Molecular basis of adult-onset and chronic GM2 gangliosidoses in patients of Ashkenazi Jewish origin: substitution of serine for glycine at position 269 of the alpha-subunit of beta-hexosaminidase.
- 1 April 1989
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 86 (7), 2413-2417
- https://doi.org/10.1073/pnas.86.7.2413
Abstract
Chronic and adult-onset GM2 gangliosidoses are neurological disorders caused by marked deficiency of the A isoenzyme of .beta.-hexosaminidase; they occur in the Ashkenazi Jewish population, though less frequently than classic (infantile) Tay-Sachs disease. Earlier biosynthetic studies had identified a defective .alpha.-subunit that failed to associate with the .beta.-subunit. We have now found a guanosine to adenosine transition at the 3'' end of exon 7, which causes substitution of serine for glycine at position 269 of the .alpha.-subunit [designated 269 (Gly .fwdarw. Ser) substitution]. An RNase protection assay was used to localize the mutation to a segment of mRNA from fibroblasts of a patient with the adult-onset disorder. That segment of mRNA (after reverse transcription) and a corresponding segment of genomic DNA were amplified by the polymerase chain reaction and sequenced by the dideoxy method. The sequence analysis, together with an assay based on the loss of a ScrFI restriction site, showed that the patient was a compound heterozygote who had inherited the 269 (Gly .fwdarw. Ser) mutation from his father and an allelic null mutation from his mother. The 269 (Gly .fwdarw. Ser) mutation, in compound heterozygosity with a presumed null allele, was also found in fetal fibroblasts with an association-defective phenotype and in cells from five patients with chronic GM2 gangliosidosis. It was not found in .beta.-hexosaminidase A-deficient cells obtained from patients with infantile Tay-Sachs disease nor in cells from individuals who do not have .beta.-hexosaminidase A deficiency. However, there must be additional mutations with similar consequences, since the 269 (Gly .fwdarw. Ser) substitution was not present in fibroblasts from two patients with juvenile GM2 gangliosidosis even though these had an association-defective .alpha.-subunit.This publication has 32 references indexed in Scilit:
- A Point Mutation in the Coding Sequence of the β‐Hexosaminidase α Gene Results in Defective Processing of the Enzyme Protein in an Unusual GM2‐Gangliosidosis VariantJournal of Neurochemistry, 1988
- Hexosaminidase a deficiency manifesting as spinal muscular atrophy of late onsetAnnals of Neurology, 1988
- Identification of an altered splice site in Ashkenazi Tay-Sachs diseaseNature, 1988
- A splicing defect due to an exon-intron junctional mutation results in abnormal β-hexosaminidase α chain mRNAs in Ashkenazi Jewish patients with Tay-Sachs diseaseBiochemical and Biophysical Research Communications, 1988
- Primer-Directed Enzymatic Amplification of DNA with a Thermostable DNA PolymeraseScience, 1988
- Mutation in GM2‐Gangliosidosis B1 VariantJournal of Neurochemistry, 1988
- Adult-onset GM2 gangliosidosis diagnosed in a fetusPrenatal Diagnosis, 1986
- Detection of Single Base Substitutions by Ribonuclease Cleavage at Mismatches in RNA:DNA DuplexesScience, 1985
- Juvenile spinal muscular atrophy: A new hexosaminidase deficiency phenotypeAnnals of Neurology, 1982
- Adult GM 2 gangliosidosis in association with Tay‐Sachs diseaseNeurology, 1981