Description:
NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE III; HSAN3
INHIBITOR OF KAPPA LIGHT POLYPEPTIDE GENE ENHANCER IN B CELLS, KINASE-COMPLEX ASSOCIATED PROTEIN; IKBKAP
GLUCOSIDASE, ACID BETA; GBA
HEXOSAMINIDASE A; HEXA
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Repository
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NIGMS Human Genetic Cell Repository
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| Subcollection |
Heritable Diseases |
| Class |
Disorders of the Nervous System |
| Quantity |
25 µg |
| Quantitation Method |
Please see our FAQ |
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Biopsy Source
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Peripheral vein
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Cell Type
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B-Lymphocyte
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Tissue Type
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Blood
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Transformant
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Epstein-Barr Virus
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Sample Source
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DNA from LCL
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Race
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White
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Ethnicity
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ASHKENAZI
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Family Member
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1
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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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| IDENTIFICATION OF SPECIES OF ORIGIN |
Species of Origin Confirmed by Nucleoside Phosphorylase, Glucose-6-Phosphate Dehydrogenase, and Lactate Dehydrogenase Isoenzyme Electrophoresis |
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| GENE MAPPING & DOSAGE STUDIES - Y CHROMOSOME |
PCR analysis of DNA from this cell culture gave a positive result with a primer for Yq11, DYS227. |
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| Gene |
IKBKAP |
| Chromosomal Location |
9q31 |
| Allelic Variant 1 |
603722.0001; FAMILIAL DYSAUTONOMIA |
| Identified Mutation |
c.2204+6T>C (IVS20+6T>C); Slaugenhaupt et al. (2001) found that more than 99.5% of disease alleles causing familial dysautonomia (223900) in Ashkenazi Jewish individuals carried a donor splice site mutation (IVS20+6T-C) which leads to deletion of exon 20 from mRNA. Haplotype analyses were consistent with a common founder. Anderson et al. (2001) identified the same mutation in Ashkenazi Jewish patients with familial dysautonomia. |
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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 |
HEXA |
| Chromosomal Location |
15q23-q24 |
| Allelic Variant 1 |
606869.0035; BETA-HEXOSAMINIDASE A, PSEUDODEFICIENCY OF |
| Identified Mutation |
ARG247TRP; Triggs-Raine et al. (1992) identified a C-to-T transition at nucleotide 739, resulting in an arg247-to-trp substitution as the basis of pseudodeficiency of beta-hexosaminidase A. This allele accounted for 32% (20/62) of non-Jewish enzyme-defined Tay-Sachs disease carriers but for none of 36 Jewish enzyme-defined carriers who did not have one of the 3 known mutations common to the Jewish group. In combination with a 'true' Tay-Sachs disease allele, the arg247-to-trp allele causes HEXA pseudodeficiency. Given both the large proportion of non-Jewish carriers with this allele and the fact that standard biochemical screening cannot differentiate between heterozygotes for the arg247-to-trp mutation and Tay-Sachs disease carriers, DNA testing for this mutation in at-risk couples is essential. Contrary to the findings of Triggs-Raine et al. (1992) of no cases of the C739-to-T pseudodeficiency allele among Jewish carriers, Tomczak et al. (1993) found that of 33 carriers who had none of the 3 common mutations, the pseudodeficiency mutation was present in 6 of 19 Jews and 8 of 14 non-Jews. Tomczak et al. (1993) suggested that DNA analysis should be part of a comprehensive screening program because 2 mutant alleles, the pseudodeficiency allele and the adult allele, are indistinguishable from the lethal infantile mutations by means of enzyme assay yet have very different phenotypic significance and together may account for as many as 12% of enzyme-defined carriers.
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| Gene |
HEXA |
| Chromosomal Location |
15q23-q24 |
| Allelic Variant 2 |
606869.0035; BETA-HEXOSAMINIDASE A, PSEUDODEFICIENCY OF |
| Identified Mutation |
ARG247TRP; Triggs-Raine et al. (1992) identified a C-to-T transition at nucleotide 739, resulting in an arg247-to-trp substitution as the basis of pseudodeficiency of beta-hexosaminidase A. This allele accounted for 32% (20/62) of non-Jewish enzyme-defined Tay-Sachs disease carriers but for none of 36 Jewish enzyme-defined carriers who did not have one of the 3 known mutations common to the Jewish group. In combination with a 'true' Tay-Sachs disease allele, the arg247-to-trp allele causes HEXA pseudodeficiency. Given both the large proportion of non-Jewish carriers with this allele and the fact that standard biochemical screening cannot differentiate between heterozygotes for the arg247-to-trp mutation and Tay-Sachs disease carriers, DNA testing for this mutation in at-risk couples is essential. Contrary to the findings of Triggs-Raine et al. (1992) of no cases of the C739-to-T pseudodeficiency allele among Jewish carriers, Tomczak et al. (1993) found that of 33 carriers who had none of the 3 common mutations, the pseudodeficiency mutation was present in 6 of 19 Jews and 8 of 14 non-Jews. Tomczak et al. (1993) suggested that DNA analysis should be part of a comprehensive screening program because 2 mutant alleles, the pseudodeficiency allele and the adult allele, are indistinguishable from the lethal infantile mutations by means of enzyme assay yet have very different phenotypic significance and together may account for as many as 12% of enzyme-defined carriers.
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| Gene |
IKBKAP |
| Chromosomal Location |
9q31 |
| Allelic Variant 2 |
603722.0001; FAMILIAL DYSAUTONOMIA |
| Identified Mutation |
c.2204+6T>C (IVS20+6T>C); Slaugenhaupt et al. (2001) found that more than 99.5% of disease alleles causing familial dysautonomia (223900) in Ashkenazi Jewish individuals carried a donor splice site mutation (IVS20+6T-C) which leads to deletion of exon 20 from mRNA. Haplotype analyses were consistent with a common founder. Anderson et al. (2001) identified the same mutation in Ashkenazi Jewish patients with familial dysautonomia. |
| Remarks |
Clinically affected; severe postural hypotension; episodic hypertension; muscular fasciculations of shoulders and arms occurred when erect for 10 minutes; bilateral tarsorraphies since age 5; dense corneal opacity on left; continual overflow tears in right eye; mild scoliosis; azotemia; BUN is 32 and creatinine is 1.6 (rising); persistent proteinuria; mild anemia; no vomiting problems; possible vagal irritation; nocturia; no acute respiratory problems; affected sister is GM09299; unaffected sister is GM09294; mother is GM09300; father is GM09301; donor subject is homozygous for the 2507+6T>C mutation in the IKBKAP gene; this donor splice site mutation (IVS20+6T>C) leads to deletion of exon 20 from the mRNA; 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)] [codons are numbered from the first codon of the mature protein; the cDNA is numbered from the first initiating AUG]; donor subject is also homozygous for a benign C>T mutation at nucleotide 739 in exon 7 of the HEXA gene (739C>T) resulting in the substitution of tryptophan for arginine at codon 247 [Arg247Trp (R247W)] |
| dbSNP |
dbSNP ID: 11243 |
| Gene Cards |
ELP1 |
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GBA |
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HEXA |
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IKBKAP |
| Gene Ontology |
GO:0004348 glucosylceramidase activity |
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GO:0004563 beta-N-acetylhexosaminidase activity |
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GO:0004871 signal transducer activity |
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GO:0005764 lysosome |
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GO:0005975 carbohydrate metabolism |
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GO:0006461 protein complex assembly |
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GO:0006468 protein amino acid phosphorylation |
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GO:0006665 sphingolipid metabolism |
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GO:0006687 glycosphingolipid metabolism |
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GO:0006955 immune response |
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GO:0007040 lysosome organization and biogenesis |
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GO:0008607 phosphorylase kinase regulator activity |
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GO:0016020 membrane |
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GO:0016798 hydrolase activity, acting on glycosyl bonds |
| NCBI Gene |
Gene ID:2629 |
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Gene ID:3073 |
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Gene ID:8518 |
| NCBI GTR |
223900 NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE III; HSAN3 |
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603722 ELONGATOR COMPLEX PROTEIN 1; ELP1 |
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606463 GLUCOSIDASE, BETA, ACID; GBA |
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606869 HEXOSAMINIDASE A; HEXA |
| OMIM |
223900 NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE III; HSAN3 |
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603722 ELONGATOR COMPLEX PROTEIN 1; ELP1 |
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606463 GLUCOSIDASE, BETA, ACID; GBA |
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606869 HEXOSAMINIDASE A; HEXA |
| Omim Description |
DYSAUTONOMIA, FAMILIAL; DYS |
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FD |
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HEREDITARY SENSORY AND AUTONOMIC NEUROPATHY III |
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HSAN-III |
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RILEY-DAY SYNDROME |
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