, who presented with spastic diplegia and was initially diagnosed with cerebral palsy, also showed clinical improvement. Interphase fluorescence in situ hybridization analyses identified a PLP gene duplication in both patients. The same analyses in family members indicated that the duplication in both patients occurred as a de novo event. Neither skewing of X inactivation in the peripheral lymphocytes nor PLP gene coding alterations were identified in either patient. These findings indicated that females with a PLP gene duplication can occasionally manifest an early-onset neurologic phenotype. Inoue et al. (2001) hypothesized that the remarkable clinical improvement was a result of myelin compensation by oligodendrocytes expressing 1 copy of the PLP gene secondary to selection for a favorable X-inactivation pattern. These findings indicated plasticity of oligodendrocytes in the formation of central nervous system myelin and suggested a potential role for stem cell transplantation therapies.

In a detailed review, Inoue (2005) noted that genomic rearrangements that result in PLP1 gene duplication are the most common cause of PMD (60 to 70% of cases). Neither common PLP1 alleles nor founder effects have been observed in PMD. Mutations in exon 3B, which is spliced out in DM20, predominantly result in an SPG2 phenotype, as DM20 is putatively intact. Similarly, truncating mutations result in a relatively mild phenotype, most likely because of the degradation of mutant mRNAs by nonsense-mediated decay. The fact that most point mutations result in severe dysmyelinating disease suggests that the mutant proteins exert a cytotoxic effect, presumably via accumulation of misfolded proteins.

Using clinical data compiled from a chart review at Wayne State University comprising 40 pedigrees with PMD including 55 males and 56 carrier females, Hurst et al. (2006) investigated neurologic symptoms in carrier females. They categorized patients according to disease severity and type of genetic lesion within the PLP1 gene and then analyzed the clinical data using nonparametric t tests and analyses of variance. Hurst et al. (2006) concluded that their analyses formally demonstrated the link between mild disease in males and symptoms in carrier female relatives. Conversely, mutations causing severe disease in males rarely cause clinical signs in carrier females. The greatest risk of disease in females was found for nonsense/indel or null mutations. Missense mutations carried moderate risk. The lowest risk, which represents the bulk of families with PMD, is associated with PLP1 gene duplications. Hurst et al. (2006) concluded that effective genetic counseling of PMD and spastic paraplegia carrier females must include an assessment of disease severity in affected male relatives.


Cytogenetics

Woodward et al. (2005) described genomic structures of 59 segmental duplications of the X chromosome that included the PLP1 gene in patients with Pelizaeus-Merzbacher disease. They reported 13 junction sequences that gave insight into underlying mechanisms. Although proximal breakpoints were highly variable, distal breakpoints tended to cluster around low-copy repeats (LCRs) (in 50% of cases), and each duplication event appeared to be unique. They interpreted the data to indicate that the tandem duplications are formed by a coupled homologous and nonhomologous recombination mechanism. They suggested repair of a double-stranded break by 1-sided homologous strand invasion of a sister chromatid, followed by DNA synthesis and nonhomologous end joining with the other end of the break. This is in contrast to other genomic disorders.

Using array CGH and breakpoint sequence analysis of different sized PMD-associated PLP1 nonrecurrent duplications, Lee et al. (2007) found interspersed stretches of DNA of normal copy number, as well as triplicated sequences contained within duplications and sequence complexity at junctions. The findings were not consistent with a simple recombination model. Lee et al. (2007) proposed a model of replication fork stalling and template switching (FoSTeS) to explain the complex duplication and deletion rearrangements associated with the disorder.

Carvalho et al. (2011) identified complex genomic rearrangements consisting of intermixed duplications and triplications of genomic segments at the MECP2 (300005) and the PLP1 loci. These complex rearrangements were characterized by a triplicated segment embedded within a duplication in 11 unrelated subjects. Notably, only 2 breakpoint junctions were generated during each rearrangement formation. All the complex rearrangement products shared a common genomic organization, duplication-inverted triplication-duplication (DUP-TRP/INV-DUP), in which the triplicated segment is inverted and located between directly oriented duplicated genomic segments. Carvalho et al. (2011) provided evidence that the DUP-TRP/INV-DUP structures are mediated by inverted repeats that can be separated by more than 300 kb, a genomic architecture that apparently leads to susceptibility to such complex rearrangements.

Bahrambeigi et al. (2019) analyzed genomic rearrangements in 50 unrelated male patients with Pelizaeus-Merzbacher disease and PLP1 copy number gains. Analysis with a high-density customized array showed that 33 patients had single duplications, ranging from 122 kb to approximately 4.5 Mb, and 17 patients had complex genomic rearrangements (CGR). Of the CGR patients, 9 had a pattern of interspersed duplications separated by a copy neutral region, 3 had a triplication flanked by duplications, and rearrangements with other complexities were identified in the other 5 individuals. In 40 of the 50 patients, the authors ascertained at least one breakpoint junction via PCR amplification. Microhomology was found in 26% of sequenced join-points, ranging from 2 to 9 bp, and evidence for microhomeology was observed in approximately 33% of join-points. Bahrambeigi et al. (2019) also performed a metaanalysis of published PLP1 rearrangements, including 159 join-points from 124 unrelated individuals. They found single duplications in 55% of individuals and a triplication flanked by duplications as the most common CGR in 20% of individuals. In approximately 32% of join-points, there was evidence for microhomeology, and in 22% of cases of join-points, there was evidence for microhomology. Bahrambeigi et al. (2019) concluded that microhomeology may play a role in genomic rearrangements at the PLP1 locus by facilitating template switches, and could be an indicator of microhomology-mediated break-induced replication (MMBIR). This potentially supported the role of FoSTeS/MMBIR as a predominant mechanism leading to rearrangements at the PLP1 locus.


Animal Model

Readhead et al. (1994) generated normal mouse lines expressing autosomal copies of the wildtype Plp gene and found that a 2-fold increase in Plp gene dosage resulted in hypomyelination, astrocytosis, seizures, and premature death. They concluded that the myelination process is exquisitely sensitive to the accurate level of PLP gene expression.

Jung et al. (1996) noted that 3 mutations in the mouse Plp gene are associated with dysmyelination: 'jimpy,' a splicing mutation that leads to loss of transmembrane domain-4 (TM4), 'jimpy(msd),' an ala242-to-val mutation in TM4, and 'rumpshaker,' an ile186-to-thr mutation in TM2. Using antibodies directed against a cell surface epitope and the C terminus of Plp, Jung et al. (1996) showed that all 3 of these mouse Plp mutations result in protein misfolding. They concluded that misfolding of mutant PLP and DM20 proteins causes their intracellular retention and interferes with oligodendrocyte differentiation and survival.

Edgar et al. (2004) found that axons of the optic nerve of Plp1-null mice developed progressive focal accumulations of membranous organelles in areas distal to nodal complexes. The axon proximal to the node was either normal or was affected to a much lesser degree, suggesting a defect in fast retrograde axonal transport. The axonal cytoskeleton was disrupted within areas of swelling, and neurofilaments and microtubules were replaced by a fine granular amorphous material. The absence of Plp1 from oligodendrocytes resulted in impaired transport in the underlying axon, leading to multifocal accumulation of membranous organelles. Edgar et al. (2004) concluded that oligodendrocytes play a role in the regulation of certain axonal transport functions.


ALLELIC VARIANTS ( 27 Selected Examples):

.0001 PELIZAEUS-MERZBACHER DISEASE

PLP1, PRO215SER
  
RCV000011822...

In a patient with the classic form (type I) of PMD (312080), Gencic et al. (1989) described a missense mutation in exon 5 of the PLP gene, with a C-to-T transition creating a serine substitution for proline at the carboxy end of the protein. Abuelo et al. (1989) also demonstrated a single nucleotide change in exon 5 of PLP that resulted in substitution of serine for proline as residue 215. They found the mutation in the carrier mother and in 2 sisters of 2 affected males.


.0002 PELIZAEUS-MERZBACHER DISEASE

PLP1, TRP162ARG
  
RCV000011823...

In the family with classic PMD (312080) investigated by Koeppen et al. (1987), Hudson et al. (1989) found a T-to-C transition resulting in the substitution of a charged amino acid residue, arginine, for tryptophan in 1 of the 4 hydrophobic domains of the PLP protein. A change of CGG to TGG in exon 4 was responsible for the substitution of trp162.


.0003 PELIZAEUS-MERZBACHER DISEASE

PLP1, PRO14LEU
  
RCV000011824...

By the polymerase chain reaction (PCR), Trofatter et al. (1989) amplified, cloned and sequenced the exons of the PLP gene in a male with PMD (312080) from an extensively affected Indiana family. They found a basepair transition from C-to-T at the nucleotide 40 of the second exon. In a second, unrelated PMD kindred with a milder form of disease, the C-to-T transition was not found. They found perfect linkage between the C-to-T transition and disease in this kindred; lod score = 4.27 at theta = 0.0. The C-to-T mutation predicted a pro14-to-leu substitution.


.0004 PELIZAEUS-MERZBACHER DISEASE

PLP1, THR155ILE
  
RCV000011825

Pratt et al. (1991) identified a C-to-T transition in exon 4 of the PLP gene in 2 affected males and 2 obligate carriers in a German family with PMD (312080). The mutation, which alters amino acid 155 from threonine to isoleucine and eliminates an HphI site, was absent in 108 normal chromosomes. Linkage analysis in the family showed 5 concordant and 1 discordant result compared with those obtained by magnetic resonance imaging.


.0005 PELIZAEUS-MERZBACHER DISEASE

PLP1, VAL218PHE
  
RCV000011826

Pham-Dinh et al. (1991) used DNA amplification by PCR to study the PLP gene coding regions from 17 patients in 15 unrelated families with similar Pelizaeus-Merzbacher (312080) phenotype. In 1 case amplification of peripheral nerve PLP cDNA showed a silent T-to-C transition that was unrelated to the disease. In 1 family a change of valine-218 to phenylalanine was observed. Pham-Dinh et al. (1991) investigated the inheritance of the mutant allele in 19 subjects in this 4-generation family and found a strict cosegregation of the phe-218 substitution with transmission and expression of the disease. A G-to-T transversion in exon 5 was responsible for the amino acid substitution. Affected members of this family presented in early infancy with hypotonia, spasticity, and abnormal head and ocular movements. Two patients had died at ages 36 and 45 years. One patient was capable of walking autonomously, using the telephone, and typewriting.


.0006 PELIZAEUS-MERZBACHER DISEASE

PLP1, DEL
   RCV000011827

In a family with affected males in 4 generations, Raskind et al. (1991) found that PMD (312080) was associated with complete absence of a band in Southern analysis using PLP probes encompassing the promoter region, the entire coding region, and the 3-prime untranslated region and spanning at least 29 kb of genomic DNA. DNA from unaffected relatives gave the expected band pattern.


.0007 PELIZAEUS-MERZBACHER DISEASE

PLP1, THR181PRO
  
RCV000011828

In 2 obligate female carriers of PMD (312080), Strautnieks et al. (1992) used single-strand conformation polymorphism (SSCP) analysis to identify an A-to-C transversion at nucleotide 541 resulting in a thr181-to-pro substitution in the region of the protein presumed to represent a transmembrane segment. The mutation was found in exon 4 of the PLP gene and was used in prenatal diagnosis to predict an unaffected fetus.


.0008 PELIZAEUS-MERZBACHER DISEASE

PLP1, LEU223PRO
  
RCV000011829...

In a second family with PMD (312080), Strautnieks et al. (1992) used SSCP analysis to demonstrate a variant band pattern in exon 5 in the PLP gene which was shown by sequencing to be due to a T-to-C transition at nucleotide 668 resulting in a leu223-to-pro amino acid substitution.


.0009 PELIZAEUS-MERZBACHER DISEASE

PLP1, ASP202HIS
  
RCV000011830

By a combination of SSCP analysis and direct sequencing of PCR-amplified DNA, Doll et al. (1992) identified an asp202-to-his substitution in exon 4 of the PLP gene in a patient with leukodystrophy of unknown etiology.


.0010 PELIZAEUS-MERZBACHER DISEASE

PLP1, GLY73ARG
  
RCV000011831

By a combination of SSCP analysis and direct sequencing of PCR-amplified DNA, Doll et al. (1992) identified a gly73-to-arg substitution in exon 3 of the PLP gene in a patient with leukodystrophy of unknown etiology.


.0011 PELIZAEUS-MERZBACHER DISEASE, CONNATAL

PLP1, GLY220CYS
  
RCV000011832

In a Japanese family with Pelizaeus-Merzbacher disease (312080), Iwaki et al. (1993) found a G-to-T transition in exon 5 of the PLP gene, which led to a glycine-to-cysteine substitution at residue 220. The disorder in this family was present in 2 boys who showed similar clinical signs from birth, with autopsy confirmation of the diagnosis in 1 of the brothers. In the older patient, laryngeal stridor developed immediately after birth and his muscles were flaccid. He had poor head control and a coarse nystagmus. Spastic paraparesis was evident by age 4 years. He could not walk or speak and died of pneumonia at age 13. Autopsy showed almost complete deficiency of myelin within the central nervous system except for patchy, slight preservations of myelin in the pons. In studies of the postmortem brain, Iwaki et al. (1993) found a nearly complete loss of mRNA expression of both PLP and myelin basic protein (MBP; 159430), 2 major myelin proteins produced by oligodendrocytes, yet mRNA levels of glial fibrillary acidic protein (GFAP; 137780), an astrocyte marker, appeared to be normal. The findings supported the pathologic observation that oligodendrocytes are specifically lost in the PMD brain.


.0012 SPASTIC PARAPLEGIA 2

PLP1, HIS139TYR
  
RCV000011833...

While narrowing the genetic interval containing the gene for X-linked spastic paraplegia-2 (312920) in a large pedigree previously reported by Bonneau et al. (1993), Saugier-Veber et al. (1994) found that PLP was the closest marker to the disease locus, implicating PLP as a possible candidate gene. They went on to find a his139-to-tyr mutation in exon 3B of the PLP gene in an affected male. The mutation resulted in a mutant form of PLP, but the other protein encoded by the PLP gene, DM20, was normal. The his139-to-tyr mutation segregated with the disease; maximum lod = 6.63 at theta = 0.00. Thus, SPG2 and PMD (312080) are allelic disorders.


.0013 SPASTIC PARAPLEGIA 2

PLP1, ILE186THR
  
RCV000011834...

The family with spastic paraplegia (312920) reported by Johnston and McKusick (1962) as one of the earliest examples of X-linked SPG showed a disorder that began as 'pure' spastic paraparesis. The patients later developed nystagmus, dysarthria, sensory disturbance or mental retardation, with half the patients having optic atrophy. Later symptoms included muscle wasting, joint contractures, and a requirement for crutches or wheelchair by early adult life. Kobayashi et al. (1994) demonstrated linkage to the Xq21.3-q24 region, which includes the PLP locus and, furthermore, demonstrated an ile186-to-thr mutation in the PLP gene. This mutation is identical to that previously identified in the 'rumpshaker' mouse.

This same mutation, a 557T-C nucleotide transition, was identified by Naidu et al. (1997) in a 3.5-year-old boy with onset of manifestations at birth who was subsequently shown to be a member of the same family as that reported by Johnston and McKusick (1962).

In the 'rumpshaker' mouse, Edgar et al. (2004) observed a late-onset distal degeneration of the axons of the longest spinal tract, the fasciculus gracilis. This was said to be the first report of Wallerian type degeneration in mice with spontaneous mutation of the Plp gene.


.0014 PELIZAEUS-MERZBACHER DISEASE

PLP1, THR42ILE
  
RCV000011835

In a patient with PMD (312080), Pratt et al. (1995) described a thr42-to-ile mutation which they could determine had originated de novo in the X chromosome contributed by the maternal great-grandfather of the propositus. This was determined from the pattern of inheritance of the AhaII polymorphism and a series of microsatellite markers located near PLP on Xq22. Pratt et al. (1995) commented on the fact that, with one exception, each mutation that has been found is unique to the particular family.


.0015 PELIZAEUS-MERZBACHER DISEASE, MILD

PLP1, MET1ILE
  
RCV000011836...

In a Dutch family with a relatively mild form of Pelizaeus-Merzbacher disease (312080), Sistermans et al. (1996) described a G-to-A transition in the initiation codon of the PLP gene. This mutation caused the total absence of PLP and is therefore in agreement with the hypothesis that absence of PLP leads to a mild form of PMD. Most mutations in PLP cause either overexpression or expression of a truncated form of PLP resulting in oligodendrocyte cell death because of accumulation of PLP in the endoplasmic reticulum. Only 1 patient with complete deletion of the PLP gene had been described to that time (300401.0007). This same mutation is found in the beta-globin gene as a cause of beta-0-thalassemia (141900.0456) and in the PAH gene resulting in phenylketonuria (261600.0048).

The proband in the family reported by Sistermans et al. (1996) came to the attention of the investigators at the age of 33 years because of slowly progressive deterioration of his mental condition and progression of his spastic tetraplegia. Neurologic examination revealed a spastic atactic tetraplegia. Motor dysfunction had been first noted at the age of 4 years and he was admitted to an institution for the mentally disabled at age 14 with mental deficiency and spastic paraplegia. His sister's son was observed to have spastic tetraplegia and poor balance control by the age of 1 year. By the age of 6 years he was dependent on help for activities of daily living and was wheelchair-bound, although he was able to crawl.


.0016 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE

PLP1, -34C-T, 5-PRIME UTR
  
RCV000204678...

This variant, formerly titled PELIZAEUS-MERZBACHER DISEASE, MILD, has been reclassified based on the report of Lek et al. (2016).

In a 7-year-old boy with clinical and neuroradiologic features consistent with classic PMD (312080), Kawanishi et al. (1996) found a C-to-T transition at nucleotide position -34 in the 5-prime flanking region of exon 1 of the PLP gene. The mother was heterozygous for the mutation which was not found in 117 X chromosomes from unrelated Japanese. This was said to be the first report of a 5-prime UTR mutation in the PLP gene.

Lek et al. (2016) noted that the -34C-T variant was found in hemizygosity in 61 males in the ExAC database and had a high allele frequency (0.014) in the Latino population, suggesting that it is not pathogenic.


.0017 SPASTIC PARAPLEGIA 2

PLP1, PHE236SER
  
RCV000011838...

Donnelly et al. (1996) described a phe236-to-ser mutation of the PLP gene in males affected with SPG2 (312920) from a family in which 8 affected boys in 5 generations had suffered from a complicated form of spastic paraplegia.


.0018 PELIZAEUS-MERZBACHER DISEASE, ATYPICAL

PLP1, TRP144TER
  
RCV000011839...

In a family displaying atypical features of Pelizaeus-Merzbacher disease (312080), Hodes et al. (1997) identified a G-to-A transition at nucleotide 431 in exon 3, resulting in a stop codon (TAG) instead of tryptophan (TGG) at amino acid 144. The clinical picture resembled somewhat that of X-linked spastic paraplegia. It differed from that condition and from both the classic and the connatal forms of PMD in that it was relatively mild, onset was delayed beyond age 2 years, nystagmus was absent, tremors were prominent, mental retardation was not severe, and some patients showed dementia or personality disorders. The disease was progressive rather than static in some, and several females showed signs of disease. The nonsense mutation, which was in exon 3B, was predicted to block synthesis of normal PLP but spared DM20, the isoform whose persistence has been associated with mild forms of PLP-associated disease in both humans and mice.


.0019 PELIZAEUS-MERZBACHER DISEASE, CONNATAL

PLP1, ALA242VAL
  
RCV000011840

The jimpy(msd) mouse carries an ala242-to-val (A242V) mutation in the Plp gene. The phenotype has been used as a model of the human connatal type of PMD (312080) in research (Gow and Lazzarini (1996)). Yamamoto et al. (1998) described a Japanese male infant with prenatal PMD and the same A242V substitution. The substitution resulted from a 725C-T transition in exon 6. Pendular nystagmus and psychomotor developmental delay had been noted at the age of 4 months. The infant died suddenly at 9 months, and demyelinated white matter of the brain was observed at autopsy.


.0020 SPASTIC PARAPLEGIA 2

PLP1, SER169PHE
  
RCV000011841...

Hodes et al. (1998) described a boy with spastic paraplegia-2 (312920) and a C-to-T transition at nucleotide 506 in exon 4 of the PLP gene, resulting in substitution of phenylalanine for serine-169 in the third transmembrane domain of the protein. His mother did not have the mutation. The patient was first seen for evaluation of 'cerebral palsy' at the age of 7 years. There was no nystagmus, but funduscopy showed optic nerve pallor. There was more spasticity in the legs than in the arms, deep tendon reflexes were 1+ in the arms and 3+ in the legs, and there was prominent scissoring while he sat. MRI scan showed global lack of myelination with sparing of only a few transverse fibers in the pons.


.0021 PELIZAEUS-MERZBACHER DISEASE

PLP1, DUP
   RCV000011842

Although linkage analysis had shown homogeneity at the PLP1 gene in patients with PMD (312080), exonic mutations in the PLP1 gene had been identified in only 10 to 25% of all cases. Using comparative multiplex PCR (CM-PCR) as a semiquantitative assay of gene dosage, Inoue et al. (1996) examined 5 families with PMD who did not carry exonic mutations in PLP1 gene. PLP1 gene duplications were identified in 4 families by CM-PCR and confirmed in 3 families by densitometric RFLP analysis. The authors suggested that PLP gene overdosage may be an important abnormality in PMD and may affect myelin formation.

Sistermans et al. (1998) studied 2 groups of patients: one with 10 independent PMD families and one with 24 sporadic patients suspected of PMD. Duplications of the PLP1 gene were identified in 50% of cases of group 1 and in 21% of cases of group 2. The authors concluded that duplications of the PLP1 gene are the major cause of PMD.

Woodward et al. (1998) showed that PLP1 gene duplication can be detected by interphase FISH. The extent of the duplication was analyzed in 5 patients and their 4 asymptomatic mothers, and a large duplication (500 kb or more) was detected, with breakpoints that differed between families, at the proximal end. The results of this study suggested that intrachromosomal rearrangements may be a common mechanism by which duplications arise in PMD.

Woodward et al. (2000) found that carriers of a duplication of the PLP1 gene showed skewed X inactivation, whereas carriers of point mutations showed random X inactivation. The skewed pattern observed in most duplication carriers suggested that there is selection against those cells in which the duplicated X chromosome is active, and that other expressed sequences within the duplicated region rather than mutant PLP may be responsible.

Woodward et al. (2003) reported cytogenetic and molecular findings in a family in which PMD had arisen by a submicroscopic duplication of the PLP1 gene involving the insertion of approximately 600 kb from chromosome Xq22 into Xq26.3.


.0022 PELIZAEUS-MERZBACHER DISEASE

PLP1, IVS6DS, G-T, +3
  
RCV000011843

In a family with severe Pelizaeus-Merzbacher disease (312080) originally reported by Carango et al. (1995), Hobson et al. (2000) identified a G-to-T transversion in the donor splice site of intron 6 of the PLP1 gene, which resulted in the skipping of exon 6. The 2 affected brothers demonstrated hypotonia at birth, later developing nystagmus, slowly progressive spastic paraplegia, and seizures. The mother, who was shown to be a carrier of the mutation, had mild spastic paraplegia and walked with a cane. Hobson et al. (2000) postulated that the mutation caused misfolding and retention of the protein in the endoplasmic reticulum, leading to oligodendrocyte apoptosis. Carango et al. (1995) had demonstrated a 6-fold increase in mRNA for DM20 in skin fibroblasts from these 2 brothers.


.0023 PELIZAEUS-MERZBACHER DISEASE

PLP1, IVS3DS, T-C, +2
  
RCV000011844...

In a patient with classic PMD (312080), Hobson et al. (2000) identified a T-to-C transition in the donor splice site of intron 3 of the PLP1 gene, in the area where alternative 5-prime splicing of the PLP gene yields either PLP or DM20. This position is virtually invariant in splice donor sites, strongly suggesting that it is the causative mutation. The patient had onset of head titubations and nystagmus at about 4 months of age. The mother and sister were found to be carriers of the mutation.


.0024 PELIZAEUS-MERZBACHER DISEASE

PLP1, IVS3DS, A-G, +4
  
RCV000011845

In a patient with classic PMD (312080), Hobson et al. (2000) identified a mutation in the donor splice site of intron 3 of the PLP1 gene. The patient showed hypotonia at birth and later developed head titubations and nystagmus. There was no family history of the disease.


.0025 PELIZAEUS-MERZBACHER DISEASE, ATYPICAL

PLP1, IVS3, 19-BP DEL, +28
   RCV000011846...

In a male patient with relatively late onset of nystagmus and rapidly progressive ataxia, Hobson et al. (2000) identified a 19-bp deletion in intron 3 near the splice donor site. The authors suggested that the deletion may define a highly conserved intron enhancer sequence that governs the alternative splicing of PLP and DM20. Three female family members were carriers of the mutation. Hobson et al. (2002) characterized the clinical phenotype of the previously reported male patient who at age 6 years had onset of difficulty in walking, rendering him wheelchair-bound by age 11 years with spastic paraparesis, cerebellar findings, optic atrophy, nystagmus, dysarthria, and cognitive decline. Sequential MRI studies showed delay in myelin formation and diffuse abnormal white matter signals, while MRS studies showed findings consistent with increased turnover of myelin and neuronal and axonal loss. Studies of the deletion in cultured oligodendrocytes showed that it contains a sequence that is critical for efficient PLP-specific splicing. Hobson et al. (2002) concluded that deletion of this region in PLP intron 3 causes a reduction in PLP message and protein, which affects myelin stability and axonal integrity.


.0026 SPASTIC PARAPLEGIA 2

PLP1, ARG137TRP
  
RCV000011847...

In a boy with SPG2 (312920), Gorman et al. (2007) identified a hemizygous 409C-T transition in exon 3B of the PLP1 gene, resulting in an arg137-to-trp (R137W) substitution. He presented at age 10 years with poor school performance, diplopia, and clumsiness after an upper respiratory infection. MRI showed multifocal areas of T2 white matter hyperintensities. Treatment with high-dose intravenous methylprednisolone resulted in clinical improvement. Over the next few years, he had episodes of neurologic deterioration characterized by nystagmus, dysmetria, ataxia, tremor, and progressive cognitive decline. These episodes responded temporarily to methylprednisolone treatment, suggesting an inflammatory process. The patient even fulfilled the criteria for relapsing-remitting multiple sclerosis (MS; 128200), including the presence of oligoclonal bands in the CSF. His mother, who carried the mutation, developed tremor and incoordination in her late forties, although this was complicated by alcohol abuse. A grandfather with the mutation was asymptomatic except for mild tremor.


.0027 PELIZAEUS-MERZBACHER DISEASE

PLP1, ASP57TYR
  
RCV000011848

In affected members of a 2-generation African American family with X-linked spastic paraplegia, originally reported by Arena et al. (1992), Stevenson et al. (2009) identified a hemizygous mutation in the PLP1 gene, resulting in an asp57-to-tyr (D58Y) substitution in an extracellular loop of the protein. The mutation segregated with the disorder and was not identified in 300 male controls. The findings indicated that the family in fact had Pelizaeus-Merzbacher disease (312080). Arena et al. (1992) reported that all had severe mental retardation, lower limb spasticity and atrophy, absent or dysarthric speech, and impaired ambulation requiring wheelchairs from childhood. Other features included nystagmus, dystonic posturing, and ataxia. Brain imaging studies showed macrogyria, lack of myelination, and increased paramagnetic signal suggestive of iron deposition. Stevenson et al. (2009) noted that, although altered signals in the basal ganglia and thalamus are not specific for iron deposition, MRI findings suggestive of iron deposition in the basal ganglia have been reported in other patients with PMD.


See Also:

REFERENCES

  1. Abuelo, D. N., Ambler, M., Gencic, S., Berndt, J., Hudson, L. Heterozygote detection in Pelizaeus-Merzbacher disease. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A169, 1989.

  2. Arena, J. F., Schwartz, C., Stevenson, R., Lawrence, L., Carpenter, A., Duara, R., Ledbetter, D., Huang, T., Lehner, T., Ott, J., Lubs, H. A. Spastic paraplegia with iron deposits in the basal ganglia: a new X-linked mental retardation syndrome. Am. J. Med. Genet. 43: 479-490, 1992. [PubMed: 1605230, related citations] [Full Text]

  3. Bahrambeigi, V., Song, X., Sperle, K., Beck, C. R., Hijazi, H., Grochowski, C. M., Gu, S., Seeman, P., Woodward, K. J., Carvalho, C. M. B., Hobson, G. M., Lupski, J. R. Distinct patterns of complex rearrangements and a mutational signature of microhomeology are frequently observed in PLP1 copy number gain structural variants. Genome Med. 11: 80, 2019. Note: Electronic Article. [PubMed: 31818324, images, related citations] [Full Text]

  4. Bonneau, D., Rozet, J.-M., Bulteau, C., Berthier, M., Mettey, R., Gil, R., Munnich, A., Le Merrer, M. X linked spastic paraplegia (SPG2): clinical heterogeneity at a single gene locus. J. Med. Genet. 30: 381-384, 1993. [PubMed: 8320699, related citations] [Full Text]

  5. Buckle, V. J., Edwards, J. H., Evans, E. P., Jonasson, J. A., Lyon, M. F., Peters, J., Searle, A. G. Comparative maps of human and mouse X chromosomes. (Abstract) Cytogenet. Cell Genet. 40: 594-595, 1985.

  6. Cailloux, F., Gauthier-Barichard, F., Mimault, C., Isabelle, V., Courtois, V., Giraud, G., Dastugue, B., Boespflug-Tanguy, O., Clinical European Network on Brain Dysmyelinating Disease. Genotype-phenotype correlation in inherited brain myelination defects due to proteolipid protein gene mutations. Europ. J. Hum. Genet. 8: 837-845, 2000. [PubMed: 11093273, related citations] [Full Text]

  7. Carango, P., Funanage, V. L., Quiros, R. E., Debruyn, C. S., Marks, H. G. Overexpression of DM20 messenger RNA in two brothers with Pelizaeus-Merzbacher disease. Ann. Neurol. 38: 610-617, 1995. [PubMed: 7574457, related citations] [Full Text]

  8. Carvalho, C. M. B., Ramocki, M. B., Pehlivan, D., Franco, L. M., Gonzaga-Jauregui, C., Fang, P., McCall, A., Pivnick, E. K., Hines-Dowell, S., Seaver, L. H., Friehling, L., Lee, S., and 9 others. Inverted genomic segments and complex triplication rearrangements are mediated by inverted repeats in the human genome. Nature Genet. 43: 1074-1081, 2011. [PubMed: 21964572, images, related citations] [Full Text]

  9. Cremers, F. P. M., Pfeiffer, R. A., van de Pol, T. J. R., Hofker, M. H., Kruse, T. A., Wieringa, B., Ropers, H. H. An interstitial duplication of the X chromosome in a male allows physical fine mapping of probes from the Xq13-q22 region. Hum. Genet. 77: 23-27, 1987. [PubMed: 3476455, related citations] [Full Text]

  10. Dhaunchak, A.-S., Nave, K.-A. A common mechanism of PLP/DM20 misfolding causes cysteine-mediated endoplasmic reticulum retention in oligodendrocytes and Pelizaeus-Merzbacher disease. Proc. Nat. Acad. Sci. 104: 17813-17818, 2007. [PubMed: 17962415, images, related citations] [Full Text]

  11. Diehl, H.-J., Schaich, M., Budzinski, R.-M., Stoffel, W. Individual exons encode the integral membrane domains of human myelin proteolipid protein. Proc. Nat. Acad. Sci. 83: 9807-9811, 1986. Note: Erratum: Hum. Genet. 86: 617-618, 1991. [PubMed: 3467339, related citations] [Full Text]

  12. Doll, R., Natowicz, M. R., Schiffmann, R., Smith, F. I. Molecular diagnostics for myelin proteolipid protein gene mutations in Pelizaeus-Merzbacher disease. Am. J. Hum. Genet. 51: 161-169, 1992. [PubMed: 1376966, related citations]

  13. Donnelly, A., Colley, A., Crimmins, D., Mulley, J. A novel mutation in exon 6 (F236S) of the proteolipid protein gene is associated with spastic paraplegia. Hum. Mutat. 8: 384-385, 1996. [PubMed: 8956049, related citations] [Full Text]

  14. Edgar, J. M., McLaughlin, M., Barrie, J. A., McCulloch, M. C., Garbern, J., Griffiths, I. R. Age-related axonal and myelin changes in the rumpshaker mutation of the Plp gene. Acta Neuropath. 107: 331-335, 2004. [PubMed: 14745569, related citations] [Full Text]

  15. Edgar, J. M., McLaughlin, M., Yool, D., Zhang, S.-C., Fowler, J. H., Montague, P., Barrie, J. A., McCulloch, M. C., Duncan, I. D., Garbern, J., Nave, K. A., Griffiths, I. R. Oligodendroglial modulation of fast axonal transport in a mouse model of hereditary spastic paraplegia. J. Cell Biol. 166: 121-131, 2004. [PubMed: 15226307, images, related citations] [Full Text]

  16. Gencic, S., Abuelo, D., Ambler, M., Hudson, L. D. Pelizaeus-Merzbacher disease: an X-linked neurologic disorder of myelin metabolism with a novel mutation in the gene encoding proteolipid protein. Am. J. Hum. Genet. 45: 435-442, 1989. [PubMed: 2773936, related citations]

  17. Gorman, M. P., Golomb, M. R., Walsh, L. E., Hobson, G. M., Garbern, J. Y., Kinkel, R. P., Darras, B. T., Urion, D. K., Eksioglu, Y. Z. Steroid-responsive neurologic relapses in a child with a proteolipid protein-1 mutation. Neurology 68: 1305-1307, 2007. [PubMed: 17438221, related citations] [Full Text]

  18. Gow, A., Lazzarini, R. A. A cellular mechanism governing the severity of Pelizaeus-Merzbacher disease. Nature Genet. 13: 422-428, 1996. [PubMed: 8696336, related citations] [Full Text]

  19. Hobson, G. M., Davis, A. P., Stowell, N. C., Kolodny, E. H., Sistermans, E. A., de Coo, I. F. M., Funanage, V. L., Marks, H. G. Mutations in noncoding regions of the proteolipid protein gene in Pelizaeus-Merzbacher disease. Neurology 55: 1089-1096, 2000. [PubMed: 11071483, related citations] [Full Text]

  20. Hobson, G. M., Huang, Z., Sperle, K., Stabley, D. L., Marks, H. G., Cambi, F. A PLP splicing abnormality is associated with an unusual presentation of PMD. Ann. Neurol. 52: 477-488, 2002. [PubMed: 12325077, related citations] [Full Text]

  21. Hodes, M. E., Blank, C. A., Pratt, V. M., Morales, J., Napier, J., Dlouhy, S. R. Nonsense mutation in exon 3 of the proteolipid protein gene (PLP) in a family with an unusual form of Pelizaeus-Merzbacher disease. Am. J. Med. Genet. 69: 121-125, 1997. [PubMed: 9056547, related citations]

  22. Hodes, M. E., Hadjisavvas, A., Butler, I. J., Aydanian, A., Dlouhy, S. R. X-linked spastic paraplegia due to a mutation (C506T; ser169phe) in exon 4 of the proteolipid protein gene (PLP). Am. J. Med. Genet. 75: 516-517, 1998. [PubMed: 9489796, related citations] [Full Text]

  23. Hodes, M. E., Pratt, V. M., Dlouhy, S. R. Genetics of Pelizaeus-Merzbacher disease. Dev. Neurosci. 15: 383-394, 1993. [PubMed: 7530633, related citations] [Full Text]

  24. Hodes, M. E., Woodward, K., Spinner, N. B., Emanuel, B. S., Enrico-Simon, A., Kamholz, J., Stambolian, D., Zackai, E. H., Pratt, V. M., Thomas, I. T., Crandall, K., Dlouhy, S. R., Malcolm, S. Additional copies of the proteolipid protein gene causing Pelizaeus-Merzbacher disease arise by separate integration into the X chromosome. Am. J. Hum. Genet. 67: 14-22, 2000. [PubMed: 10827108, images, related citations] [Full Text]

  25. Hodes, M. E., Zimmerman, A. W., Aydanian, A., Naidu, S., Miller, N. R., Oller, J. L. G., Barker, B., Aleck, K.A., Hurley, T. D., Dlouhy, S. R. Different mutations in the same codon of the proteolipid protein gene, PLP, may help in correlating genotype with phenotype in Pelizaeus-Merzbacher disease/X-linked spastic paraplegia (PMD/SPG2). Am. J. Med. Genet. 82: 132-139, 1999. [PubMed: 9934976, related citations] [Full Text]

  26. Hudson, L. D., Puckett, C., Berndt, J., Chan, J., Gencic, S. Mutation of the proteolipid protein gene PLP in a human X chromosome-linked myelin disorder. Proc. Nat. Acad. Sci. 86: 8128-8131, 1989. [PubMed: 2479017, related citations] [Full Text]

  27. Hurst, S., Garbern, J., Trepanier, A., Gow, A. Quantifying the carrier female phenotype in Pelizaeus-Merzbacher disease. Genet. Med. 8: 371-378, 2006. [PubMed: 16778599, related citations] [Full Text]

  28. Inoue, K., Osaka, H., Sugiyama, N., Kawanishi, C., Onishi, H., Nezu, A., Kimura, K., Kimura, S., Yamada, Y., Kosaka, K. A duplicated PLP gene causing Pelizaeus-Merzbacher disease detected by comparative multiplex PCR. Am. J. Hum. Genet. 59: 32-39, 1996. [PubMed: 8659540, related citations]

  29. Inoue, K., Osaka, H., Thurston, V. C., Clarke, J. T. R., Yoneyama, A., Rosenbarker, L., Bird, T. D., Hodes, M. E., Shaffer, L. G., Lupski, J. R. Genomic rearrangements resulting in PLP1 deletion occur by nonhomologous end joining and cause different dysmyelinating phenotypes in males and females. Am. J. Hum. Genet. 71: 838-853, 2002. [PubMed: 12297985, images, related citations] [Full Text]

  30. Inoue, K., Tanaka, H., Scaglia, F., Araki, A., Shaffer, L. G., Lupski, J. R. Compensating for central nervous system dysmyelination: females with a proteolipid protein gene duplication and sustained clinical improvement. Ann. Neurol. 50: 747-754, 2001. [PubMed: 11761472, related citations] [Full Text]

  31. Inoue, K. PLP1-related inherited dysmyelinating disorders: Pelizaeus-Merzbacher disease and spastic paraplegia type 2. Neurogenetics 6: 1-16, 2005. [PubMed: 15627202, related citations] [Full Text]

  32. Iwaki, A., Muramoto, T., Iwaki, T., Furumi, H., Dario-deLeon, M. L., Tateishi, J., Fukumaki, Y. A missense mutation in the proteolipid protein gene responsible for Pelizaeus-Merzbacher disease in a Japanese family. Hum. Molec. Genet. 2: 19-22, 1993. [PubMed: 7683951, related citations] [Full Text]

  33. Johnston, A. W., McKusick, V. A. A sex-linked recessive form of spastic paraplegia. Am. J. Hum. Genet. 14: 83-94, 1962. [PubMed: 14452137, related citations]

  34. Jung, M., Sommer, I., Schachner, M., Nave, K.-A. Monoclonal antibody O10 defines a conformationally sensitive cell-surface epitope of proteolipid protein (PLP): evidence that PLP misfolding underlies dysmyelination in mutant mice. J. Neurosci. 16: 7920-7929, 1996. [PubMed: 8987820, images, related citations] [Full Text]

  35. Kawanishi, C., Sugiyama, N., Osaka, H., Inoue, K., Suzuki, K., Onishi, H., Yamada, Y., Nezu, A., Kimura, S., Kosaka, K. Pelizaeus-Merzbacher disease: a novel mutation in the 5-prime untranslated region of the proteolipid protein gene. Hum. Mutat. 7: 355-357, 1996. [PubMed: 8723686, related citations] [Full Text]

  36. Kobayashi, H., Hoffman, E. P., Marks, H. G. The rumpshaker mutation in spastic paraplegia. (Letter) Nature Genet. 7: 351-352, 1994. [PubMed: 7522741, related citations] [Full Text]

  37. Koeppen, A. H., Ronca, N. A., Greenfield, E. A., Hans, M. B. Defective biosynthesis of proteolipid protein in Pelizaeus-Merzbacher disease. Ann. Neurol. 21: 159-170, 1987. [PubMed: 3827224, related citations] [Full Text]

  38. Lauriat, T. L., Shiue, L., Haroutunian, V., Verbitsky, M., Ares, M., Jr., Ospina, L., McInnes, L. A. Developmental expression profile of quaking, a candidate gene for schizophrenia, and its target genes in human prefrontal cortex and hippocampus shows regional specificity. J. Neurosci. Res. 86: 785-796, 2008. [PubMed: 17918747, related citations] [Full Text]

  39. Lee, J. A., Carvalho, C. M. B., Lupski, J. R. A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell 131: 1235-1247, 2007. [PubMed: 18160035, related citations] [Full Text]

  40. Lee, J. A., Madrid, R. E., Sperle, K., Ritterson, C. M., Hobson, G. M., Garbern, J., Lupski, J. R., Inoue, K. Spastic paraplegia type 2 associated with axonal neuropathy and apparent PLP1 position effect. Ann. Neurol. 59: 398-403, 2006. [PubMed: 16374829, related citations] [Full Text]

  41. Lek, M., Karczewski, K. J., Minikel, E. V., Samocha, K. E., Banks, E., Fennell, T., O'Donnell-Luria, A. H., Ware, J. S., Hill, A. J., Cummings, B. B., Tukiainen, T., Birnbaum, D. P., and 68 others. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536: 285-291, 2016. [PubMed: 27535533, images, related citations] [Full Text]

  42. Mattei, M. G., Alliel, P. M., Dautigny, A., Passage, E., Pham-Dinh, D., Mattei, J. F., Jolles, P. The gene encoding for the major brain proteolipid (PLP) maps on the q-22 band of the human X chromosome. Hum. Genet. 72: 352-353, 1986. [PubMed: 3457761, related citations] [Full Text]

  43. Mimault, C., Giraud, G., Courtois, V., Cailloux, F., Boire, J. Y., Dastugue, B., Boespflug-Tanguy, O., Clinical European Network on Brain Dysmyelinating Disease. Proteolipoprotein gene analysis in 82 patients with sporadic Pelizaeus-Merzbacher disease: duplications, the major cause of the disease, originate more frequently in male germ cells, but point mutations do not. Am. J. Hum. Genet. 65: 360-369, 1999. [PubMed: 10417279, related citations] [Full Text]

  44. Naidu, S., Dlouhy, S. R., Geraghty, M. T., Hodes, M. E. A male child with the rumpshaker mutation, X-linked spastic paraplegia/Pelizaeus-Merzbacher disease and lysinuria. J. Inherit. Metab. Dis. 20: 811-816, 1997. [PubMed: 9427151, related citations] [Full Text]

  45. Pham-Dinh, D., Popot, J.-L., Boespflug-Tanguy, O., Landrieu, P., Deleuze, J.-F., Boue, J., Jolles, P., Dautigny, A. Pelizaeus-Merzbacher disease: a valine to phenylalanine point mutation in a putative extracellular loop of myelin proteolipid. Proc. Nat. Acad. Sci. 88: 7562-7566, 1991. [PubMed: 1715570, related citations] [Full Text]

  46. Pratt, V. M., Boyadjiev, S., Green, K., Hodes, M. E., Dlouhy, S. R. Pelizaeus-Merzbacher disease caused by a de novo mutation that originated in exon 2 of the maternal great-grandfather of the propositus. Am. J. Med. Genet. 58: 70-73, 1995. [PubMed: 7573159, related citations] [Full Text]

  47. Pratt, V. M., Trofatter, J. A., Larsen, M. B., Hodes, M. E., Dlouhy, S. R. New variant in exon 3 of the proteolipid protein (PLP) gene in a family with Pelizaeus-Merzbacher disease. Am. J. Med. Genet. 43: 642-646, 1992. [PubMed: 1376553, related citations] [Full Text]

  48. Pratt, V. M., Trofatter, J. A., Schinzel, A., Dlouhy, S. R., Conneally, P. M., Hodes, M. E. A new mutation in the proteolipid protein (PLP) gene in a German family with Pelizaeus-Merzbacher disease. Am. J. Med. Genet. 38: 136-139, 1991. [PubMed: 1707231, related citations] [Full Text]

  49. Raskind, W. H., Williams, C. A., Hudson, L. D., Bird, T. D. Complete deletion of the proteolipid protein gene (PLP) in a family with X-linked Pelizaeus-Merzbacher disease. Am. J. Hum. Genet. 49: 1355-1360, 1991. [PubMed: 1720927, related citations]

  50. Readhead, C., Schneider, A., Griffiths, I., Nave, K.-A. Premature arrest of myelin formation in transgenic mice with increased proteolipid protein gene dosage. Neuron 12: 583-595, 1994. [PubMed: 7512350, related citations] [Full Text]

  51. Saugier-Veber, P., Munnich, A., Bonneau, D., Rozet, J.-M., Le Merrer, M., Gil, R., Boespflug-Tanguy, O. X-linked spastic paraplegia and Pelizaeus-Merzbacher disease are allelic disorders at the proteolipid protein locus. Nature Genet. 6: 257-262, 1994. [PubMed: 8012387, related citations] [Full Text]

  52. Simons, M., Kramer, E.-M., Macchi, P., Rathke-Hartlieb, S., Trotter, J., Nave, K.-A., Schulz, J. B. Overexpression of the myelin proteolipid protein leads to accumulation of cholesterol and proteolipid protein in endosomes/lysosomes: implications for Pelizaeus-Merzbacher disease. J. Cell Biol. 157: 327-336, 2002. [PubMed: 11956232, images, related citations] [Full Text]

  53. Sistermans, E. A., de Coo, R. F., De Wijs, I. J., Van Oost, B. A. Duplication of the proteolipid protein gene is the major cause of Pelizaeus-Merzbacher disease. Neurology 50: 1749-1754, 1998. [PubMed: 9633722, related citations] [Full Text]

  54. Sistermans, E. A., de Wijs, I. J., de Coo, R. F. M., Smit, L. M. E., Menko, F. H., van Oost, B. A. A (G-to-A) mutation in the initiation codon of the proteolipid protein gene causing a relatively mild form of Pelizaeus-Merzbacher disease in a Dutch family. Hum. Genet. 97: 337-339, 1996. [PubMed: 8786077, related citations] [Full Text]

  55. Stevenson, R. E., Tarpey, P., May, M. M., Stratton, M. R., Schwartz, C. E. Arena syndrome is caused by a missense mutation in PLP1. (Letter) Am. J. Med. Genet. 149A: 1081 only, 2009. [PubMed: 19396823, related citations] [Full Text]

  56. Strautnieks, S., Rutland, P., Winter, R. M., Baraitser, M., Malcolm, S. Pelizaeus-Merzbacher disease: detection of mutations thr181-to-pro and leu223-to-pro in the proteolipid protein gene, and prenatal diagnosis. Am. J. Hum. Genet. 51: 871-878, 1992. [PubMed: 1384324, related citations]

  57. Swanton, E., Holland, A., High, S., Woodman, P. Disease-associated mutations cause premature oligomerization of myelin proteolipid protein in the endoplasmic reticulum. Proc. Nat. Acad. Sci. 102: 4342-4347, 2005. [PubMed: 15753308, images, related citations] [Full Text]

  58. Trofatter, J. A., Dlouhy, S. R., DeMyer, W., Conneally, P. M., Hodes, M. E. Pelizaeus-Merzbacher disease: tight linkage to proteolipid protein gene exon variant. Proc. Nat. Acad. Sci. 86: 9427-9430, 1989. [PubMed: 2480601, related citations] [Full Text]

  59. Trofatter, J. A., Pratt, V. M., Dlouhy, S. R., Hodes, M. E. AhaII polymorphism in human X-linked proteolipid protein gene (PLP). Nucleic Acids Res. 19: 6057, 1991. [PubMed: 1719490, related citations] [Full Text]

  60. Wilkins, P. J., D'Souza, C. R., Bridge, P. J. Correction of the published sequence for the human proteolipid protein gene. Hum. Genet. 86: 617-618, 1991. [PubMed: 1709135, related citations] [Full Text]

  61. Willard, H. F., Munroe, D. L. G., Riordan, J. R., McCloskey, D. Regional assignment of the proteolipid protein (PLP) gene to Xq21.2-q22 and gene analysis in X-linked Pelizaeus-Merzbacher disease. (Abstract) Cytogenet. Cell Genet. 46: 716, 1987.

  62. Willard, H. F., Riordan, J. R. Assignment of the gene for myelin proteolipid protein to the X chromosome: implications for X-linked myelin disorders. Science 230: 940-942, 1985. [PubMed: 3840606, related citations] [Full Text]

  63. Woodward, K., Cundall, M., Palmer, R., Surtees, R., Winter, R. M., Malcolm, S. Complex chromosomal rearrangement and associated counseling issues in a family with Pelizaeus-Merzbacher disease. Am. J. Med. Genet. 118A: 15-24, 2003. [PubMed: 12605435, related citations] [Full Text]

  64. Woodward, K. J., Cundall, M., Sperle, K., Sistermans, E. A., Ross, M., Howell, G., Gribble, S. M., Burford, D. C., Carter, N. P., Hobson, D. L., Garbern, J. Y., Kamholz, J., Heng, H., Hodes, M. E., Malcolm, S., Hobson, G. M. Heterogeneous duplications in patients with Pelizaeus-Merzbacher disease suggest a mechanism of coupled homologous and nonhomologous recombination. Am. J. Hum. Genet. 77: 966-987, 2005. [PubMed: 16380909, images, related citations] [Full Text]

  65. Woodward, K., Kendall, E., Vetrie, D., Malcolm, S. Pelizaeus-Merzbacher disease: identification of Xq22 proteolipid-protein duplications and characterization of breakpoints by interphase FISH. Am. J. Hum. Genet. 63: 207-217, 1998. [PubMed: 9634530, related citations] [Full Text]

  66. Woodward, K., Kirtland, K., Dlouhy, S., Raskind, W., Bird, T., Malcolm, S., Abeliovich, D. X inactivation phenotype in carriers of Pelizaeus-Merzbacher disease: skewed in carriers of a duplication and random in carriers of point mutations. Europ. J. Hum. Genet. 8: 449-454, 2000. [PubMed: 10878666, related citations] [Full Text]

  67. Yamamoto, T., Nanba, E., Zhang, H., Sasaki, M., Komaki, H., Takeshita, K. Jimpy(msd) mouse mutation and connatal Pelizaeus-Merzbacher disease. (Letter) Am. J. Med. Genet. 75: 439-440, 1998. [PubMed: 9482656, related citations]

  68. Yool, D. A., Edgar, J. M., Montague, P., Malcolm, S. The proteolipid protein gene and myelin disorders in man and animal models. Hum. Molec. Genet. 9: 987-992, 2000. [PubMed: 10767322, related citations] [Full Text]


Hilary J. Vernon - updated : 10/20/2020
Ada Hamosh - updated : 12/01/2016
Ada Hamosh - updated : 7/23/2012
Patricia A. Hartz - updated : 6/24/2010
Cassandra L. Kniffin - updated : 10/16/2009
Patricia A. Hartz - updated : 2/24/2009
Cassandra L. Kniffin - updated : 5/16/2008
Patricia A. Hartz - updated : 2/7/2008
Cassandra L. Kniffin - updated : 12/5/2007
Ada Hamosh - updated : 7/25/2007
Cassandra L. Kniffin - updated : 5/4/2006
Cassandra L. Kniffin - updated : 4/13/2006
Victor A. McKusick - updated : 12/12/2005
Cassandra L. Kniffin - updated : 7/25/2005
Cassandra L. Kniffin - updated : 4/18/2005
Victor A. McKusick - updated : 12/16/2004
Victor A. McKusick - updated : 4/16/2003
Cassandra L. Kniffin - updated : 12/4/2002
Victor A. McKusick - updated : 10/30/2002
Creation Date:
Cassandra L. Kniffin : 6/27/2002
carol : 05/28/2024
carol : 10/20/2020
carol : 12/02/2016
alopez : 12/01/2016
alopez : 12/01/2016
mcolton : 04/29/2014
carol : 10/2/2013
carol : 3/21/2013
alopez : 7/24/2012
terry : 7/23/2012
mgross : 6/28/2010
terry : 6/24/2010
wwang : 11/6/2009
ckniffin : 10/16/2009
mgross : 2/24/2009
terry : 2/24/2009
wwang : 6/12/2008
ckniffin : 5/16/2008
wwang : 3/10/2008
mgross : 2/19/2008
mgross : 2/19/2008
terry : 2/7/2008
wwang : 1/14/2008
ckniffin : 12/5/2007
alopez : 8/2/2007
terry : 7/25/2007
carol : 3/28/2007
alopez : 10/13/2006
terry : 9/29/2006
carol : 8/24/2006
carol : 5/10/2006
ckniffin : 5/4/2006
wwang : 4/19/2006
ckniffin : 4/13/2006
alopez : 12/16/2005
terry : 12/12/2005
wwang : 8/18/2005
wwang : 8/9/2005
ckniffin : 7/25/2005
wwang : 5/17/2005
wwang : 5/12/2005
ckniffin : 4/18/2005
terry : 3/3/2005
tkritzer : 1/4/2005
terry : 12/16/2004
carol : 11/10/2004
ckniffin : 11/9/2004
cwells : 11/10/2003
tkritzer : 4/25/2003
terry : 4/16/2003
cwells : 12/10/2002
ckniffin : 12/4/2002
ckniffin : 11/15/2002
carol : 11/4/2002
tkritzer : 11/1/2002
terry : 10/30/2002
carol : 8/28/2002
ckniffin : 8/28/2002
ckniffin : 7/16/2002
ckniffin : 7/16/2002

* 300401

PROTEOLIPID PROTEIN 1; PLP1


Alternative titles; symbols

PROTEOLIPID PROTEIN, MYELIN; PLP
LIPOPHILIN


Other entities represented in this entry:

DM20, INCLUDED

HGNC Approved Gene Symbol: PLP1

SNOMEDCT: 64855000;   ICD10CM: E75.27;  


Cytogenetic location: Xq22.2   Genomic coordinates (GRCh38) : X:103,776,506-103,792,619 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Xq22.2 Pelizaeus-Merzbacher disease 312080 X-linked recessive 3
Spastic paraplegia 2, X-linked 312920 X-linked recessive 3

TEXT

Description

Proteolipid protein, or lipophilin, is the primary constituent of myelin in the central nervous system (CNS) (Diehl et al., 1986).


Cloning and Expression

Using a PLP-specific cDNA clone, Diehl et al. (1986) isolated the human gene encoding PLP from a human genomic library. The gene encodes a 276-amino acid polypeptide with 5 strongly hydrophobic domains that interact with the lipid bilayer as trans- and cis-membrane segments.

The 2 isoforms of the myelin proteolipid protein, PLP and DM20, are very hydrophobic integral membrane proteins that account for about half of the protein content of adult CNS myelin. The mRNAs encoding them are synthesized through alternative splicing of the primary transcript of a single gene. The nucleotide sequence of the protein-encoding regions of the PLP gene is highly conserved among all species studied. There is, for example, no amino acid difference between human, rat, and mouse PLP (Yool et al., 2000).

Dhaunchak and Nave (2007) stated that both PLP and DM20 are tetraspanins with intracellular N and C termini, 2 extracellular loops (EC1 and EC2), and an intracellular loop, which is shorter in DM20 than in full-length PLP. EC1 and EC2 interact in vivo with the opposing membrane in myelin, and EC2 contains 2 disulfide bridges.

Using quantitative RT-PCR, Lauriat et al. (2008) found that expression of both PLP and DM20 showed a linear increase with age from fetus to adulthood (up to 46 years of age) in human prefrontal cortex. Expression was also developmentally regulated in the hippocampus, with a large increase between 1 to 2 months and 1 to 2 years of age, followed by leveling off in older children and adults.


Gene Structure

Diehl et al. (1986) determined that the human PLP gene contains 7 exons and spans approximately 17 kb. Wilkins et al. (1991) reported a correction to the base sequence of the intronic region 5-prime to exon 6 of the PLP gene as published by Diehl et al. (1986); the site in question contained 3 rather than 4 thymidines.


Mapping

Using a bovine cDNA probe in Southern blot analysis of somatic cell hybrid DNA, Willard and Riordan (1985) assigned the gene to human Xq13-q22. They assigned the gene to the mouse X chromosome also.

Mattei et al. (1986) mapped PLP to Xq22 by in situ hybridization. With a panel of hybrids segregating portions of the X chromosome defined by radiation-induced breaks, Willard et al. (1987) found that PLP maps distal to PGK1 (311800) and proximal to PRPS (311850); however, PLP showed complete cosegregation with GLA (300644) to which it must be very close.


Gene Function

Swanton et al. (2005) found that endogenous Plp from porcine brains formed stable oligomers in myelin with molecular masses of approximately 40 and 60 kD, corresponding to dimers and trimers, respectively. In vitro studies with mouse Plp showed that wildtype Plp leaves the endoplasmic reticulum (ER) as a monomer and forms stable oligomers, most likely at the cell surface, after a period of over 24 hours. In contrast, various forms of mutant Plp, including A242V (300401.0019), rapidly assembled into stable oligomers resembling wildtype oligomers while still in the ER. Most of the mutant oligomers were retained in the ER. Swanton et al. (2005) postulated a gain-of-function effect of mutant PLP in which the oligomers may overwhelm ER degradation machinery or may be toxic to the cell.

Quaking (QKI; 609590) proteins bind RNA and regulate RNA splicing, intracellular localization, stability, and translation. Using quantitative RT-PCR, Lauriat et al. (2008) found that expression of Plp1 was reduced in brains of qk(e5) mice, which show decreased expression of all 3 Qki isoforms. Lauriat et al. (2008) concluded that QKI may be required for PLP1 expression.

Myelin rafts in oligodendrocytes are specialized membrane domains that are enriched in cholesterol and galactosylceramide. PLP associates with myelin rafts during biosynthesis and is transported with rafts to the plasma membrane. Using baby hamster kidney (BHK) cells and primary mouse oligodendrocytes, Simons et al. (2002) showed that overexpressed wildtype Plp accumulated in the endosomal/lysosomal compartment and sequestered cholesterol there, rather than accompanying myelin rafts to the plasma membrane. Endosomal/lysosomal accumulation of Plp and cholesterol led to an increase in the amount of detergent-insoluble cholesterol and Plp and to missorting of myelin raft markers. Immunohistochemical analysis showed 10-fold increased colocalization of Plp and the lysosomal marker Lamp1 (153330) in sagittal brain sections of transgenic mice overexpressing Plp compared with wildtype mice. Simons et al. (2002) concluded that overexpression of PLP results in endosomal/lysosomal accumulation of cholesterol and PLP and mistrafficking of raft components, leading to perturbed myelination and reduced viability of oligodendrocytes.


Molecular Genetics

Willard et al. (1987) investigated the structure of the PLP gene in 9 boys with Pelizaeus-Merzbacher disease (PMD; 312080), using a PLP cDNA and genomic probes upstream from and within the PLP gene. One of the 9 samples showed an abnormal Southern blotting pattern consistent with a defect in the PLP gene.

Cremers et al. (1987) found an insertional translocation into the proximal long arm of the X chromosome in a boy who showed findings typical of PMD at autopsy. Duplication of Xq21-q22 was identified using a large number of X-specific and several X-Y-specific probes. There appeared to be 2 intact copies of the PLP gene present. The duplication was apparently due to a de novo mutation, because the mother had a normal female karyotype. The duplication must have resulted from interaction between the 2 maternal X chromosomes during the first meiotic division, as evidenced by the presence of 2 distinguishable alleles at 2 of the marker loci studied.

In a family in which 4 males had classic manifestations of PMD, Pratt et al. (1992) found a C-to-G transversion at nucleotide 193 of exon 3. The change should not result in an amino acid change in the protein but did cause the loss of a HaeIII restriction site which was concordant with the disease in the family. The change was not found in 110 unrelated X chromosomes. No other sequence defect was found in the PLP exons of the affected males, and the cause of disease in this family remained unknown. Trofatter et al. (1991) reported a silent mutation in exon 4 that caused gain of an AhaII restriction site. Unlike the HaeIII variant, the AhaII polymorphism was frequent (0.26) in the normal population.

Hodes et al. (1993) provided an extensive review of the proteolipid protein, which included a tabulation of 36 allelic variants found to be associated with disease. These included point mutations in all 7 of the exons, primarily within exons 3, 4, and 5. In addition, there was 1 mutation in the 3-prime untranslated region, 4 duplications, 1 complete deletion, and a rearrangement. They found that about 30% of patients with the diagnosis of Pelizaeus-Merzbacher disease had a mutation in the coding portion of the proteolipid protein gene. Although the mutations were generally recessive, some mutations were frequently expressed in females.

Using the candidate gene approach, Saugier-Veber et al. (1994) showed that the mutation in the form of X-linked spastic paraplegia that maps to Xq22 (SPG2; 312920) is due to mutation in the PLP gene (see 300401.0012). The his139-to-tyr mutation found in SPG2 resulted in mutant PLP but normal DM20.

Inoue et al. (1996) examined 5 families with PMD without exonic mutations in the PLP gene, using comparative multiplex PCR as a semiquantitative assay of gene dosage. PLP gene duplications were identified in 4 families and confirmed in 3 families by densitometric RFLP analysis. PMD may thus be caused by duplication or deletion of the PLP gene (Raskind et al., 1991), as well as by point mutations. This situation is similar to that in Charcot-Marie-Tooth disease type 1a (CMT1A; 118220), which may be caused by duplication, deletion, or point mutation in the PMP22 gene (601097). Inoue et al. (1996) suggested that since the homologous myelin protein gene PMP22 is duplicated in the majority of patients with CMT1A, PLP gene overdosage may be an important genetic abnormality in PMD and affect myelin formation.

Duplication of the PLP1 gene is responsible for PMD in most patients, whereas deletion of PLP1 is infrequent. Inoue et al. (2002) studied genomic mechanisms for these submicroscopic chromosomal rearrangements. They identified 3 families with PLP1 deletions (including 1 family described by Raskind et al. (1991)) that arose by 3 distinct processes. In 1 family, PLP1 deletion resulted from a maternal balanced submicroscopic insertional translocation of the entire PLP1 gene to the telomere of chromosome 19. PLP1 on the 19q telomere was probably inactive by virtue of a position effect, because a healthy male sib carried the same der(19) chromosome along with a normal X chromosome. Genomic mapping of the deleted segments revealed that the deletions were smaller than most of the PLP1 duplications and involved only 2 other genes. Inoue et al. (2002) hypothesized that a deletion is infrequent because only the smaller deletions can avoid causing either infertility or lethality. Analyses of the DNA sequence flanking the deletion breakpoints revealed Alu-Alu recombination in the family with translocation. In the other 2 families, no homologous sequence flanking the breakpoints was found, but distal breakpoints were embedded in novel low-copy repeats, suggesting the potential involvement of genome architecture in stimulating these rearrangements. In 1 family, junction sequences revealed a complex recombination event. The data suggested that PLP1 deletions are likely caused by nonhomologous end joining.

Hodes et al. (1999) pointed out that 4 codons of the PLP molecule are known in which more than 1 amino acid substitution has been identified: valine-165 to glutamate or glycine, leucine-45 to proline or arginine, aspartate-202 to asparagine or histidine, and leucine-223 to isoleucine or proline.

Mimault et al. (1999) investigated 82 strictly selected sporadic cases of PMD and found PLP mutations in 77%. Complete PLP gene duplication was the most frequent abnormality (62%), whereas point mutations in coding or splice site regions of the gene were involved less frequently (38%). In the case of the 22 point mutations, 68% of mothers were heterozygous for the mutation, a value identical to the two-thirds of carrier mothers that would be expected if there was an equal mutation rate in male and female germ cells. In sharp contrast, among the 34 duplicated cases, 91% of mothers were carriers, a value significantly in favor of a male bias, with an estimation of the male/female mutation frequency (k) of 9.3. Moreover, Mimault et al. (1999) observed de novo mutations between parental and grandparental generations in 17 three-generation families, which allowed a direct estimate of the k value (k of 11). Again, a significant male mutation imbalance was observed only for the duplications. The mechanism responsible for this strong male bias in the duplications may involve an unequal sister chromatid exchange, since 2 deletion events, responsible for mild clinical manifestations, had been reported in PLP-related disorders.

Hodes et al. (2000) described 2 families in which males affected with PMD had a copy of the PLP gene on the short arm of the X chromosome, in addition to a normal copy on Xq22. In the first family, the extra copy was first detected by the presence of heterozygosity of the AhaII dimorphism within the PLP gene. FISH analysis showed an additional copy of PLP on Xp22.1, although no chromosomal rearrangements could be detected by standard karyotype analysis. Another 3 affected males from the family had similar findings. In a second unrelated family with signs of PMD, cytogenetic analysis showed a pericentric inversion of the X chromosome. In the inverted X chromosome carried by several affected family members, FISH showed PLP signals at Xp11.4 and Xq22. The authors noted that Woodward et al. (1998) had reported a family in which affected members had an extra copy of the PLP gene detected at Xq26 in a chromosome with an otherwise normal banding pattern. The identification of 3 separate families in which PLP is duplicated at a noncontiguous site suggested that such duplications could be a relatively common but previously undetected cause of genetic disorders.

Hobson et al. (2000) identified 4 novel mutation in noncoding regions of the PLP1 gene in 5 patients with PMD from 4 families. Three of the mutations, 2 point mutations and 1 deletion (300401.0023-300401.0025), involved the splice donor site of intron 3, which is involved in alternative splicing of PLP and DM20. The fourth mutation (300401.0022) resulted in skipping of exon 6. Female carriers of the mutations, who were mildly symptomatic or asymptomatic, were detected in 3 of the 4 families.

Yool et al. (2000) reviewed the mechanisms of PLP mutations in human disease and in animal models.

Lee et al. (2006) reported a patient with a mild form of SPG2. Although there were no mutations, duplications, or deletions in the PLP1 gene, detailed molecular analysis detected a small duplication of less than 150 kb approximately 136 kb downstream of the PLP1 gene in the patient and his unaffected mother. Lee et al. (2006) suggested that the duplication resulted in silencing of the PLP1 gene by position effect since the patient's relatively mild phenotype resembled that seen with PLP1-null mutations.

Dhaunchak and Nave (2007) found that most PMD-associated mutations mapping to EC2 of PLP/DM20 interfered with formation of correct intramolecular disulfide bridges in transfected oligodendrocytes, leading to abnormal protein crosslinks, ER retention, and activation of the unfolded protein response. Surface expression of mutant PLP/DM20 was restored and the unfolded protein response was reverted by removal of 2 cysteines. Dhaunchak and Nave (2007) concluded that covalent protein crosslinks are the cause, rather than the consequence, of ER retention.


Genotype/Phenotype Correlations

Cailloux et al. (2000) investigated 52 PMD and 28 SPG families without large PLP duplications or deletions by PCR amplification and sequencing of the 7 coding regions and splice sites of the PLP1 gene. Abnormalities were identified in 29 (56%) of the PMD and 4 (14%) of the SPG cases. Of the 33 mutations detected, 23 were missense mutations, 3 were deletion/insertions with frameshifts, and 7 were splice site mutations. Clinical severity was found to be correlated with the nature of the mutation. The severe forms of PMD were most frequently associated with missense mutations in exons 2 and 4, leading to amino acid changes at positions highly conserved in other DM proteins. The mild forms of PMD were frequently caused by mutations, resulting in the production of truncated proteins or by missense mutations. The mutations mostly affected exon 5, leading to the substitution of amino acids only partly conserved in the extracytoplasmic C-D loop. SPG was associated with splice site mutations or changes in the PLP-specific B-C loop.

Carrier females with the submicroscopic duplication in the PLP gene that causes PMD are usually asymptomatic. Inoue et al. (2001) described 2 unrelated female patients who presented with mild PMD or spastic paraplegia. In 1 patient, clinical features as well as cranial magnetic resonance imaging and brainstem auditory evoked potential results improved dramatically over a 10-year period. The other patient, who presented with spastic diplegia and was initially diagnosed with cerebral palsy, also showed clinical improvement. Interphase fluorescence in situ hybridization analyses identified a PLP gene duplication in both patients. The same analyses in family members indicated that the duplication in both patients occurred as a de novo event. Neither skewing of X inactivation in the peripheral lymphocytes nor PLP gene coding alterations were identified in either patient. These findings indicated that females with a PLP gene duplication can occasionally manifest an early-onset neurologic phenotype. Inoue et al. (2001) hypothesized that the remarkable clinical improvement was a result of myelin compensation by oligodendrocytes expressing 1 copy of the PLP gene secondary to selection for a favorable X-inactivation pattern. These findings indicated plasticity of oligodendrocytes in the formation of central nervous system myelin and suggested a potential role for stem cell transplantation therapies.

In a detailed review, Inoue (2005) noted that genomic rearrangements that result in PLP1 gene duplication are the most common cause of PMD (60 to 70% of cases). Neither common PLP1 alleles nor founder effects have been observed in PMD. Mutations in exon 3B, which is spliced out in DM20, predominantly result in an SPG2 phenotype, as DM20 is putatively intact. Similarly, truncating mutations result in a relatively mild phenotype, most likely because of the degradation of mutant mRNAs by nonsense-mediated decay. The fact that most point mutations result in severe dysmyelinating disease suggests that the mutant proteins exert a cytotoxic effect, presumably via accumulation of misfolded proteins.

Using clinical data compiled from a chart review at Wayne State University comprising 40 pedigrees with PMD including 55 males and 56 carrier females, Hurst et al. (2006) investigated neurologic symptoms in carrier females. They categorized patients according to disease severity and type of genetic lesion within the PLP1 gene and then analyzed the clinical data using nonparametric t tests and analyses of variance. Hurst et al. (2006) concluded that their analyses formally demonstrated the link between mild disease in males and symptoms in carrier female relatives. Conversely, mutations causing severe disease in males rarely cause clinical signs in carrier females. The greatest risk of disease in females was found for nonsense/indel or null mutations. Missense mutations carried moderate risk. The lowest risk, which represents the bulk of families with PMD, is associated with PLP1 gene duplications. Hurst et al. (2006) concluded that effective genetic counseling of PMD and spastic paraplegia carrier females must include an assessment of disease severity in affected male relatives.


Cytogenetics

Woodward et al. (2005) described genomic structures of 59 segmental duplications of the X chromosome that included the PLP1 gene in patients with Pelizaeus-Merzbacher disease. They reported 13 junction sequences that gave insight into underlying mechanisms. Although proximal breakpoints were highly variable, distal breakpoints tended to cluster around low-copy repeats (LCRs) (in 50% of cases), and each duplication event appeared to be unique. They interpreted the data to indicate that the tandem duplications are formed by a coupled homologous and nonhomologous recombination mechanism. They suggested repair of a double-stranded break by 1-sided homologous strand invasion of a sister chromatid, followed by DNA synthesis and nonhomologous end joining with the other end of the break. This is in contrast to other genomic disorders.

Using array CGH and breakpoint sequence analysis of different sized PMD-associated PLP1 nonrecurrent duplications, Lee et al. (2007) found interspersed stretches of DNA of normal copy number, as well as triplicated sequences contained within duplications and sequence complexity at junctions. The findings were not consistent with a simple recombination model. Lee et al. (2007) proposed a model of replication fork stalling and template switching (FoSTeS) to explain the complex duplication and deletion rearrangements associated with the disorder.

Carvalho et al. (2011) identified complex genomic rearrangements consisting of intermixed duplications and triplications of genomic segments at the MECP2 (300005) and the PLP1 loci. These complex rearrangements were characterized by a triplicated segment embedded within a duplication in 11 unrelated subjects. Notably, only 2 breakpoint junctions were generated during each rearrangement formation. All the complex rearrangement products shared a common genomic organization, duplication-inverted triplication-duplication (DUP-TRP/INV-DUP), in which the triplicated segment is inverted and located between directly oriented duplicated genomic segments. Carvalho et al. (2011) provided evidence that the DUP-TRP/INV-DUP structures are mediated by inverted repeats that can be separated by more than 300 kb, a genomic architecture that apparently leads to susceptibility to such complex rearrangements.

Bahrambeigi et al. (2019) analyzed genomic rearrangements in 50 unrelated male patients with Pelizaeus-Merzbacher disease and PLP1 copy number gains. Analysis with a high-density customized array showed that 33 patients had single duplications, ranging from 122 kb to approximately 4.5 Mb, and 17 patients had complex genomic rearrangements (CGR). Of the CGR patients, 9 had a pattern of interspersed duplications separated by a copy neutral region, 3 had a triplication flanked by duplications, and rearrangements with other complexities were identified in the other 5 individuals. In 40 of the 50 patients, the authors ascertained at least one breakpoint junction via PCR amplification. Microhomology was found in 26% of sequenced join-points, ranging from 2 to 9 bp, and evidence for microhomeology was observed in approximately 33% of join-points. Bahrambeigi et al. (2019) also performed a metaanalysis of published PLP1 rearrangements, including 159 join-points from 124 unrelated individuals. They found single duplications in 55% of individuals and a triplication flanked by duplications as the most common CGR in 20% of individuals. In approximately 32% of join-points, there was evidence for microhomeology, and in 22% of cases of join-points, there was evidence for microhomology. Bahrambeigi et al. (2019) concluded that microhomeology may play a role in genomic rearrangements at the PLP1 locus by facilitating template switches, and could be an indicator of microhomology-mediated break-induced replication (MMBIR). This potentially supported the role of FoSTeS/MMBIR as a predominant mechanism leading to rearrangements at the PLP1 locus.


Animal Model

Readhead et al. (1994) generated normal mouse lines expressing autosomal copies of the wildtype Plp gene and found that a 2-fold increase in Plp gene dosage resulted in hypomyelination, astrocytosis, seizures, and premature death. They concluded that the myelination process is exquisitely sensitive to the accurate level of PLP gene expression.

Jung et al. (1996) noted that 3 mutations in the mouse Plp gene are associated with dysmyelination: 'jimpy,' a splicing mutation that leads to loss of transmembrane domain-4 (TM4), 'jimpy(msd),' an ala242-to-val mutation in TM4, and 'rumpshaker,' an ile186-to-thr mutation in TM2. Using antibodies directed against a cell surface epitope and the C terminus of Plp, Jung et al. (1996) showed that all 3 of these mouse Plp mutations result in protein misfolding. They concluded that misfolding of mutant PLP and DM20 proteins causes their intracellular retention and interferes with oligodendrocyte differentiation and survival.

Edgar et al. (2004) found that axons of the optic nerve of Plp1-null mice developed progressive focal accumulations of membranous organelles in areas distal to nodal complexes. The axon proximal to the node was either normal or was affected to a much lesser degree, suggesting a defect in fast retrograde axonal transport. The axonal cytoskeleton was disrupted within areas of swelling, and neurofilaments and microtubules were replaced by a fine granular amorphous material. The absence of Plp1 from oligodendrocytes resulted in impaired transport in the underlying axon, leading to multifocal accumulation of membranous organelles. Edgar et al. (2004) concluded that oligodendrocytes play a role in the regulation of certain axonal transport functions.


ALLELIC VARIANTS 27 Selected Examples):

.0001   PELIZAEUS-MERZBACHER DISEASE

PLP1, PRO215SER
SNP: rs132630278, ClinVar: RCV000011822, RCV000079100

In a patient with the classic form (type I) of PMD (312080), Gencic et al. (1989) described a missense mutation in exon 5 of the PLP gene, with a C-to-T transition creating a serine substitution for proline at the carboxy end of the protein. Abuelo et al. (1989) also demonstrated a single nucleotide change in exon 5 of PLP that resulted in substitution of serine for proline as residue 215. They found the mutation in the carrier mother and in 2 sisters of 2 affected males.


.0002   PELIZAEUS-MERZBACHER DISEASE

PLP1, TRP162ARG
SNP: rs132630279, ClinVar: RCV000011823, RCV000079097

In the family with classic PMD (312080) investigated by Koeppen et al. (1987), Hudson et al. (1989) found a T-to-C transition resulting in the substitution of a charged amino acid residue, arginine, for tryptophan in 1 of the 4 hydrophobic domains of the PLP protein. A change of CGG to TGG in exon 4 was responsible for the substitution of trp162.


.0003   PELIZAEUS-MERZBACHER DISEASE

PLP1, PRO14LEU
SNP: rs11543022, ClinVar: RCV000011824, RCV001851798

By the polymerase chain reaction (PCR), Trofatter et al. (1989) amplified, cloned and sequenced the exons of the PLP gene in a male with PMD (312080) from an extensively affected Indiana family. They found a basepair transition from C-to-T at the nucleotide 40 of the second exon. In a second, unrelated PMD kindred with a milder form of disease, the C-to-T transition was not found. They found perfect linkage between the C-to-T transition and disease in this kindred; lod score = 4.27 at theta = 0.0. The C-to-T mutation predicted a pro14-to-leu substitution.


.0004   PELIZAEUS-MERZBACHER DISEASE

PLP1, THR155ILE
SNP: rs132630280, ClinVar: RCV000011825

Pratt et al. (1991) identified a C-to-T transition in exon 4 of the PLP gene in 2 affected males and 2 obligate carriers in a German family with PMD (312080). The mutation, which alters amino acid 155 from threonine to isoleucine and eliminates an HphI site, was absent in 108 normal chromosomes. Linkage analysis in the family showed 5 concordant and 1 discordant result compared with those obtained by magnetic resonance imaging.


.0005   PELIZAEUS-MERZBACHER DISEASE

PLP1, VAL218PHE
SNP: rs132630281, ClinVar: RCV000011826

Pham-Dinh et al. (1991) used DNA amplification by PCR to study the PLP gene coding regions from 17 patients in 15 unrelated families with similar Pelizaeus-Merzbacher (312080) phenotype. In 1 case amplification of peripheral nerve PLP cDNA showed a silent T-to-C transition that was unrelated to the disease. In 1 family a change of valine-218 to phenylalanine was observed. Pham-Dinh et al. (1991) investigated the inheritance of the mutant allele in 19 subjects in this 4-generation family and found a strict cosegregation of the phe-218 substitution with transmission and expression of the disease. A G-to-T transversion in exon 5 was responsible for the amino acid substitution. Affected members of this family presented in early infancy with hypotonia, spasticity, and abnormal head and ocular movements. Two patients had died at ages 36 and 45 years. One patient was capable of walking autonomously, using the telephone, and typewriting.


.0006   PELIZAEUS-MERZBACHER DISEASE

PLP1, DEL
ClinVar: RCV000011827

In a family with affected males in 4 generations, Raskind et al. (1991) found that PMD (312080) was associated with complete absence of a band in Southern analysis using PLP probes encompassing the promoter region, the entire coding region, and the 3-prime untranslated region and spanning at least 29 kb of genomic DNA. DNA from unaffected relatives gave the expected band pattern.


.0007   PELIZAEUS-MERZBACHER DISEASE

PLP1, THR181PRO
SNP: rs132630282, gnomAD: rs132630282, ClinVar: RCV000011828

In 2 obligate female carriers of PMD (312080), Strautnieks et al. (1992) used single-strand conformation polymorphism (SSCP) analysis to identify an A-to-C transversion at nucleotide 541 resulting in a thr181-to-pro substitution in the region of the protein presumed to represent a transmembrane segment. The mutation was found in exon 4 of the PLP gene and was used in prenatal diagnosis to predict an unaffected fetus.


.0008   PELIZAEUS-MERZBACHER DISEASE

PLP1, LEU223PRO
SNP: rs132630283, ClinVar: RCV000011829, RCV003511973

In a second family with PMD (312080), Strautnieks et al. (1992) used SSCP analysis to demonstrate a variant band pattern in exon 5 in the PLP gene which was shown by sequencing to be due to a T-to-C transition at nucleotide 668 resulting in a leu223-to-pro amino acid substitution.


.0009   PELIZAEUS-MERZBACHER DISEASE

PLP1, ASP202HIS
SNP: rs132630284, ClinVar: RCV000011830

By a combination of SSCP analysis and direct sequencing of PCR-amplified DNA, Doll et al. (1992) identified an asp202-to-his substitution in exon 4 of the PLP gene in a patient with leukodystrophy of unknown etiology.


.0010   PELIZAEUS-MERZBACHER DISEASE

PLP1, GLY73ARG
SNP: rs132630285, ClinVar: RCV000011831

By a combination of SSCP analysis and direct sequencing of PCR-amplified DNA, Doll et al. (1992) identified a gly73-to-arg substitution in exon 3 of the PLP gene in a patient with leukodystrophy of unknown etiology.


.0011   PELIZAEUS-MERZBACHER DISEASE, CONNATAL

PLP1, GLY220CYS
SNP: rs132630286, ClinVar: RCV000011832

In a Japanese family with Pelizaeus-Merzbacher disease (312080), Iwaki et al. (1993) found a G-to-T transition in exon 5 of the PLP gene, which led to a glycine-to-cysteine substitution at residue 220. The disorder in this family was present in 2 boys who showed similar clinical signs from birth, with autopsy confirmation of the diagnosis in 1 of the brothers. In the older patient, laryngeal stridor developed immediately after birth and his muscles were flaccid. He had poor head control and a coarse nystagmus. Spastic paraparesis was evident by age 4 years. He could not walk or speak and died of pneumonia at age 13. Autopsy showed almost complete deficiency of myelin within the central nervous system except for patchy, slight preservations of myelin in the pons. In studies of the postmortem brain, Iwaki et al. (1993) found a nearly complete loss of mRNA expression of both PLP and myelin basic protein (MBP; 159430), 2 major myelin proteins produced by oligodendrocytes, yet mRNA levels of glial fibrillary acidic protein (GFAP; 137780), an astrocyte marker, appeared to be normal. The findings supported the pathologic observation that oligodendrocytes are specifically lost in the PMD brain.


.0012   SPASTIC PARAPLEGIA 2

PLP1, HIS139TYR
SNP: rs132630287, ClinVar: RCV000011833, RCV004595481

While narrowing the genetic interval containing the gene for X-linked spastic paraplegia-2 (312920) in a large pedigree previously reported by Bonneau et al. (1993), Saugier-Veber et al. (1994) found that PLP was the closest marker to the disease locus, implicating PLP as a possible candidate gene. They went on to find a his139-to-tyr mutation in exon 3B of the PLP gene in an affected male. The mutation resulted in a mutant form of PLP, but the other protein encoded by the PLP gene, DM20, was normal. The his139-to-tyr mutation segregated with the disease; maximum lod = 6.63 at theta = 0.00. Thus, SPG2 and PMD (312080) are allelic disorders.


.0013   SPASTIC PARAPLEGIA 2

PLP1, ILE186THR
SNP: rs132630288, ClinVar: RCV000011834, RCV004595482

The family with spastic paraplegia (312920) reported by Johnston and McKusick (1962) as one of the earliest examples of X-linked SPG showed a disorder that began as 'pure' spastic paraparesis. The patients later developed nystagmus, dysarthria, sensory disturbance or mental retardation, with half the patients having optic atrophy. Later symptoms included muscle wasting, joint contractures, and a requirement for crutches or wheelchair by early adult life. Kobayashi et al. (1994) demonstrated linkage to the Xq21.3-q24 region, which includes the PLP locus and, furthermore, demonstrated an ile186-to-thr mutation in the PLP gene. This mutation is identical to that previously identified in the 'rumpshaker' mouse.

This same mutation, a 557T-C nucleotide transition, was identified by Naidu et al. (1997) in a 3.5-year-old boy with onset of manifestations at birth who was subsequently shown to be a member of the same family as that reported by Johnston and McKusick (1962).

In the 'rumpshaker' mouse, Edgar et al. (2004) observed a late-onset distal degeneration of the axons of the longest spinal tract, the fasciculus gracilis. This was said to be the first report of Wallerian type degeneration in mice with spontaneous mutation of the Plp gene.


.0014   PELIZAEUS-MERZBACHER DISEASE

PLP1, THR42ILE
SNP: rs132630289, ClinVar: RCV000011835

In a patient with PMD (312080), Pratt et al. (1995) described a thr42-to-ile mutation which they could determine had originated de novo in the X chromosome contributed by the maternal great-grandfather of the propositus. This was determined from the pattern of inheritance of the AhaII polymorphism and a series of microsatellite markers located near PLP on Xq22. Pratt et al. (1995) commented on the fact that, with one exception, each mutation that has been found is unique to the particular family.


.0015   PELIZAEUS-MERZBACHER DISEASE, MILD

PLP1, MET1ILE
SNP: rs132630290, ClinVar: RCV000011836, RCV001851799

In a Dutch family with a relatively mild form of Pelizaeus-Merzbacher disease (312080), Sistermans et al. (1996) described a G-to-A transition in the initiation codon of the PLP gene. This mutation caused the total absence of PLP and is therefore in agreement with the hypothesis that absence of PLP leads to a mild form of PMD. Most mutations in PLP cause either overexpression or expression of a truncated form of PLP resulting in oligodendrocyte cell death because of accumulation of PLP in the endoplasmic reticulum. Only 1 patient with complete deletion of the PLP gene had been described to that time (300401.0007). This same mutation is found in the beta-globin gene as a cause of beta-0-thalassemia (141900.0456) and in the PAH gene resulting in phenylketonuria (261600.0048).

The proband in the family reported by Sistermans et al. (1996) came to the attention of the investigators at the age of 33 years because of slowly progressive deterioration of his mental condition and progression of his spastic tetraplegia. Neurologic examination revealed a spastic atactic tetraplegia. Motor dysfunction had been first noted at the age of 4 years and he was admitted to an institution for the mentally disabled at age 14 with mental deficiency and spastic paraplegia. His sister's son was observed to have spastic tetraplegia and poor balance control by the age of 1 year. By the age of 6 years he was dependent on help for activities of daily living and was wheelchair-bound, although he was able to crawl.


.0016   RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE

PLP1, -34C-T, 5-PRIME UTR
SNP: rs2233695, gnomAD: rs2233695, ClinVar: RCV000204678, RCV000514040, RCV001258262, RCV001815250, RCV002500653

This variant, formerly titled PELIZAEUS-MERZBACHER DISEASE, MILD, has been reclassified based on the report of Lek et al. (2016).

In a 7-year-old boy with clinical and neuroradiologic features consistent with classic PMD (312080), Kawanishi et al. (1996) found a C-to-T transition at nucleotide position -34 in the 5-prime flanking region of exon 1 of the PLP gene. The mother was heterozygous for the mutation which was not found in 117 X chromosomes from unrelated Japanese. This was said to be the first report of a 5-prime UTR mutation in the PLP gene.

Lek et al. (2016) noted that the -34C-T variant was found in hemizygosity in 61 males in the ExAC database and had a high allele frequency (0.014) in the Latino population, suggesting that it is not pathogenic.


.0017   SPASTIC PARAPLEGIA 2

PLP1, PHE236SER
SNP: rs132630291, ClinVar: RCV000011838, RCV004595483

Donnelly et al. (1996) described a phe236-to-ser mutation of the PLP gene in males affected with SPG2 (312920) from a family in which 8 affected boys in 5 generations had suffered from a complicated form of spastic paraplegia.


.0018   PELIZAEUS-MERZBACHER DISEASE, ATYPICAL

PLP1, TRP144TER
SNP: rs132630292, ClinVar: RCV000011839, RCV000801130, RCV004595484

In a family displaying atypical features of Pelizaeus-Merzbacher disease (312080), Hodes et al. (1997) identified a G-to-A transition at nucleotide 431 in exon 3, resulting in a stop codon (TAG) instead of tryptophan (TGG) at amino acid 144. The clinical picture resembled somewhat that of X-linked spastic paraplegia. It differed from that condition and from both the classic and the connatal forms of PMD in that it was relatively mild, onset was delayed beyond age 2 years, nystagmus was absent, tremors were prominent, mental retardation was not severe, and some patients showed dementia or personality disorders. The disease was progressive rather than static in some, and several females showed signs of disease. The nonsense mutation, which was in exon 3B, was predicted to block synthesis of normal PLP but spared DM20, the isoform whose persistence has been associated with mild forms of PLP-associated disease in both humans and mice.


.0019   PELIZAEUS-MERZBACHER DISEASE, CONNATAL

PLP1, ALA242VAL
SNP: rs132630293, ClinVar: RCV000011840

The jimpy(msd) mouse carries an ala242-to-val (A242V) mutation in the Plp gene. The phenotype has been used as a model of the human connatal type of PMD (312080) in research (Gow and Lazzarini (1996)). Yamamoto et al. (1998) described a Japanese male infant with prenatal PMD and the same A242V substitution. The substitution resulted from a 725C-T transition in exon 6. Pendular nystagmus and psychomotor developmental delay had been noted at the age of 4 months. The infant died suddenly at 9 months, and demyelinated white matter of the brain was observed at autopsy.


.0020   SPASTIC PARAPLEGIA 2

PLP1, SER169PHE
SNP: rs132630294, ClinVar: RCV000011841, RCV001786328

Hodes et al. (1998) described a boy with spastic paraplegia-2 (312920) and a C-to-T transition at nucleotide 506 in exon 4 of the PLP gene, resulting in substitution of phenylalanine for serine-169 in the third transmembrane domain of the protein. His mother did not have the mutation. The patient was first seen for evaluation of 'cerebral palsy' at the age of 7 years. There was no nystagmus, but funduscopy showed optic nerve pallor. There was more spasticity in the legs than in the arms, deep tendon reflexes were 1+ in the arms and 3+ in the legs, and there was prominent scissoring while he sat. MRI scan showed global lack of myelination with sparing of only a few transverse fibers in the pons.


.0021   PELIZAEUS-MERZBACHER DISEASE

PLP1, DUP
ClinVar: RCV000011842

Although linkage analysis had shown homogeneity at the PLP1 gene in patients with PMD (312080), exonic mutations in the PLP1 gene had been identified in only 10 to 25% of all cases. Using comparative multiplex PCR (CM-PCR) as a semiquantitative assay of gene dosage, Inoue et al. (1996) examined 5 families with PMD who did not carry exonic mutations in PLP1 gene. PLP1 gene duplications were identified in 4 families by CM-PCR and confirmed in 3 families by densitometric RFLP analysis. The authors suggested that PLP gene overdosage may be an important abnormality in PMD and may affect myelin formation.

Sistermans et al. (1998) studied 2 groups of patients: one with 10 independent PMD families and one with 24 sporadic patients suspected of PMD. Duplications of the PLP1 gene were identified in 50% of cases of group 1 and in 21% of cases of group 2. The authors concluded that duplications of the PLP1 gene are the major cause of PMD.

Woodward et al. (1998) showed that PLP1 gene duplication can be detected by interphase FISH. The extent of the duplication was analyzed in 5 patients and their 4 asymptomatic mothers, and a large duplication (500 kb or more) was detected, with breakpoints that differed between families, at the proximal end. The results of this study suggested that intrachromosomal rearrangements may be a common mechanism by which duplications arise in PMD.

Woodward et al. (2000) found that carriers of a duplication of the PLP1 gene showed skewed X inactivation, whereas carriers of point mutations showed random X inactivation. The skewed pattern observed in most duplication carriers suggested that there is selection against those cells in which the duplicated X chromosome is active, and that other expressed sequences within the duplicated region rather than mutant PLP may be responsible.

Woodward et al. (2003) reported cytogenetic and molecular findings in a family in which PMD had arisen by a submicroscopic duplication of the PLP1 gene involving the insertion of approximately 600 kb from chromosome Xq22 into Xq26.3.


.0022   PELIZAEUS-MERZBACHER DISEASE

PLP1, IVS6DS, G-T, +3
SNP: rs1569428537, ClinVar: RCV000011843

In a family with severe Pelizaeus-Merzbacher disease (312080) originally reported by Carango et al. (1995), Hobson et al. (2000) identified a G-to-T transversion in the donor splice site of intron 6 of the PLP1 gene, which resulted in the skipping of exon 6. The 2 affected brothers demonstrated hypotonia at birth, later developing nystagmus, slowly progressive spastic paraplegia, and seizures. The mother, who was shown to be a carrier of the mutation, had mild spastic paraplegia and walked with a cane. Hobson et al. (2000) postulated that the mutation caused misfolding and retention of the protein in the endoplasmic reticulum, leading to oligodendrocyte apoptosis. Carango et al. (1995) had demonstrated a 6-fold increase in mRNA for DM20 in skin fibroblasts from these 2 brothers.


.0023   PELIZAEUS-MERZBACHER DISEASE

PLP1, IVS3DS, T-C, +2
SNP: rs1556267388, ClinVar: RCV000011844, RCV000598719

In a patient with classic PMD (312080), Hobson et al. (2000) identified a T-to-C transition in the donor splice site of intron 3 of the PLP1 gene, in the area where alternative 5-prime splicing of the PLP gene yields either PLP or DM20. This position is virtually invariant in splice donor sites, strongly suggesting that it is the causative mutation. The patient had onset of head titubations and nystagmus at about 4 months of age. The mother and sister were found to be carriers of the mutation.


.0024   PELIZAEUS-MERZBACHER DISEASE

PLP1, IVS3DS, A-G, +4
SNP: rs1569427707, ClinVar: RCV000011845

In a patient with classic PMD (312080), Hobson et al. (2000) identified a mutation in the donor splice site of intron 3 of the PLP1 gene. The patient showed hypotonia at birth and later developed head titubations and nystagmus. There was no family history of the disease.


.0025   PELIZAEUS-MERZBACHER DISEASE, ATYPICAL

PLP1, IVS3, 19-BP DEL, +28
ClinVar: RCV000011846, RCV004589506

In a male patient with relatively late onset of nystagmus and rapidly progressive ataxia, Hobson et al. (2000) identified a 19-bp deletion in intron 3 near the splice donor site. The authors suggested that the deletion may define a highly conserved intron enhancer sequence that governs the alternative splicing of PLP and DM20. Three female family members were carriers of the mutation. Hobson et al. (2002) characterized the clinical phenotype of the previously reported male patient who at age 6 years had onset of difficulty in walking, rendering him wheelchair-bound by age 11 years with spastic paraparesis, cerebellar findings, optic atrophy, nystagmus, dysarthria, and cognitive decline. Sequential MRI studies showed delay in myelin formation and diffuse abnormal white matter signals, while MRS studies showed findings consistent with increased turnover of myelin and neuronal and axonal loss. Studies of the deletion in cultured oligodendrocytes showed that it contains a sequence that is critical for efficient PLP-specific splicing. Hobson et al. (2002) concluded that deletion of this region in PLP intron 3 causes a reduction in PLP message and protein, which affects myelin stability and axonal integrity.


.0026   SPASTIC PARAPLEGIA 2

PLP1, ARG137TRP
SNP: rs132630295, ClinVar: RCV000011847, RCV004595485

In a boy with SPG2 (312920), Gorman et al. (2007) identified a hemizygous 409C-T transition in exon 3B of the PLP1 gene, resulting in an arg137-to-trp (R137W) substitution. He presented at age 10 years with poor school performance, diplopia, and clumsiness after an upper respiratory infection. MRI showed multifocal areas of T2 white matter hyperintensities. Treatment with high-dose intravenous methylprednisolone resulted in clinical improvement. Over the next few years, he had episodes of neurologic deterioration characterized by nystagmus, dysmetria, ataxia, tremor, and progressive cognitive decline. These episodes responded temporarily to methylprednisolone treatment, suggesting an inflammatory process. The patient even fulfilled the criteria for relapsing-remitting multiple sclerosis (MS; 128200), including the presence of oligoclonal bands in the CSF. His mother, who carried the mutation, developed tremor and incoordination in her late forties, although this was complicated by alcohol abuse. A grandfather with the mutation was asymptomatic except for mild tremor.


.0027   PELIZAEUS-MERZBACHER DISEASE

PLP1, ASP57TYR
SNP: rs132630296, ClinVar: RCV000011848

In affected members of a 2-generation African American family with X-linked spastic paraplegia, originally reported by Arena et al. (1992), Stevenson et al. (2009) identified a hemizygous mutation in the PLP1 gene, resulting in an asp57-to-tyr (D58Y) substitution in an extracellular loop of the protein. The mutation segregated with the disorder and was not identified in 300 male controls. The findings indicated that the family in fact had Pelizaeus-Merzbacher disease (312080). Arena et al. (1992) reported that all had severe mental retardation, lower limb spasticity and atrophy, absent or dysarthric speech, and impaired ambulation requiring wheelchairs from childhood. Other features included nystagmus, dystonic posturing, and ataxia. Brain imaging studies showed macrogyria, lack of myelination, and increased paramagnetic signal suggestive of iron deposition. Stevenson et al. (2009) noted that, although altered signals in the basal ganglia and thalamus are not specific for iron deposition, MRI findings suggestive of iron deposition in the basal ganglia have been reported in other patients with PMD.


See Also:

Buckle et al. (1985)

REFERENCES

  1. Abuelo, D. N., Ambler, M., Gencic, S., Berndt, J., Hudson, L. Heterozygote detection in Pelizaeus-Merzbacher disease. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A169, 1989.

  2. Arena, J. F., Schwartz, C., Stevenson, R., Lawrence, L., Carpenter, A., Duara, R., Ledbetter, D., Huang, T., Lehner, T., Ott, J., Lubs, H. A. Spastic paraplegia with iron deposits in the basal ganglia: a new X-linked mental retardation syndrome. Am. J. Med. Genet. 43: 479-490, 1992. [PubMed: 1605230] [Full Text: https://doi.org/10.1002/ajmg.1320430172]

  3. Bahrambeigi, V., Song, X., Sperle, K., Beck, C. R., Hijazi, H., Grochowski, C. M., Gu, S., Seeman, P., Woodward, K. J., Carvalho, C. M. B., Hobson, G. M., Lupski, J. R. Distinct patterns of complex rearrangements and a mutational signature of microhomeology are frequently observed in PLP1 copy number gain structural variants. Genome Med. 11: 80, 2019. Note: Electronic Article. [PubMed: 31818324] [Full Text: https://doi.org/10.1186/s13073-019-0676-0]

  4. Bonneau, D., Rozet, J.-M., Bulteau, C., Berthier, M., Mettey, R., Gil, R., Munnich, A., Le Merrer, M. X linked spastic paraplegia (SPG2): clinical heterogeneity at a single gene locus. J. Med. Genet. 30: 381-384, 1993. [PubMed: 8320699] [Full Text: https://doi.org/10.1136/jmg.30.5.381]

  5. Buckle, V. J., Edwards, J. H., Evans, E. P., Jonasson, J. A., Lyon, M. F., Peters, J., Searle, A. G. Comparative maps of human and mouse X chromosomes. (Abstract) Cytogenet. Cell Genet. 40: 594-595, 1985.

  6. Cailloux, F., Gauthier-Barichard, F., Mimault, C., Isabelle, V., Courtois, V., Giraud, G., Dastugue, B., Boespflug-Tanguy, O., Clinical European Network on Brain Dysmyelinating Disease. Genotype-phenotype correlation in inherited brain myelination defects due to proteolipid protein gene mutations. Europ. J. Hum. Genet. 8: 837-845, 2000. [PubMed: 11093273] [Full Text: https://doi.org/10.1038/sj.ejhg.5200537]

  7. Carango, P., Funanage, V. L., Quiros, R. E., Debruyn, C. S., Marks, H. G. Overexpression of DM20 messenger RNA in two brothers with Pelizaeus-Merzbacher disease. Ann. Neurol. 38: 610-617, 1995. [PubMed: 7574457] [Full Text: https://doi.org/10.1002/ana.410380409]

  8. Carvalho, C. M. B., Ramocki, M. B., Pehlivan, D., Franco, L. M., Gonzaga-Jauregui, C., Fang, P., McCall, A., Pivnick, E. K., Hines-Dowell, S., Seaver, L. H., Friehling, L., Lee, S., and 9 others. Inverted genomic segments and complex triplication rearrangements are mediated by inverted repeats in the human genome. Nature Genet. 43: 1074-1081, 2011. [PubMed: 21964572] [Full Text: https://doi.org/10.1038/ng.944]

  9. Cremers, F. P. M., Pfeiffer, R. A., van de Pol, T. J. R., Hofker, M. H., Kruse, T. A., Wieringa, B., Ropers, H. H. An interstitial duplication of the X chromosome in a male allows physical fine mapping of probes from the Xq13-q22 region. Hum. Genet. 77: 23-27, 1987. [PubMed: 3476455] [Full Text: https://doi.org/10.1007/BF00284707]

  10. Dhaunchak, A.-S., Nave, K.-A. A common mechanism of PLP/DM20 misfolding causes cysteine-mediated endoplasmic reticulum retention in oligodendrocytes and Pelizaeus-Merzbacher disease. Proc. Nat. Acad. Sci. 104: 17813-17818, 2007. [PubMed: 17962415] [Full Text: https://doi.org/10.1073/pnas.0704975104]

  11. Diehl, H.-J., Schaich, M., Budzinski, R.-M., Stoffel, W. Individual exons encode the integral membrane domains of human myelin proteolipid protein. Proc. Nat. Acad. Sci. 83: 9807-9811, 1986. Note: Erratum: Hum. Genet. 86: 617-618, 1991. [PubMed: 3467339] [Full Text: https://doi.org/10.1073/pnas.83.24.9807]

  12. Doll, R., Natowicz, M. R., Schiffmann, R., Smith, F. I. Molecular diagnostics for myelin proteolipid protein gene mutations in Pelizaeus-Merzbacher disease. Am. J. Hum. Genet. 51: 161-169, 1992. [PubMed: 1376966]

  13. Donnelly, A., Colley, A., Crimmins, D., Mulley, J. A novel mutation in exon 6 (F236S) of the proteolipid protein gene is associated with spastic paraplegia. Hum. Mutat. 8: 384-385, 1996. [PubMed: 8956049] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1996)8:4<384::AID-HUMU17>3.0.CO;2-Z]

  14. Edgar, J. M., McLaughlin, M., Barrie, J. A., McCulloch, M. C., Garbern, J., Griffiths, I. R. Age-related axonal and myelin changes in the rumpshaker mutation of the Plp gene. Acta Neuropath. 107: 331-335, 2004. [PubMed: 14745569] [Full Text: https://doi.org/10.1007/s00401-003-0808-9]

  15. Edgar, J. M., McLaughlin, M., Yool, D., Zhang, S.-C., Fowler, J. H., Montague, P., Barrie, J. A., McCulloch, M. C., Duncan, I. D., Garbern, J., Nave, K. A., Griffiths, I. R. Oligodendroglial modulation of fast axonal transport in a mouse model of hereditary spastic paraplegia. J. Cell Biol. 166: 121-131, 2004. [PubMed: 15226307] [Full Text: https://doi.org/10.1083/jcb.200312012]

  16. Gencic, S., Abuelo, D., Ambler, M., Hudson, L. D. Pelizaeus-Merzbacher disease: an X-linked neurologic disorder of myelin metabolism with a novel mutation in the gene encoding proteolipid protein. Am. J. Hum. Genet. 45: 435-442, 1989. [PubMed: 2773936]

  17. Gorman, M. P., Golomb, M. R., Walsh, L. E., Hobson, G. M., Garbern, J. Y., Kinkel, R. P., Darras, B. T., Urion, D. K., Eksioglu, Y. Z. Steroid-responsive neurologic relapses in a child with a proteolipid protein-1 mutation. Neurology 68: 1305-1307, 2007. [PubMed: 17438221] [Full Text: https://doi.org/10.1212/01.wnl.0000259522.49388.53]

  18. Gow, A., Lazzarini, R. A. A cellular mechanism governing the severity of Pelizaeus-Merzbacher disease. Nature Genet. 13: 422-428, 1996. [PubMed: 8696336] [Full Text: https://doi.org/10.1038/ng0896-422]

  19. Hobson, G. M., Davis, A. P., Stowell, N. C., Kolodny, E. H., Sistermans, E. A., de Coo, I. F. M., Funanage, V. L., Marks, H. G. Mutations in noncoding regions of the proteolipid protein gene in Pelizaeus-Merzbacher disease. Neurology 55: 1089-1096, 2000. [PubMed: 11071483] [Full Text: https://doi.org/10.1212/wnl.55.8.1089]

  20. Hobson, G. M., Huang, Z., Sperle, K., Stabley, D. L., Marks, H. G., Cambi, F. A PLP splicing abnormality is associated with an unusual presentation of PMD. Ann. Neurol. 52: 477-488, 2002. [PubMed: 12325077] [Full Text: https://doi.org/10.1002/ana.10320]

  21. Hodes, M. E., Blank, C. A., Pratt, V. M., Morales, J., Napier, J., Dlouhy, S. R. Nonsense mutation in exon 3 of the proteolipid protein gene (PLP) in a family with an unusual form of Pelizaeus-Merzbacher disease. Am. J. Med. Genet. 69: 121-125, 1997. [PubMed: 9056547]

  22. Hodes, M. E., Hadjisavvas, A., Butler, I. J., Aydanian, A., Dlouhy, S. R. X-linked spastic paraplegia due to a mutation (C506T; ser169phe) in exon 4 of the proteolipid protein gene (PLP). Am. J. Med. Genet. 75: 516-517, 1998. [PubMed: 9489796] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19980217)75:5<516::aid-ajmg11>3.0.co;2-n]

  23. Hodes, M. E., Pratt, V. M., Dlouhy, S. R. Genetics of Pelizaeus-Merzbacher disease. Dev. Neurosci. 15: 383-394, 1993. [PubMed: 7530633] [Full Text: https://doi.org/10.1159/000111361]

  24. Hodes, M. E., Woodward, K., Spinner, N. B., Emanuel, B. S., Enrico-Simon, A., Kamholz, J., Stambolian, D., Zackai, E. H., Pratt, V. M., Thomas, I. T., Crandall, K., Dlouhy, S. R., Malcolm, S. Additional copies of the proteolipid protein gene causing Pelizaeus-Merzbacher disease arise by separate integration into the X chromosome. Am. J. Hum. Genet. 67: 14-22, 2000. [PubMed: 10827108] [Full Text: https://doi.org/10.1086/302965]

  25. Hodes, M. E., Zimmerman, A. W., Aydanian, A., Naidu, S., Miller, N. R., Oller, J. L. G., Barker, B., Aleck, K.A., Hurley, T. D., Dlouhy, S. R. Different mutations in the same codon of the proteolipid protein gene, PLP, may help in correlating genotype with phenotype in Pelizaeus-Merzbacher disease/X-linked spastic paraplegia (PMD/SPG2). Am. J. Med. Genet. 82: 132-139, 1999. [PubMed: 9934976] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19990115)82:2<132::aid-ajmg6>3.0.co;2-4]

  26. Hudson, L. D., Puckett, C., Berndt, J., Chan, J., Gencic, S. Mutation of the proteolipid protein gene PLP in a human X chromosome-linked myelin disorder. Proc. Nat. Acad. Sci. 86: 8128-8131, 1989. [PubMed: 2479017] [Full Text: https://doi.org/10.1073/pnas.86.20.8128]

  27. Hurst, S., Garbern, J., Trepanier, A., Gow, A. Quantifying the carrier female phenotype in Pelizaeus-Merzbacher disease. Genet. Med. 8: 371-378, 2006. [PubMed: 16778599] [Full Text: https://doi.org/10.1097/01.gim.0000223551.95862.c3]

  28. Inoue, K., Osaka, H., Sugiyama, N., Kawanishi, C., Onishi, H., Nezu, A., Kimura, K., Kimura, S., Yamada, Y., Kosaka, K. A duplicated PLP gene causing Pelizaeus-Merzbacher disease detected by comparative multiplex PCR. Am. J. Hum. Genet. 59: 32-39, 1996. [PubMed: 8659540]

  29. Inoue, K., Osaka, H., Thurston, V. C., Clarke, J. T. R., Yoneyama, A., Rosenbarker, L., Bird, T. D., Hodes, M. E., Shaffer, L. G., Lupski, J. R. Genomic rearrangements resulting in PLP1 deletion occur by nonhomologous end joining and cause different dysmyelinating phenotypes in males and females. Am. J. Hum. Genet. 71: 838-853, 2002. [PubMed: 12297985] [Full Text: https://doi.org/10.1086/342728]

  30. Inoue, K., Tanaka, H., Scaglia, F., Araki, A., Shaffer, L. G., Lupski, J. R. Compensating for central nervous system dysmyelination: females with a proteolipid protein gene duplication and sustained clinical improvement. Ann. Neurol. 50: 747-754, 2001. [PubMed: 11761472] [Full Text: https://doi.org/10.1002/ana.10036]

  31. Inoue, K. PLP1-related inherited dysmyelinating disorders: Pelizaeus-Merzbacher disease and spastic paraplegia type 2. Neurogenetics 6: 1-16, 2005. [PubMed: 15627202] [Full Text: https://doi.org/10.1007/s10048-004-0207-y]

  32. Iwaki, A., Muramoto, T., Iwaki, T., Furumi, H., Dario-deLeon, M. L., Tateishi, J., Fukumaki, Y. A missense mutation in the proteolipid protein gene responsible for Pelizaeus-Merzbacher disease in a Japanese family. Hum. Molec. Genet. 2: 19-22, 1993. [PubMed: 7683951] [Full Text: https://doi.org/10.1093/hmg/2.1.19]

  33. Johnston, A. W., McKusick, V. A. A sex-linked recessive form of spastic paraplegia. Am. J. Hum. Genet. 14: 83-94, 1962. [PubMed: 14452137]

  34. Jung, M., Sommer, I., Schachner, M., Nave, K.-A. Monoclonal antibody O10 defines a conformationally sensitive cell-surface epitope of proteolipid protein (PLP): evidence that PLP misfolding underlies dysmyelination in mutant mice. J. Neurosci. 16: 7920-7929, 1996. [PubMed: 8987820] [Full Text: https://doi.org/10.1523/JNEUROSCI.16-24-07920.1996]

  35. Kawanishi, C., Sugiyama, N., Osaka, H., Inoue, K., Suzuki, K., Onishi, H., Yamada, Y., Nezu, A., Kimura, S., Kosaka, K. Pelizaeus-Merzbacher disease: a novel mutation in the 5-prime untranslated region of the proteolipid protein gene. Hum. Mutat. 7: 355-357, 1996. [PubMed: 8723686] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1996)7:4<355::AID-HUMU10>3.0.CO;2-1]

  36. Kobayashi, H., Hoffman, E. P., Marks, H. G. The rumpshaker mutation in spastic paraplegia. (Letter) Nature Genet. 7: 351-352, 1994. [PubMed: 7522741] [Full Text: https://doi.org/10.1038/ng0794-351]

  37. Koeppen, A. H., Ronca, N. A., Greenfield, E. A., Hans, M. B. Defective biosynthesis of proteolipid protein in Pelizaeus-Merzbacher disease. Ann. Neurol. 21: 159-170, 1987. [PubMed: 3827224] [Full Text: https://doi.org/10.1002/ana.410210208]

  38. Lauriat, T. L., Shiue, L., Haroutunian, V., Verbitsky, M., Ares, M., Jr., Ospina, L., McInnes, L. A. Developmental expression profile of quaking, a candidate gene for schizophrenia, and its target genes in human prefrontal cortex and hippocampus shows regional specificity. J. Neurosci. Res. 86: 785-796, 2008. [PubMed: 17918747] [Full Text: https://doi.org/10.1002/jnr.21534]

  39. Lee, J. A., Carvalho, C. M. B., Lupski, J. R. A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell 131: 1235-1247, 2007. [PubMed: 18160035] [Full Text: https://doi.org/10.1016/j.cell.2007.11.037]

  40. Lee, J. A., Madrid, R. E., Sperle, K., Ritterson, C. M., Hobson, G. M., Garbern, J., Lupski, J. R., Inoue, K. Spastic paraplegia type 2 associated with axonal neuropathy and apparent PLP1 position effect. Ann. Neurol. 59: 398-403, 2006. [PubMed: 16374829] [Full Text: https://doi.org/10.1002/ana.20732]

  41. Lek, M., Karczewski, K. J., Minikel, E. V., Samocha, K. E., Banks, E., Fennell, T., O'Donnell-Luria, A. H., Ware, J. S., Hill, A. J., Cummings, B. B., Tukiainen, T., Birnbaum, D. P., and 68 others. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536: 285-291, 2016. [PubMed: 27535533] [Full Text: https://doi.org/10.1038/nature19057]

  42. Mattei, M. G., Alliel, P. M., Dautigny, A., Passage, E., Pham-Dinh, D., Mattei, J. F., Jolles, P. The gene encoding for the major brain proteolipid (PLP) maps on the q-22 band of the human X chromosome. Hum. Genet. 72: 352-353, 1986. [PubMed: 3457761] [Full Text: https://doi.org/10.1007/BF00290964]

  43. Mimault, C., Giraud, G., Courtois, V., Cailloux, F., Boire, J. Y., Dastugue, B., Boespflug-Tanguy, O., Clinical European Network on Brain Dysmyelinating Disease. Proteolipoprotein gene analysis in 82 patients with sporadic Pelizaeus-Merzbacher disease: duplications, the major cause of the disease, originate more frequently in male germ cells, but point mutations do not. Am. J. Hum. Genet. 65: 360-369, 1999. [PubMed: 10417279] [Full Text: https://doi.org/10.1086/302483]

  44. Naidu, S., Dlouhy, S. R., Geraghty, M. T., Hodes, M. E. A male child with the rumpshaker mutation, X-linked spastic paraplegia/Pelizaeus-Merzbacher disease and lysinuria. J. Inherit. Metab. Dis. 20: 811-816, 1997. [PubMed: 9427151] [Full Text: https://doi.org/10.1023/a:1005328019832]

  45. Pham-Dinh, D., Popot, J.-L., Boespflug-Tanguy, O., Landrieu, P., Deleuze, J.-F., Boue, J., Jolles, P., Dautigny, A. Pelizaeus-Merzbacher disease: a valine to phenylalanine point mutation in a putative extracellular loop of myelin proteolipid. Proc. Nat. Acad. Sci. 88: 7562-7566, 1991. [PubMed: 1715570] [Full Text: https://doi.org/10.1073/pnas.88.17.7562]

  46. Pratt, V. M., Boyadjiev, S., Green, K., Hodes, M. E., Dlouhy, S. R. Pelizaeus-Merzbacher disease caused by a de novo mutation that originated in exon 2 of the maternal great-grandfather of the propositus. Am. J. Med. Genet. 58: 70-73, 1995. [PubMed: 7573159] [Full Text: https://doi.org/10.1002/ajmg.1320580114]

  47. Pratt, V. M., Trofatter, J. A., Larsen, M. B., Hodes, M. E., Dlouhy, S. R. New variant in exon 3 of the proteolipid protein (PLP) gene in a family with Pelizaeus-Merzbacher disease. Am. J. Med. Genet. 43: 642-646, 1992. [PubMed: 1376553] [Full Text: https://doi.org/10.1002/ajmg.1320430335]

  48. Pratt, V. M., Trofatter, J. A., Schinzel, A., Dlouhy, S. R., Conneally, P. M., Hodes, M. E. A new mutation in the proteolipid protein (PLP) gene in a German family with Pelizaeus-Merzbacher disease. Am. J. Med. Genet. 38: 136-139, 1991. [PubMed: 1707231] [Full Text: https://doi.org/10.1002/ajmg.1320380129]

  49. Raskind, W. H., Williams, C. A., Hudson, L. D., Bird, T. D. Complete deletion of the proteolipid protein gene (PLP) in a family with X-linked Pelizaeus-Merzbacher disease. Am. J. Hum. Genet. 49: 1355-1360, 1991. [PubMed: 1720927]

  50. Readhead, C., Schneider, A., Griffiths, I., Nave, K.-A. Premature arrest of myelin formation in transgenic mice with increased proteolipid protein gene dosage. Neuron 12: 583-595, 1994. [PubMed: 7512350] [Full Text: https://doi.org/10.1016/0896-6273(94)90214-3]

  51. Saugier-Veber, P., Munnich, A., Bonneau, D., Rozet, J.-M., Le Merrer, M., Gil, R., Boespflug-Tanguy, O. X-linked spastic paraplegia and Pelizaeus-Merzbacher disease are allelic disorders at the proteolipid protein locus. Nature Genet. 6: 257-262, 1994. [PubMed: 8012387] [Full Text: https://doi.org/10.1038/ng0394-257]

  52. Simons, M., Kramer, E.-M., Macchi, P., Rathke-Hartlieb, S., Trotter, J., Nave, K.-A., Schulz, J. B. Overexpression of the myelin proteolipid protein leads to accumulation of cholesterol and proteolipid protein in endosomes/lysosomes: implications for Pelizaeus-Merzbacher disease. J. Cell Biol. 157: 327-336, 2002. [PubMed: 11956232] [Full Text: https://doi.org/10.1083/jcb.200110138]

  53. Sistermans, E. A., de Coo, R. F., De Wijs, I. J., Van Oost, B. A. Duplication of the proteolipid protein gene is the major cause of Pelizaeus-Merzbacher disease. Neurology 50: 1749-1754, 1998. [PubMed: 9633722] [Full Text: https://doi.org/10.1212/wnl.50.6.1749]

  54. Sistermans, E. A., de Wijs, I. J., de Coo, R. F. M., Smit, L. M. E., Menko, F. H., van Oost, B. A. A (G-to-A) mutation in the initiation codon of the proteolipid protein gene causing a relatively mild form of Pelizaeus-Merzbacher disease in a Dutch family. Hum. Genet. 97: 337-339, 1996. [PubMed: 8786077] [Full Text: https://doi.org/10.1007/BF02185767]

  55. Stevenson, R. E., Tarpey, P., May, M. M., Stratton, M. R., Schwartz, C. E. Arena syndrome is caused by a missense mutation in PLP1. (Letter) Am. J. Med. Genet. 149A: 1081 only, 2009. [PubMed: 19396823] [Full Text: https://doi.org/10.1002/ajmg.a.32795]

  56. Strautnieks, S., Rutland, P., Winter, R. M., Baraitser, M., Malcolm, S. Pelizaeus-Merzbacher disease: detection of mutations thr181-to-pro and leu223-to-pro in the proteolipid protein gene, and prenatal diagnosis. Am. J. Hum. Genet. 51: 871-878, 1992. [PubMed: 1384324]

  57. Swanton, E., Holland, A., High, S., Woodman, P. Disease-associated mutations cause premature oligomerization of myelin proteolipid protein in the endoplasmic reticulum. Proc. Nat. Acad. Sci. 102: 4342-4347, 2005. [PubMed: 15753308] [Full Text: https://doi.org/10.1073/pnas.0407287102]

  58. Trofatter, J. A., Dlouhy, S. R., DeMyer, W., Conneally, P. M., Hodes, M. E. Pelizaeus-Merzbacher disease: tight linkage to proteolipid protein gene exon variant. Proc. Nat. Acad. Sci. 86: 9427-9430, 1989. [PubMed: 2480601] [Full Text: https://doi.org/10.1073/pnas.86.23.9427]

  59. Trofatter, J. A., Pratt, V. M., Dlouhy, S. R., Hodes, M. E. AhaII polymorphism in human X-linked proteolipid protein gene (PLP). Nucleic Acids Res. 19: 6057, 1991. [PubMed: 1719490] [Full Text: https://doi.org/10.1093/nar/19.21.6057-a]

  60. Wilkins, P. J., D'Souza, C. R., Bridge, P. J. Correction of the published sequence for the human proteolipid protein gene. Hum. Genet. 86: 617-618, 1991. [PubMed: 1709135] [Full Text: https://doi.org/10.1007/BF00201552]

  61. Willard, H. F., Munroe, D. L. G., Riordan, J. R., McCloskey, D. Regional assignment of the proteolipid protein (PLP) gene to Xq21.2-q22 and gene analysis in X-linked Pelizaeus-Merzbacher disease. (Abstract) Cytogenet. Cell Genet. 46: 716, 1987.

  62. Willard, H. F., Riordan, J. R. Assignment of the gene for myelin proteolipid protein to the X chromosome: implications for X-linked myelin disorders. Science 230: 940-942, 1985. [PubMed: 3840606] [Full Text: https://doi.org/10.1126/science.3840606]

  63. Woodward, K., Cundall, M., Palmer, R., Surtees, R., Winter, R. M., Malcolm, S. Complex chromosomal rearrangement and associated counseling issues in a family with Pelizaeus-Merzbacher disease. Am. J. Med. Genet. 118A: 15-24, 2003. [PubMed: 12605435] [Full Text: https://doi.org/10.1002/ajmg.a.10103]

  64. Woodward, K. J., Cundall, M., Sperle, K., Sistermans, E. A., Ross, M., Howell, G., Gribble, S. M., Burford, D. C., Carter, N. P., Hobson, D. L., Garbern, J. Y., Kamholz, J., Heng, H., Hodes, M. E., Malcolm, S., Hobson, G. M. Heterogeneous duplications in patients with Pelizaeus-Merzbacher disease suggest a mechanism of coupled homologous and nonhomologous recombination. Am. J. Hum. Genet. 77: 966-987, 2005. [PubMed: 16380909] [Full Text: https://doi.org/10.1086/498048]

  65. Woodward, K., Kendall, E., Vetrie, D., Malcolm, S. Pelizaeus-Merzbacher disease: identification of Xq22 proteolipid-protein duplications and characterization of breakpoints by interphase FISH. Am. J. Hum. Genet. 63: 207-217, 1998. [PubMed: 9634530] [Full Text: https://doi.org/10.1086/301933]

  66. Woodward, K., Kirtland, K., Dlouhy, S., Raskind, W., Bird, T., Malcolm, S., Abeliovich, D. X inactivation phenotype in carriers of Pelizaeus-Merzbacher disease: skewed in carriers of a duplication and random in carriers of point mutations. Europ. J. Hum. Genet. 8: 449-454, 2000. [PubMed: 10878666] [Full Text: https://doi.org/10.1038/sj.ejhg.5200480]

  67. Yamamoto, T., Nanba, E., Zhang, H., Sasaki, M., Komaki, H., Takeshita, K. Jimpy(msd) mouse mutation and connatal Pelizaeus-Merzbacher disease. (Letter) Am. J. Med. Genet. 75: 439-440, 1998. [PubMed: 9482656]

  68. Yool, D. A., Edgar, J. M., Montague, P., Malcolm, S. The proteolipid protein gene and myelin disorders in man and animal models. Hum. Molec. Genet. 9: 987-992, 2000. [PubMed: 10767322] [Full Text: https://doi.org/10.1093/hmg/9.6.987]


Contributors:
Hilary J. Vernon - updated : 10/20/2020
Ada Hamosh - updated : 12/01/2016
Ada Hamosh - updated : 7/23/2012
Patricia A. Hartz - updated : 6/24/2010
Cassandra L. Kniffin - updated : 10/16/2009
Patricia A. Hartz - updated : 2/24/2009
Cassandra L. Kniffin - updated : 5/16/2008
Patricia A. Hartz - updated : 2/7/2008
Cassandra L. Kniffin - updated : 12/5/2007
Ada Hamosh - updated : 7/25/2007
Cassandra L. Kniffin - updated : 5/4/2006
Cassandra L. Kniffin - updated : 4/13/2006
Victor A. McKusick - updated : 12/12/2005
Cassandra L. Kniffin - updated : 7/25/2005
Cassandra L. Kniffin - updated : 4/18/2005
Victor A. McKusick - updated : 12/16/2004
Victor A. McKusick - updated : 4/16/2003
Cassandra L. Kniffin - updated : 12/4/2002
Victor A. McKusick - updated : 10/30/2002

Creation Date:
Cassandra L. Kniffin : 6/27/2002

Edit History:
carol : 05/28/2024
carol : 10/20/2020
carol : 12/02/2016
alopez : 12/01/2016
alopez : 12/01/2016
mcolton : 04/29/2014
carol : 10/2/2013
carol : 3/21/2013
alopez : 7/24/2012
terry : 7/23/2012
mgross : 6/28/2010
terry : 6/24/2010
wwang : 11/6/2009
ckniffin : 10/16/2009
mgross : 2/24/2009
terry : 2/24/2009
wwang : 6/12/2008
ckniffin : 5/16/2008
wwang : 3/10/2008
mgross : 2/19/2008
mgross : 2/19/2008
terry : 2/7/2008
wwang : 1/14/2008
ckniffin : 12/5/2007
alopez : 8/2/2007
terry : 7/25/2007
carol : 3/28/2007
alopez : 10/13/2006
terry : 9/29/2006
carol : 8/24/2006
carol : 5/10/2006
ckniffin : 5/4/2006
wwang : 4/19/2006
ckniffin : 4/13/2006
alopez : 12/16/2005
terry : 12/12/2005
wwang : 8/18/2005
wwang : 8/9/2005
ckniffin : 7/25/2005
wwang : 5/17/2005
wwang : 5/12/2005
ckniffin : 4/18/2005
terry : 3/3/2005
tkritzer : 1/4/2005
terry : 12/16/2004
carol : 11/10/2004
ckniffin : 11/9/2004
cwells : 11/10/2003
tkritzer : 4/25/2003
terry : 4/16/2003
cwells : 12/10/2002
ckniffin : 12/4/2002
ckniffin : 11/15/2002
carol : 11/4/2002
tkritzer : 11/1/2002
terry : 10/30/2002
carol : 8/28/2002
ckniffin : 8/28/2002
ckniffin : 7/16/2002
ckniffin : 7/16/2002