NA02528
DNA from Fibroblast
Description:
MUCOLIPIDOSIS IV
GLUCOSIDASE, ACID BETA; GBA
MUCOLIPIN 1; MCOLN1
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Repository
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NIGMS Human Genetic Cell Repository
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| Subcollection |
Heritable Diseases
Lysosomal Storage Diseases
GeT-RM Samples |
| Class |
Disorders of Carbohydrate Metabolism |
| Quantity |
10 µg |
| Quantitation Method |
Please see our FAQ |
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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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Sample Source
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DNA from Fibroblast
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Race
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White
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Ethnicity
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ASHKENAZI
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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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| PDL at Freeze |
1.69 |
| Passage Frozen |
24 |
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| IDENTIFICATION OF SPECIES OF ORIGIN |
Species of Origin Confirmed by Nucleoside Phosphorylase Isoenzyme Electrophoresis |
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| MUTATION VERIFICATION |
The IVS3-2A>G gene mutation in this sample has been verified by 6 laboratories and the N370S mutation has been verified by 5 laboratories. |
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| Gene |
GBA |
| Chromosomal Location |
1q21 |
| Allelic Variant 1 |
606463.0003; GAUCHER DISEASE, TYPE I |
| Identified Mutation |
ASN370SER; By nucleotide sequence analysis of a genomic clone from an Ashkenazi Jewish patient with type I, Tsuji et al. [Proc. Nat. Acad. Sci. 85: 2349-2352 (1988] found a single-base mutation (adenosine to guanosine transition) in exon 9 of the glucocerebrosidase gene. This change resulted in the amino acid substitution of serine for asparagine. Transient expression studies following oligonucleotide-directed mutagenesis of the normal cDNA confirmed that the mutation results in loss of glucocerebrosidase activity. This mutation [1226G (N370S)] accounts for approximately 70% of mutations in the Jewish population. |
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| Gene |
MCOLN1 |
| Chromosomal Location |
19p13.3-p13.2 |
| Allelic Variant 1 |
605248.0001; MUCOLIPIDOSIS IV |
| Identified Mutation |
IVS3AS,A>G,-2; In 12 of 21 Ashkenazi Jewish patients with mucolipidosis IV (252650) associated with the major Ashkenazi founder haplotype defined by Slaugenhaupt et al. (Am J Hum Genet 65:773-778, 1999), Bargal et al. (Nat Genet 26:118-121, 2000) identified a homozygous A-to-G transition in the acceptor splice site of the third intron of the MCOLN1 gene. One heterozygote was found among 60 Ashkenazi normal controls; this was consistent with the estimated frequency of heterozygotes (1/50) in this population. Bassi et al. (Am J Hum Genet 67:1110-1120, 2000) identified this acceptor splice site mutation, which they designated 486-2A-G, as the major founder mutation in Ashkenazi Jewish patients. The mutation disrupted the GT-AG rule of splicing and resulted in a transcript lacking 165 bp, because of the skipping of exon 4. This caused a frameshift leading to a premature translation termination 374 bp downstream. The predicted truncated protein retained only the first 21 amino acids of the wildtype protein. |
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| Gene |
MCOLN1 |
| Chromosomal Location |
19p13.3-p13.2 |
| Allelic Variant 2 |
605248.0001; MUCOLIPIDOSIS IV |
| Identified Mutation |
IVS3AS,A>G,-2; In 12 of 21 Ashkenazi Jewish patients with mucolipidosis IV (252650) associated with the major Ashkenazi founder haplotype defined by Slaugenhaupt et al. (Am J Hum Genet 65:773-778, 1999), Bargal et al. (Nat Genet 26:118-121, 2000) identified a homozygous A-to-G transition in the acceptor splice site of the third intron of the MCOLN1 gene. One heterozygote was found among 60 Ashkenazi normal controls; this was consistent with the estimated frequency of heterozygotes (1/50) in this population. Bassi et al. (Am J Hum Genet 67:1110-1120, 2000) identified this acceptor splice site mutation, which they designated 486-2A-G, as the major founder mutation in Ashkenazi Jewish patients. The mutation disrupted the GT-AG rule of splicing and resulted in a transcript lacking 165 bp, because of the skipping of exon 4. This caused a frameshift leading to a premature translation termination 374 bp downstream. The predicted truncated protein retained only the first 21 amino acids of the wildtype protein. |
| Remarks |
Ashkenazi; fibroblasts show grossly abnormal storage bodies and normal levels of acid hydrolases; donor subject is homozygous for an A>G transition in the acceptor splice site of the third intron of the MCOLN1 gene [IVS3-2A>G] resulting in the skipping of exon 4; donor subject is also heterozygous for an A>G transition at nucleotide 1226 in exon 9 of the GBA gene [1226A>G] resulting in a substitution of serine for asparagine at codon 370 [Asn370Ser (N370S)].
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| Chen Y1,2, Jian J1, Hettinghouse A1, Zhao X3, Setchell KDR3, Sun Y3, Liu CJ4,5, Progranulin associates with hexosaminidase A and ameliorates GM2 ganglioside accumulation and lysosomal storage in Tay-Sachs disease J Mol Med96:1359-1373 2018 |
| PubMed ID: 30341570 |
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| Xu M, Liu K, Swaroop M, Sun W, Dehdashti SJ, McKew JC, Zheng W, A phenotypic compound screening assay for lysosomal storage diseases Journal of biomolecular screening19:168-75 2013 |
| PubMed ID: 23983233 |
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| Kalman L, Wilson JA, Buller A, Dixon J, Edelmann L, Geller L, Highsmith WE, Holtegaard L, Kornreich R, Rohlfs EM, Payeur TL, Sellers T, Toji L, Muralidharan K, Development of genomic DNA reference materials for genetic testing of disorders common in people of ashkenazi jewish descent The Journal of molecular diagnostics : JMD11:530-6 2009 |
| PubMed ID: 19815695 |
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| Berman ER, Livni N, Shapira E, Merin S, Levij IS, Congenital corneal clouding with abnormal systemic storage bodies: a new variant of mucolipidosis. J Pediatr84:519-26 1974 |
| PubMed ID: 4365943 |
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