Alternative titles; symbols
HGNC Approved Gene Symbol: GNPTAB
SNOMEDCT: 65764006;
Cytogenetic location: 12q23.2 Genomic coordinates (GRCh38) : 12:101,745,499-101,830,959 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q23.2 | Mucolipidosis II alpha/beta | 252500 | Autosomal recessive | 3 |
| Mucolipidosis III alpha/beta | 252600 | Autosomal recessive | 3 |
UDP-N-acetylglucosamine:lysosomal-enzyme N-acetylglucosamine-1-phosphotransferase (GlcNAc-phosphotransferase; EC 2.7.8.17) catalyzes the initial step in the synthesis of the mannose 6-phosphate determinant required for efficient intracellular targeting of newly synthesized lysosomal hydrolases to the lysosome. GlcNAc-phosphotransferase is an alpha-2/beta-2/gamma-2 hexameric complex. The GNPTAB gene encodes both the alpha and beta subunits; the gamma subunit is encoded by the GNPTG gene (607838).
Bao et al. (1996, 1996) determined that bovine GlcNAc-phosphotransferase is a 54-kD alpha-2/beta-2/gamma-2 hexameric complex. Canfield et al. (1998) indicated that the alpha and beta subunits are derived from a single cDNA. The individual subunits are apparently generated by proteolytic processing at a lys-asp bond following synthesis of an alpha/beta precursor, generating a 928-amino acid N-terminal alpha subunit and a 328-amino acid C-terminal beta subunit. The gamma subunit is encoded by a separate gene (GNPTG; 607838).
By database analysis, Tiede et al. (2005) identified the human GNPTAB gene. The deduced 1256-amino acid protein has a predicted molecular mass of 144 kD. Hydrophobicity analysis showed 2 transmembrane domains and 19 potential N-glycosylation sites. Sequence comparisons showed that GNPTAB has a complex modular structure composed of at least 6 domains including an N-terminal domain with a putative nucleotide binding site, 2 Notch repeat-like domains, and a DMAP1 (605077) binding-like domain.
By database analysis, Tiede et al. (2005) determined that the GNPTAB gene contains 21 exons and spans 85 kb.
Vidgoff et al. (1982) found possible linkage of ML II to MN (111300) on 4q, with a lod score of 1.3. Mueller et al. (1987) determined the chromosome assignment of the structural gene altered in the common forms of ML II and ML III by linkage analysis, somatic cell hybrids, and gene dosage. Linkage data with ML II families indicated that the ML II locus is located between GC (139200) and MNS. The combined data indicated that GNPTA maps to 4q21-q23.
By genomic sequence analysis, Tiede et al. (2005) mapped the GNPTAB gene to chromosome 12q23.3.
Paton et al. (2014) stated that the mouse Gnptab gene maps to chromosome 10.
Canfield et al. (1998) found that in 4 of 4 patients with mucolipidosis II (ML II; 252500), the 6.2-kb alpha/beta transcript was absent. In 2 of 2 patients with mucolipidosis IIIA (252600), the alpha/beta transcript was present but greatly reduced. In all patients examined, the gamma transcript was present at normal levels.
By retroviral transduction of fibroblasts from an individual with mucolipidosis II, Tiede et al. (2005) demonstrated expression and localization of GNPTAB in the Golgi apparatus, accompanied by correction of the hypersecretion of lysosomal enzymes. Tiede et al. (2005) concluded that GNPTAB encodes a subunit of GlcNAc-phosphotransferase that is defective in individuals with ML II.
Kudo et al. (2005) cloned the cDNA and genomic DNA encoding the alpha/beta-subunits precursor gene (GNPTAB). With the cloning of the gamma-subunit gene (GNPTG; 607838), it could be concluded that GlcNAc-phosphotransferase is the product of 2 genes, an uncommon exception to the Garrod-Beadle principle of 1 enzyme-1 gene.
Marschner et al. (2011) found that the alpha/beta subunit of the N-acetylglucosamine-1-phosphotransferase complex is cleaved by the site-1 protease (S1P; 603355) that activates sterol regulatory element-binding proteins in response to cholesterol deprivation. S1P-deficient cells failed to activate the alpha/beta subunit precursor and exhibited a mucolipidosis II-like phenotype. Thus, Marschner et al. (2011) concluded that S1P functions in the biogenesis of lysosomes, and that lipid-independent phenotypes of S1P deficiency may be caused by lysosomal dysfunction.
In a 47-year-old female who presented with dilated cardiomyopathy and mild neuropathy and was found to have mucolipidosis III (252600), Steet et al. (2005) identified a homozygous splice site mutation of the GNPTAB gene (607840.0001).
In a 14-year-old boy with a mild clinical phenotype of mucolipidosis III, Tiede et al. (2005) identified homozygosity for an asp407-to-ala substitution in the GNPTAB gene (607840.0002). The patient was also homozygous for an ala663-to-gly substitution in the GNPTAB that was deemed a polymorphism because it was found in 5% of normal alleles. Both parents were heterozygous for both mutations.
In 3 unrelated Korean girls with mucolipidosis II (252500) and 2 unrelated Korean girls with mucolipidosis IIIA, Paik et al. (2005) identified compound heterozygosity for 7 different mutations in the GNPTAB gene (607840.0003-607840.0009).
In 6 patients with clinically and biochemically diagnosed mucolipidosis II, Tiede et al. (2005) identified homozygosity or compound heterozygosity for 7 mutations in the GNPTAB gene, all resulting in premature translational termination (e.g., 607840.0010).
To determine whether mucolipidosis II, or I-cell disease, and mucolipidosis IIIA, or classic pseudo-Hurler polydystrophy, are caused by mutations in the gene encoding the alpha/beta-subunits precursor gene, Kudo et al. (2006) sequenced GNPTAB exons and flanking intronic sequences and measured GlcNAc-phosphotransferase activity in patient fibroblasts. They identified 15 different mutations in GNPTAB from 18 pedigrees with one or the other of these 2 diseases and demonstrated that these 2 diseases are allelic. Mutations in both alleles were identified in each case, which demonstrated that GNPTAB mutations are the cause of both diseases. Some pedigrees had identical mutations. A 2-bp deletion (607840.0011), resulting in a frameshift and premature termination, predominated and was found in both ML II and ML IIIA. This mutation was found in combination with severe mutations (i.e., mutations preventing the generation of active enzyme) in ML II and with mild mutations (i.e., mutations allowing the generation of active enzyme) in ML IIIA. Some cases of ML II and ML IIIA were the result of mutations that cause aberrant splicing. Substitutions were within the invariant splice site sequence in ML II and were outside it in ML IIIA. When the mutations were analyzed along with GlcNAc-phosphotransferase activity, it was possible to distinguish with confidence these 2 related but distinct disorders.
Bargal et al. (2006) studied GNPTAB mutations in 24 patients. They suggested that there is a clinical continuum between ML III and ML II, and the classification of these diseases should be based on the age of onset, clinical symptoms, and severity.
Associations Pending Confirmation
In affected members of a large consanguineous 6-generation Pakistani family with stuttering (STUT2; 609261) showing linkage to chromosome 12q, Kang et al. (2010) identified a glu1200-to-lys (E1200K) variant in the GNPTAB gene. Thirteen affected individuals were heterozygous, and 12 were homozygous. However, the variant did not completely segregate with the disorder: 3 noncarriers were affected, and 2 homozygous E1200K carriers and 9 heterozygous E1200K carriers were unaffected. Kang et al. (2010) suggested nonpenetrance in these individuals. The authors identified 3 additional variants in the GNPTAB gene in 4 additional unrelated individuals with stuttering. None of the individuals had features of mucolipidosis. Study of additional families and individuals identified the E1200K variant in 3 other Pakistani families with stuttering, in 1 North American patient of Asian Indian ancestry, and in 1 Pakistani control. The E1200K variant was not found in 192 chromosomes from unaffected Pakistani controls or in 552 chromosomes from North American controls. By studying other genes in the lysosomal enzyme-targeting pathway, Kang et al. (2010) identified 3 variants each in the GNPTG (607838) and NAGPA (607985) genes that were found in 11 of 270 North American/British patients with stuttering but not in 276 controls. Kang et al. (2010) concluded that variations in genes governing lysosomal metabolism may be susceptibility factors for nonsyndromic persistent stuttering.
By haplotype analysis of 8 unrelated individuals who were heterozygous or homozygous for the G1200K variant, Fedyna et al. (2011) determined that it arose as a founder allele 572 generations, or 14,300 years ago. Haplotype analysis identified a common 6.67-kb haplotype containing the variant.
Otomo et al. (2009) identified 18 GNPTAB mutations, including 14 novel mutations, among 25 unrelated Japanese patients with ML II and 15 Japanese patients with ML III. The most common mutations were R1189X (607840.0004), which was found in 41% of alleles, and F374L (607840.0015), which was found in 10% of alleles. Homozygotes or compound heterozygotes of nonsense and frameshift mutations contributed to the more severe phenotype. In all, 73 GNPTAB mutations were detected in the 80 alleles. In a review of the reported clinical features, most ML II patients had impairment in standing alone, walking without support, and speaking single words compared to those with ML III. The frequencies of heart murmur, inguinal hernia, and hepatomegaly and/or splenomegaly did not differ between ML II and III patients.
Encarnacao et al. (2009) identified GNPTAB mutations in 9 mostly Portuguese patients with ML II. Eight of 9 patients had a nonsense or frameshift mutation, the most common being a 2-bp deletion (607840.0011) that was found in 45% of the mutant alleles; one patient with ML II was homozygous for a missense mutation. Three additional patients with a less severe phenotype consistent with ML III had missense mutations. Encarnacao et al. (2009) concluded that patients with ML II alpha/beta are almost all associated with the presence of nonsense or frameshift mutations in homozygosity, whereas the presence of at least 1 mild mutation in the GNPTAB gene is associated with ML III alpha/beta.
Cathey et al. (2010) identified 51 pathogenic changes in the GNPTAB gene, including 42 novel mutations, among 61 probands mostly from the U.S. with ML II or ML III. Thirty-four probands, including 13 with ML II, 14 with ML III, and 7 with an intermediate phenotype, were studied in detail. Those with ML II had a more severe phenotype, with evidence of craniofacial and orthopedic problems at birth, severe psychomotor retardation, and enzyme activity of less than 1% of control values. Growth, speech, ambulation, and cognitive function were impaired. Those with ML III had enzyme activity of 1 to 10% of control values, minimal delays in milestones, and later onset of skeletal problems. ML II was associated with frameshift or truncating mutations, whereas ML III was associated with hypomorphic mutations. The most common mutation was 3503delTC (607840.0011), found in 18 ML II and 4 ML III patients.
In an N-ethyl-N-nitrosourea mutagenesis screen, Paton et al. (2014) identified a line of mice with a novel mutation, termed Nymphe (nym), that caused growth retardation and ataxic gate. They identified the nym mutation as a c.2601T-A transversion in exon 13 of the Gnptab gene, resulting in a tyr867-to-ter (Y867X) substitution in the Gnptab preprotein prior to the cleavage signal between the alpha and beta subunits. The mutation resulted in a truncated alpha subunit, complete lack of the beta subunit, and retention of the alpha subunit in the endoplasmic reticulum. Whereas nym/+ mice appeared normal, nym/nym mutants had facial and skeletal abnormalities from birth, reduced fertility, progressive ataxia and motor incoordination, and elevated mortality. Nym/nym serum had abnormally high activity of lysosomal hydrolases, and tissues showed inclusion bodies indicative of lysosomal storage. Nym/nym brain showed atrophy, with progressive loss of cerebellar Purkinje cells. Paton et al. (2014) concluded that the nym mutation produces a mouse model that recapitulates the human pathology of mucolipidosis II.
Barnes et al. (2016) engineered mice to carry a homozygous glu1179-to-lys mutation in the Gnptab gene, which is homologous to the glu1200-to-lys mutation in human GNPTAB. Compared with wildtype pups, pups with the mutation emitted fewer vocalizations per unit time when separated from their dam. They also showed longer pauses between vocalizations and were more stereotyped in their vocalizations than wildtype littermates. Gnptab missense pups were similar to wildtype on an extensive battery of nonvocal behaviors. Speech from people who stutter showed similar abnormalities when compared with control speech.
In a 47-year-old female who presented with dilated cardiomyopathy and mild neuropathy and was found to have mucolipidosis III (252600), Steet et al. (2005) identified a homozygous G-A transition in the last nucleotide of exon 7 of the GNPTAB gene, resulting in skipping of exon 7 and the production of a minimal amount of functional enzyme. The patient exhibited none of the connective tissue anomalies characteristic of mucolipidosis III, and the authors stated that this was the first example of the disease presenting in an adult patient.
In a 14-year-old boy with a mild clinical phenotype of mucolipidosis III (252600), Tiede et al. (2005) identified homozygosity for a 1220A-C transversion in exon 10 of the GNPTAB gene, resulting in an asp407-to-ala (D407A) substitution. Both parents were heterozygous for the mutation, which was not found in 200 normal alleles.
In a 1-year-old Korean girl with mucolipidosis II (252500), Paik et al. (2005) identified compound heterozygosity for a 310C-T transition in exon 3 and a 3565C-T transition in exon 19 of the GNPTAB gene, resulting in a gln104-to-ter (Q104X) and an arg1189-to-ter (R1189X; 607840.0004) substitution, respectively. The patient had growth retardation, developmental delay, hypotonia, severe skeletal deformity with hip subluxation, gum hypertrophy, and severe mitral and aortic valve prolapse with regurgitation.
For discussion of the arg1189-to-ter (R1189X) mutation in the GNPTAB gene that was found in compound heterozygous state in a patient with mucolipidosis II (252500) by Paik et al. (2005), see 607840.0003.
Otomo et al. (2009) identified a 3565C-T transition in the GNPTAB gene, resulting in an arg1189-to-ter (R1189X) substitution in 33 (41%) of 80 mutant GNPTAB alleles from 40 unrelated Japanese patients with mucolipidosis II or mucolipidosis III (252600). Patients with the more severe mucolipidosis II tended to have the R1189X mutation in homozygosity or in compound heterozygosity with a truncating mutation. None of the patients with the less severe mucolipidosis III carried R1189X in homozygosity; most were compound heterozygous for R1189X and F374L (607840.0015).
In a 2-year-old Korean girl with mucolipidosis II (252500), Paik et al. (2005) identified compound heterozygosity for a 3173C-G transversion in exon 16 and a 2-bp deletion (3474delTA) in exon 19 of the GNPTAB gene, resulting in a ser1058-to-ter (S1058X) substitution and a frameshift leading to premature termination (607840.0006), respectively.
For discussion of the 2-bp deletion in the GNPTAB gene (3474delTA) that was found in compound heterozygous state in a patient with mucolipidosis II (252500) by Paik et al. (2005), see 607840.0005.
In a 1-year-old Korean girl with mucolipidosis II (252500), Paik et al. (2005) identified compound heterozygosity for a 2681G-A transition in exon 13 of the GNPTAB gene resulting in a trp894-to-ter (W894X) substitution and an R1189X mutation (607840.0004). The patient had growth retardation, developmental delay, gum hypertrophy, joint restriction, coxa valga, and coronary artery atresia requiring coronary artery bypass surgery.
In 2 Korean girls with mucolipidosis IIIA (252600), Paik et al. (2005) identified compound heterozygosity for a splice site mutation, a 2715+1G-A transition in intron 13 of the GNPTAB gene, with an R1189X mutation (607840.0004) and a 2-bp deletion (2574delGA) in exon 13 (607840.0009), respectively. The 2574delGA mutation results in premature termination.
For discussion of the 2-bp deletion in the GNPTAB gene (2574delGA) that was found in compound heterozygous state in patients with mucolipidosis IIIA (252600) by Paik et al. (2005), see 607840.0008.
In a patient with mucolipidosis II (252500), Tiede et al. (2005) identified homozygosity for a 1-bp insertion in exon 13 of the GNPTAB gene, resulting in a premature termination directly after the putative second Notch repeat-like domain.
In 8 of 9 pedigrees with mucolipidosis II (252500) and 5 of 7 with mucolipidosis IIIA (252600), Kudo et al. (2006) identified a frameshift mutation in the GNPTAB gene consisting of deletion of 2 nucleotides (3665_3666delTC based on numbering of the first base in the initiation codon of a BAC clone) beginning at leu1168 and leading to premature termination at amino acid 1172 (Leu1168fsTer1172). This mutation was the most frequent in their study and was found in both the homozygous and compound heterozygous state, in combination with severe mutations (i.e., mutations preventing the generation of active enzyme) in ML II and with mild mutations (i.e., mutations allowing the generation of active enzyme) in ML IIIA.
In 27 parents of 16 deceased French Canadian children with mucolipidosis II alpha/beta, Plante et al. (2008) identified the 2-bp deletion (which they referred to as 3503_3504delTC based on numbering of the first nucleotide of the start codon as +1; rs34002892) in exon 19 of the GNPTAB gene, resulting in a frameshift and premature termination. All parents carried the mutation in the heterozygous state, indicating that the children were likely homozygous. Genealogic data showed 6 founders (3 couples) with a high probability of having introduced the mutation in the population; all originated from France and were married in the Quebec region in the second half of the 17th century. Plante et al. (2008) noted that the carrier rate of mucolipidosis II is estimated to be 1 in 39 in the Saguenay-Lac-Saint-Jean region.
Encarnacao et al. (2009) identified GNPTAB mutations in 9 mostly Portuguese patients with ML II. Eight of 9 patients had a nonsense or frameshift mutation, the most common being the 2-bp deletion (3503delTC) that was found in 45% of the mutant alleles.
By haplotype analysis of 44 carriers of the 3503delTC mutation from various populations, Coutinho et al. (2011) found that 59 (97%) of 61 mutant chromosomes shared a common haplotype covering 4 of the 5 polymorphic markers analyzed, indicating a strong founder effect. The 2 remaining chromosomes, both from Italian patients, differed by alleles only at 1 marker. A common haplotype encompassing the 3503delTC mutation was shared by individuals of Italian, Arab-Muslim, Turkish, Argentinian, Brazilian, Irish Traveller, Portuguese, and Canadian origin. The mutation was estimated to have occurred about 2,063 years ago, most likely in a peri-Mediterranean region.
In a patient with type II mucolipidosis (252500), Kudo et al. (2006) described a splice site mutation in the GNPTAB gene, IVS17+1G-A, that was predicted to cause skipping of exon 17 and a frameshift beginning at pro1084 and ending with premature termination at residue 1085 (P1084fsX1085). This mutation was found in compound heterozygosity with the FS1172 mutation (607840.0011).
In a family with 2 affected sibs and in 2 patients with mucolipidosis IIIA (252900), Kudo et al. (2006) described a donor splice site mutation in intron 17 of the GNPTAB gene, IVS17+6T-G, that results in skipping of exon 17 and a frameshift with a premature termination at residue 1085 (Pro1084fsTer1172). This same result was observed in another intron 17 splice site mutation in a patient with ML II (607840.0012). The former intron 17 splice site mutation was designated type I and the latter type II. Although the mRNA sequences derived from these 2 mutations are the same, the GlcNAc-phosphotransferase activities and clinical outcomes are different; fibroblasts with the type I mutation exhibited less than 0.1% activity, whereas those carrying the type II mutation exhibited 1 to 3% GlcNAc-phosphotransferase activity. That the type II mutation was located outside the invariant splice site was suggested as a possible cause of the greater activity.
In a family and a unrelated single patient with mucolipidosis IIIA (252900), Kudo et al. (2006) identified an A-to-C transversion in exon 1 of the GNPTAB gene, resulting in a lys4-to-gln (K4Q) substitution.
Otomo et al. (2009) identified a 1120T-C transition in exon 10 of the GNPTAB gene, resulting in a phe374-to-leu (F374L) substitution in 7 of 15 unrelated Japanese patients with mucolipidosis III (252600). Most were in compound heterozygosity with R1189X (607840.0004). Only 1 of 25 patients with a diagnosis of the more severe mucolipidosis II (252500) carried the F374L mutation; the second mutant allele in this patient was not identified. However, Otomo et al. (2009) stated that this patient had a relatively attenuated course, suggesting that F374L is associated with milder clinical manifestations. The F374L mutation occurred in 8 (10%) of 80 mutant alleles. Analysis of surrounding polymorphisms suggested a founder effect.
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