Alternative titles; symbols
HGNC Approved Gene Symbol: L1CAM
SNOMEDCT: 1010630006, 71779008, 838441009;
Cytogenetic location: Xq28 Genomic coordinates (GRCh38) : X:153,861,514-153,886,173 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq28 | ?Corpus callosum, partial agenesis of | 304100 | X-linked recessive | 3 |
| Hydrocephalus, congenital, X-linked | 307000 | X-linked recessive | 3 | |
| MASA syndrome | 303350 | X-linked recessive | 3 |
The L1 cell adhesion molecule is one of a subgroup of structurally related integral membrane glycoproteins belonging to a large class of immunoglobulin superfamily cell adhesion molecules (CAMs) that mediate cell-to-cell adhesion at the cell surface. L1CAM is found primarily in the nervous system of several species and may be more aptly called a neural recognition molecule (Kenwrick et al., 2000).
Using degenerate oligonucleotides corresponding to highly conserved regions in mouse and rat L1CAM homologs as probes, Hlavin and Lemmon (1991) isolated the human L1CAM cDNA from a human fetal brain cDNA library. The cDNA encodes a deduced protein of 1,256 amino acids with a molecular mass of 143 kD. The human protein shares 92% sequence identity with mouse L1cam. Structurally, the protein has a motif of 6 repeating immunoglobulin (Ig) domains followed by 5 repeating fibronectin type III (FN) domains on the extracellular surface. These are linked to a highly conserved cytoplasmic portion of the molecule by a transmembrane domain. Kobayashi et al. (1991) cloned human cDNA L1CAM using cDNA probes from mouse brain to screen a human fetal cDNA library.
Djabali et al. (1989) used a murine cDNA clone coding for the L1 cell adhesion molecule to map the gene to Xq28 by in situ hybridization. Probes derived from a genomic clone were used to map the human gene more precisely with respect to known genes at Xq28 through physical linkage by pulsed field gel electrophoresis. Djabali et al. (1990) demonstrated that the L1 gene is located between the retinal pigment genes RCP (300822) and GCP (300821) and the gene for G6PD. This was the first known X-linked gene encoding a member of the immunoglobulin superfamily.
Djabali et al. (1990) showed that the murine L1 gene is located on the X chromosome in a region homologous, judging by its genic content, with the Xq27-q28 region of the human X. Chapman et al. (1990) established X-linkage and relative position of the CamL1 gene in the mouse by backcross matings involving M. spretus and M. musculus. Tight linkage to the murine equivalent of the colorblindness loci was found.
Reid and Hemperly (1992) identified 2 isoforms of the L1CAM protein that arise from alternative splicing: a neuronal isoform and an isoform that is expressed in some leukocytes, intestinal crypt cells, and kidney tubule epithelial cells.
Kenwrick et al. (2000) reviewed the various functions of L1CAM, including guidance of neurite outgrowth in development, neuronal cell migration, axon bundling, synaptogenesis, myelination, neuronal cell survival, and long-term potentiation.
Because of the similar chromosomal location of the gene for X-linked congenital hydrocephalus (HYCX, HSAS; 307000) and because of the plausibility that the mutation in HYCX might lie in the L1CAM gene, Rosenthal et al. (1992) looked for gross rearrangement or deletion of the L1CAM gene in DNA from the index patients of 5 HYC1 families. In 3 patients from 1 family, they detected 2 novel cDNA species caused by abnormal mRNA splicing. One of the abnormalities was a 69-bp insertion that occurred precisely at an intron-exon boundary, resulting in the addition of 23 extra amino acids into the translation product at residue 810. The second abnormality was the deletion of 116 bp corresponding to a single exon, exon Q, resulting in replacement of 447 C-terminal amino acids with 39 novel residues. The insertion and deletion started at the same intron-exon boundary and likely represented the consequence of aberrant splicing. In the proband and other affected members of the kindred, an A-to-C transversion was found 19 bp upstream of the intron-exon border in question (308840.0001). Two obligate carrier mothers were heterozygous for this mutation. The mutation was not present in 60 independent X chromosomes from persons unrelated to this family. Rosenthal et al. (1992) noted that an intermediate stage in eukaryotic hnRNA splicing is the formation of a lariat structure utilizing an adenosine residue at a branch point 10 to 50 nucleotides upstream of the 3-prime splice site of an intron. Following lariat formation, the first downstream AG dinucleotide is usually chosen as an acceptor splice site. The normal adenosine-19 residue upstream of the normal splice acceptor site mutant in this family may function as part of the normal branch point signal; mutation to a cytidine may disrupt normal branch point signal recognition. Use of alternative branch points and splice sites could then result in the 69-bp insertion or single exon-skipping events observed in this family. Rosenthal et al. (1992) pointed out that alterations in specific regions of a multidomain protein with a variety of functions can be expected to give rise to a wide spectrum of clinical features or even distinct diseases.
Jouet et al. (1994) showed that mutations in the L1CAM gene are responsible for type 1 X-linked spastic paraplegia (SPG1) and MASA syndrome (303350), which are considered part of the same disease spectrum, and described L1 primers flanking each of the 28 exons of the L1CAM gene. Vits et al. (1994) likewise found mutations in the L1CAM gene in patients with MASA syndrome. Jouet et al. (1995) stated that 14 different disease-causing L1CAM mutations had been reported. They added 9 additional mutations in X-linked hydrocephalus and MASA syndrome families, including the first examples of mutations affecting the fibronectin type III domains of the molecule.
Fryns et al. (1991) reported a family in which 5 males over 3 generations had neurologic abnormalities that varied greatly: 2 sibs apparently had HYCX, 1 had MASA, and 2 had spastic paraplegia. In this family and another with individuals satisfying the diagnosis for one or another of all 3 of the L1CAM-associated phenotypes reported by Kaepernick et al. (1994), Ruiz et al. (1995) demonstrated 2 novel L1CAM mutations: I179S (308840.0010) and G370R (308840.0011), respectively. Ruiz et al. (1995) noted that different phenotypes observed in different generations within the same family are variable expressions of the same mutation.
Gu et al. (1996) identified 5 novel mutations in the L1CAM gene in families with X-linked hydrocephalus (see, e.g., 308840.0017). Fransen et al. (1995) pointed out that the inter- and intrafamilial variability in families with an L1CAM mutation is very wide, such that patients with HYCX, MASA, SPG1, and ACC (agenesis of corpus callosum; 217990) can be present within the same family. Therefore, they proposed to refer to this clinical syndrome with the acronym CRASH, for corpus callosum hypoplasia, retardation, adducted thumbs, spastic paraplegia, and hydrocephalus.
Van Camp et al. (1996) described a locus-specific mutation database for the L1CAM locus that listed 52 mutations. Kenwrick et al. (1996) reviewed the clinical and genetic characteristics of the disorders that have been related to mutation in the L1CAM gene. In an article subtitled 'Clinical Geneticists Divide, Molecular Geneticists Unite,' Fransen et al. (1997) reviewed the clinical spectrum of disorders due to mutation in L1CAM.
MacFarlane et al. (1997) reported 9 novel mutations in the L1CAM gene in 10 X-linked hydrocephalus families. Four mutations truncated the L1 protein and eliminated cell surface expression, and 2 would produce abnormal L1 through alteration of RNA processing. Two others had small in-frame deletions that had occurred through a mechanism involving tandem repeated sequences. There was a single missense mutation among the cases. Du et al. (1998) used restriction endonuclease fingerprinting to screen 19 of the 28 exons in the L1CAM gene, using only 5 PCR reactions. They identified 6 novel mutations in the L1CAM gene in 5 patients with X-linked hydrocephalus and 2 patients with MASA. One of the mutations was common to both a patient with HYCX and a patient with MASA. Among 12 French families with HYCX and/or MASA, Saugier-Veber et al. (1998) described 9 distinct L1CAM mutations, 7 of which were novel, and an intronic variation.
Bateman et al. (1996) determined the outline structure of the immunoglobulin and fibronectin type III domains of the L1CAM molecule by showing that they have, at the key sites that determine conformation, residues similar to those in proteins of known structure. They used the outline structure to investigate the likely effects of 22 mutations that cause neurologic diseases. They found that the mutations are not randomly distributed but cluster in a few regions of the structure. They can be divided into those that act mainly by changing conformation or denaturing their domain and those that alter its surface properties.
Finckh et al. (2000) screened 153 cases with prenatally or clinically suspected X-chromosomal hydrocephalus for L1CAM mutations by SSCP analysis of the 28 coding exons and the regulatory elements in the 5-prime untranslated region of the gene. They found 46 pathogenic mutations (30.1% detection rate), most consisting of nonsense, frameshift, and splice site mutations. In 8 cases, segregation analysis disclosed recent de novo mutations. The data indicated a significant effect on mutation detection rate of family history, number of L1 disease-typical clinical findings, and presence or absence of signs not typically associated with L1CAM disease. Whereas the mutation detection rate was 74.2% for patients with at least 2 additional cases in the family, only 16 mutations were found in the 102 cases with negative family history (15.7% detection rate). The data suggested a higher than previously assumed contribution of L1CAM mutations in the pathogenesis of the heterogeneous group of congenital hydrocephalus.
Nagaraj et al. (2009) showed that 2 different pathogenic human L1CAM mutants (E309K and Y1070C) both induced normal L1CAM-mediated cell aggregation, but were defective in stimulating human epidermal growth factor receptor (EGFR; 131550) tyrosine kinase activity in vitro and were unable to rescue L1 loss-of-function conditions in a Drosophila transgenic model in vivo. Nagaraj et al. (2009) proposed that the L1 syndrome-associated phenotype might involve the disruption of L1CAM functions at different levels, either by reducing or abolishing L1CAM protein expression, interfering with L1CAM cell surface expression, (c) reducing L1CAM adhesion ability, or impeding further downstream adhesion-dependent signaling processes.
Michaelis et al. (1998) analyzed 71 published cases and 7 of their own cases with mutations in L1CAM. They found that mutations affecting the key residues in either the immunoglobulin type C-like or fibronectin type III domains were more likely to produce a phenotype with severe hydrocephalus, adducted thumbs, and life span less than 1 year compared with mutations affecting surface residues. In addition, mutations affecting the FN domains were more likely than those affecting the Ig domains to produce a phenotype with severe hydrocephalus, with less certain effects on adducted thumbs and life span. Mutations in key residues of the FN domains were particularly deleterious to infant survival.
Fransen et al. (1998) collected 108 patients from published reports. They found that mutations in the extracellular part of L1CAM leading to truncation or absence of L1 protein cause a severe phenotype; mutations in the cytoplasmic domain of L1CAM give rise to a milder phenotype than extracellular mutations; and extracellular missense mutations affecting amino acids situated on the surface of a domain cause a milder phenotype than those affecting amino acids buried in the core of the domain.
Weller and Gartner (2001) reviewed mutations in the L1CAM gene causing disorders in the cluster referred to by Finckh et al. (2000) as L1 disease. They pointed to indications of a relationship between clinical phenotype and genotype: missense mutations in extracellular domains or mutations in cytoplasmic regions cause milder phenotypes than mutations leading to truncation in extracellular domains or to nondetectable L1 protein.
De Angelis et al. (2002) examined the effects of 25 L1CAM missense mutations on binding to homophilic (L1) and heterophilic (TAX1; 190197) ligands as well as on intracellular trafficking. All but 3 of these, including H210Q (308840.0004) and D598N (308840.0005), resulted in reduced ligand binding or impaired movement to the surface of transfected cells. Mutations that were predicted to affect the structure of individual extracellular domains, including C264Y (308840.0002), G452R (308840.0006), R184Q (308840.0007), G370R (308840.0011), and V752M (308840.0014), were more likely to affect intracellular processing and/or ligand binding than those mutations affecting surface properties of the molecule.
Vos et al. (2010) identified 68 different mutations in the L1CAM gene, including 52 novel mutations, in 73 (20%) of 367 individuals referred for genetic analysis of the L1CAM gene. In 5 (7%) patients, the mutation was determined to be de novo or result from maternal germline mosaicism. Clinical data for 106 patients, 31 of whom carried a mutation, was obtained via questionnaire. In patients with 3 or more age-independent clinical characteristics, including hydrocephalus, aqueduct stenosis, adducted thumbs, and agenesis/dysgenesis of the corpus callosum, the mutation detection rate was 66%, compared to 16% in patients with fewer characteristics. The detection rate was 51% in families with more than 1 affected individual, compared to 18% for families with only 1 affected member. Children with a truncating mutation were more likely to die before age 3 years compared to those with a missense mutation. These findings indicated that select clinical characteristics and family history can be used to accurately predict the chance of detecting a L1CAM mutation in candidate patients.
MIC5, so named because it was discovered through the use of monoclonal antibodies at the Imperial Cancer Research Fund, is the gene locus defined by MoAb R1 (Hope et al., 1982). The MIC5 gene was shown to be located in the Xq27-q28 region. By use of a biochemical approach, Patel et al. (1992) identified the glycoprotein MIC5 gene product as the L1 cell adhesion molecule.
Tapanes-Castillo et al. (2010) noted that mice with a homozygous deletion in the L1cam gene (L1-6D mice) rarely display hydrocephalus on the 129/Sv background, but express severe hydrocephalus on the C57BL/6J background. Using linkage analysis, statistical testing, and quantitative trait locus analysis of hydrocephalus severity to examine both of these mouse strains, Tapanes-Castillo et al. (2010) identified a locus on mouse chromosome 5, which they termed L1cam hydrocephalus modifier-1 (L1hydro1), that appeared to modify the phenotype (p = 4.4 x 10(-11) at rs3694887; p = 0.005 after Bonferroni correction). Other candidate regions that may influence the phenotype were also identified.
The mutation in the L1CAM gene identified by Rosenthal et al. (1992) in affected members and carriers in 1 family with X-linked hydrocephalus (HYCX; 307000) was an A-to-C transversion at position -19 in a putative branchpoint sequence of the L1CAM gene. The mutation resulted in aberrant splicing with deletion of exon Q and insertion of 69 additional basepairs.
In a patient with severe X-linked hydrocephalus (HYCX; 307000), Jouet et al. (1993) observed a G-to-A transition at nucleotide 791 of the cDNA sequence, resulting in a cys264-to-tyr substitution in the third immunoglobulin type C2 domain of the mature protein. The mutation would eliminate the potential for disulfide bridge formation and have a profound effect on L1 secondary structure. From analogy to NCAM (116930) and from the conservation of cys264 in analogous proteins of rat, mouse, chicken, and Drosophila, one can conclude that the mutation was probably disruptive. Furthermore, an RsaI site created by the mutation segregated fully with the disease in the extended pedigree and did not correspond to a common polymorphism.
Van Camp et al. (1993) screened 25 X-linked hydrocephalus families for mutations. The mutation reported by Rosenthal et al. (1992) (C264Y; 308840.0002) was found in none of them. One family with hydrocephalus (HYCX; 307000), however, showed a 1.3-kb genomic duplication in the 3-prime region of L1CAM. The 1.3-kb duplication comprised the 3-prime end of the L1CAM open reading frame, part of the upstream intron, and 756 bp of 3-prime untranslated sequence. Van Camp et al. (1993) showed that the duplication gives rise to aberrant splicing of L1CAM mRNA and that translation of the new mRNA replaces the 35 carboxy-terminal amino acids of the L1CAM protein with a new 75-amino acid sequence.
In an affected member of a family with the MASA syndrome (303350), Jouet et al. (1994) observed a C-to-G transversion at nucleotide 630 converting his to gln at amino acid residue 210. The change occurred in exon 6 and produced a change in the protein in the second immunoglobulin domain of L1. All 5 affected members of the family had agenesis of the corpus callosum, and 1 of these also presented with marked hydrocephalus.
In the course of L1CAM mutation analysis in 8 unrelated patients with MASA syndrome (303350), Vits et al. (1994) found 3 different L1CAM mutations: a deletion removing part of the open reading frame and 2 point mutations resulting in amino acid substitutions. The 2 missense mutations were asp598 to asn (D598N) in the sixth immunoglobulin domain of the protein; and his210 to gln (H210Q) (308840.0004) in the second immunoglobulin domain.
In a family with a history of hydrocephalus (HYCX; 307000), Jouet et al. (1994) found a G-to-A mutation in exon 11 of the L1CAM gene that caused a gly-to-arg substitution at residue 452.
In the original hydrocephalus (HYCX; 307000) family described by Bickers and Adams (1949) and further characterized by Edwards et al. (1961), Jouet et al. (1994) used SSCP to detect a G-to-A change in exon 6 that substituted gln for arg at residue 184.
In a family reported by Kenwrick et al. (1986) as having spastic paraplegia-1, but later determined to have MASA syndrome (303350), Jouet et al. (1994) found a 2-bp deletion in exon 26 which resulted in a shift of the reading frame and the introduction of a premature stop codon 19 nucleotides downstream. This change predicts a truncated protein in which 95 of the 115 highly conserved amino acids are replaced by 7 novel residues.
Fransen et al. (1994) reported a family in which 2 males, an uncle and a nephew, had typical symptoms of MASA syndrome, and a third male, a maternal first cousin of the uncle, was born hydrocephalic (HYCX; 307000) and died at the age of 15 years in an institution for the mentally handicapped. At that time, he had extreme macrocephaly, severe spasticity, and mental retardation. The same L1CAM mutation was found in all 3 cases. A C-to-T transition in exon 28 at position 3581 of the L1CAM cDNA sequence caused a ser1194-to-leu substitution in the cytoplasmic domain of the L1CAM molecule.
In a family reported by Fryns et al. (1991) in which various members displayed features characteristic of complicated spastic paraplegia/MASA syndrome (303350) or X-linked hydrocephalus (HYCX; 307000), Ruiz et al. (1995) found an I179S mutation in the L1CAM gene; see 303350.
In a large family described by Kaepernick et al. (1994) in which different members displayed features consistent with one or another of the L1CAM-associated syndromes, spastic paraplegia type 1/MASA syndrome (303350) or X-linked hydrocephalus (HYCX; 307000), Ruiz et al. (1995) identified a G370R mutation in the L1CAM gene in all affected members; see 303350.
In a child with features of X-linked hydrocephalus (HYCX; 307000) who also had Hirschsprung disease and cleft palate, Okamoto et al. (1997) identified a 2-bp deletion of exon 18 in the L1CAM gene, resulting in a frameshift and premature termination. The mother was heterozygous for the mutation. Okamoto et al. (1997) acknowledged that X-linked hydrocephalus and Hirschsprung disease may be independent events in this patient, but suggested that L1CAM may contribute to both phenotypes.
In a family with X-linked congenital hydrocephalus (HYCX; 307000), Du et al. (1998) identified a C-to-T transition at position 924 in exon 8 of the L1CAM gene. This was predicted to have no effect on protein structure, as it affected the third position of a glycine codon (G308G). However, the C-to-T transition created a potential 5-prime splice site consensus sequence resulting in an in-frame 69-bp deletion from exon 8 with a consequent 23 amino acid deletion. RT-PCR of RNA from an affected male fetus confirmed the use of the new splice site.
Parisi et al. (2002) described a male infant who had severe hydrocephalus (HYCX; 307000) identified in the prenatal period with evidence of aqueductal stenosis and adducted thumbs at birth. He developed chronic constipation, and rectal biopsy confirmed the diagnosis of Hirschsprung disease. Molecular testing of the L1CAM gene demonstrated a 2254G-A mutation, resulting in a val752-to-met amino acid substitution (V752M). A common polymorphism in RET, but no mutation, was identified. Parisi et al. (2002) stated that this patient represented the third example of coincident hydrocephalus and Hirschsprung disease in an individual with an identified L1CAM mutation. They hypothesized that L1CAM-mediated cell adhesion may be important for the ability of ganglion cell precursors to populate the gut, and that L1CAM may modify the effects of a Hirschsprung disease-associated gene to cause intestinal aganglionosis.
In 2 brothers with hydrocephalus (HYCX; 307000) and Hirschsprung disease, Okamoto et al. (2004) identified a G-to-A transition at position +5 of the donor splice site of intron 15 of the L1CAM gene (IVS15+5G-A). Bilateral adducted thumbs and flexion contracture of the fingers were noted. The mother was heterozygous for the mutation; male first cousins and a maternal uncle of hers had X-linked hydrocephalus only.
Bott et al. (2004) described an association between X-linked hydrocephalus (HYCX; 307000) and a form of congenital idiopathic intestinal pseudoobstruction (see 300048) in which Cajal cells were lacking in an infant in whom they identified a 2920G-T transversion in exon 22 of the L1CAM gene, resulting in a gln974-to-ter (Q974X) substitution. The mother was a carrier. A maternal great uncle had mental retardation and died during childhood. By fetal ultrasonography, the patient was found at 32 weeks' gestation to have hydrocephalus and was born prematurely at 34 weeks' gestation as a result of maternal eclampsia. At birth, bilateral adducted thumbs, bilateral nystagmus, convergent strabismus, spastic paraplegia, and abdominal distention were noted. The patient's mother and grandmother had had several spontaneous abortions. Bott et al. (2004) noted that Cajal cells are the pacemaker cells of the gut. They generate the physiologic slow waves in the intestinal tract that are responsible for autonomic gastrointestinal motility (Jain et al., 2003). The KIT oncogene (164920) encodes a protein responsible for the development of Cajal cells. Bott et al. (2004) suggested that the selective expression of L1CAM in the gut or kidney may explain the association of HYCX with hydronephrosis and with hydroureter or Hirschsprung disease.
In 4 affected males from a family with X-linked hydrocephalus (HYCX; 307000), Gu et al. (1996) identified a 719C-T transition in exon 7 of the L1CAM gene, resulting in a pro240-to-leu (P240L) substitution in the third highly conserved Ig-like domain. Three of the older patients had died between 5 and 8 months of age; the proband had adducted thumbs, short stature, severe mental retardation, and spasticity.
Basel-Vanagaite et al. (2006) identified the P240L mutation in 2 male sibs with X-linked partial agenesis of the corpus callosum (304100) and mild mental retardation. Neither sib had hydrocephalus, adducted thumbs, or absent speech. The older sib also had Hirschsprung disease and congenital dislocation of the radial heads bilaterally, resulting in limited extension and supination of the elbows. Basel-Vanagaite et al. (2006) emphasized the well-known inter- and intrafamilial phenotypic variability in patients with L1CAM mutations.
In a Swedish boy with X-linked hydrocephalus, cognitive delay, and adducted thumbs (HYCX; 307000), Rehnberg et al. (2011) identified a hemizygous G-to-C transversion in intron 26 of the L1CAM gene (c.3458-1G-C), predicted to result in the deletion of exon 26 and a frameshift in exons 27 and 28. This would likely cause a loss of function of most of the cytoplasmic domain of the protein, which is a multifunctional region required for the initial protrusion of axons from the neuronal soma. Rehnberg et al. (2011) suggested that the mutation would disrupt cytoskeletal interactions. Family history was notable for 2 deceased maternal uncles with hydrocephalus, cognitive impairment, spastic paraplegia, and adducted thumbs. The mutation was also found in 3 female relatives of the proband, including his unaffected mother, maternal grandmother, and sister. Rehnberg et al. (2011) noted that the mother developed metastatic clear cell renal cell carcinoma (RCC; 144700) at age 46, and they speculated that the L1CAM mutation may have stimulated tumor migration and growth in this patient.
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