Description:
MUCOLIPIDOSIS IIIA
N-ACETYLGLUCOSAMINE-1-PHOSPHOTRANSFERASE, ALPHA/BETA SUBUNITS; GNPTAB
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Repository
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NIGMS Human Genetic Cell Repository
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| Subcollection |
Heritable Diseases
Lysosomal Storage Diseases |
| Class |
Disorders of Carbohydrate Metabolism |
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Cell Type
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Fibroblast
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Transformant
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Untransformed
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Race
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White
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Relation to Proband
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proband
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Confirmation
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Clinical summary/Case history
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Species
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Homo sapiens
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Common Name
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Human
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Remarks
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| Passage Frozen |
4 |
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| IDENTIFICATION OF SPECIES OF ORIGIN |
Species of Origin Confirmed by Nucleoside Phosphorylase Isoenzyme Electrophoresis |
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| UDP-N-acetylglucosamine--lysosomal-enzyme N-acetylglucosaminephosphotransferase |
According to the submitter, biochemical test results for this subject showed decreased enzyme activity. EC Number: 2.7.8.17 |
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| Gene |
GNPTAB |
| Chromosomal Location |
12q23.3 |
| Allelic Variant 1 |
607840.0013; MUCOLIPIDOSIS IIIA |
| Identified Mutation |
IVS17DS,T>G,+6; In a family with 2 affected sibs and in 2 patients with mucolipidosis IIIA (252900), Kudo et al. (Am J Hum Genet 78:451-463, 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 frameshift with a premature termination at residue 1085 (P1084fsX1172). 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. |
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| Gene |
GNPTAB |
| Chromosomal Location |
12q23.3 |
| Allelic Variant 2 |
607840.0011; MUCOLIPIDOSIS II |
| Identified Mutation |
2-BP DEL, 3665TC; In 8 of 9 pedigrees with ML II (252500) and 5 of 7 with ML IIIA (252600), Kudo et al. (Am J Hum Genet 78:451-463, 2006) identified a frameshift mutation in the GNPTAB gene consisting of deletion of 2 nucleotides (3665_3666delTC) beginning at leu1168 and leading to premature termination at amino acid 1172 (L1168fsX1172). 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. |
| Remarks |
Abnormal mucopolysaccharide accumulation and deficiencies for multiple acid hydrolases in fibroblasts including B-galactosidase; deficient leuko and fibro N-acetylglucosaminylphosphotransferase and increased serum B-hexosaminidase; GlcNAc-Phosphotransferase activity = 1% (measured as specific activity in cell lysate and reported as percentage of activity in normal fibroblasts); donor subject is a compound heterozygote: one allele has a donor splice site mutation in intron 17 of the GNPTAB gene [IVS17+6T>G] resulting in the skipping of exon 17 and a frameshift with a premature termination at residue 1085 [P1084fsX1085] and a second allele has a 2-bp deletion in exon 19 of the GNPTAB gene [3665_3666delTC] resulting in a frameshift and truncation of the protein in the beta subunit [L1168fsX1172]. |
| Kudo M, Brem MS, Canfield WM, Mucolipidosis II (I-Cell Disease) and Mucolipidosis IIIA (Classical Pseudo-Hurler Polydystrophy) Are Caused by Mutations in the GlcNAc-Phosphotransferase alpha / beta -Subunits Precursor Gene. Am J Hum Genet78(3):451-63 2006 |
| PubMed ID: 16465621 |
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| Varki A, Reitman ML, Vannier A, Kornfeld S, Grubb JH, Sly WS, Demonstration of the heterozygous state for I-cell disease and pseudo- Hurler polydystrophy by assay of N-acetylglucosaminylphosphotransferase in white blood cells and fibroblasts. Am J Hum Genet34:717-29 1982 |
| PubMed ID: 6289658 |
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| Reitman ML, Varki A, Kornfeld S, Fibroblasts from patients with I-cell disease and pseudo-Hurler polydystrophy are deficient in uridine 5'-diphosphate-N- acetylglucosamine: glycoprotein N-acetylglucosaminylphosphotransferase activity. J Clin Invest67:1574-9 1981 |
| PubMed ID: 6262380 |
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| Varki AP, Reitman ML, Kornfeld S, Identification of a variant of mucolipidosis III (pseudo-Hurler polydystrophy): a catalytically active N- acetylglucosaminylphosphotransferase that fails to phosphorylate lysosomal enzymes. Proc Natl Acad Sci U S A78:7773-7 1981 |
| PubMed ID: 6461005 |
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| Glaser JH, McAlister WH, Sly WS, Genetic heterogeneity in multiple lysosomal hydrolase deficiency. J Pediatr85:192-8 1974 |
| PubMed ID: 4276418 |
| Passage Frozen |
4 |
| Split Ratio |
1:4 |
| Temperature |
37 C |
| Percent CO2 |
5% |
| Medium |
Eagle's Minimum Essential Medium with Earle's salts and non-essential amino acids with 2mM L-glutamine or equivalent |
| Serum |
15% fetal bovine serum Not inactivated |
| Substrate |
None specified |
| Subcultivation Method |
trypsin-EDTA |
| Supplement |
- |
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