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An unusual genotype in an Ashkenazi Jewish patient with Tay‐Sachs disease
Author(s) -
Shore Shirah,
Tomczak Jerzy,
Grebner Eugene E.,
Myerowitz Rachel
Publication year - 1992
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.1380010606
Subject(s) - tay sachs disease , exon , genetics , biology , point mutation , mutation , stop codon , population , allele , genotype , founder effect , splice , gene , disease , medicine , haplotype , pathology , environmental health
The Ashkenazi Jewish population is enriched for carriers of a fatal form of Tay‐Sachs disease, a recessive inherited disorder caused by mutations in the α‐chain of the lysosomal enzyme β‐hexosaminidase A. Approximately 20% of the Ashkenazi carriers harbor a splice junction defect while about 78% bear a 4 base pair (bp) insertion. However, the Ashkenazi Jewish patient used in the original description of the 4 bp insertion carried this lesion in only 1 allele and was negative for the splice junction mutation. We cloned the insertion negative allele and by sequence analysis of the exons found a point mutation in exon 11 that results in substitution of Trp 392 with a premature termination codon. Nine Ashkenazi Jewish carriers that tested negative for the major and minor mutations as well as for a lesion causing an adult form of Tay‐Sachs disease did not carry the base change defect, suggesting that it may be a recent and/or rare mutation. This finding also indicates that screening the Ashkenazi population solely by recombinant DNA methods for the splice junction, 4 bp insertion, and adult mutations may result in occasional false negatives. © 1992 Wiley‐Liss, Inc.