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Tay‐Sachs disease‐causing mutations and neutral polymorphisms in the Hex A gene
Author(s) -
Myerowitz Rachel
Publication year - 1997
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/(sici)1098-1004(1997)9:3<195::aid-humu1>3.0.co;2-7
Subject(s) - biology , genetics , tay sachs disease , frameshift mutation , exon , missense mutation , population , nonsense mutation , mutation , gene , microbiology and biotechnology , disease , medicine , environmental health , pathology
Tay‐Sachs disease is an autosomal recessive disorder affecting the central nervous system. The disorder results from mutations in the gene encoding the α‐subunit of β‐hexosaminidase A, a lysosomal enzyme composed of α and β polypeptides. Seventy‐eight mutations in the Hex A gene have been described and include 65 single base substitutions, one large and 10 small deletions, and two small insertions. Because these mutations cripple the catalytic activity of β‐hexosaminidase to varying degrees, Tay‐Sachs disease displays clinical heterogeneity. Forty‐five of the single base substitutions cause missense mutations; 39 of these are disease causing, three are benign but cause a change in phenotype, and three are neutral polymorphisms. Six nonsense mutations and 14 splice site lesions result from single base substitutions, and all but one of the splice site lesions cause a severe form of Tay‐Sachs disease. Eight frameshift mutations arise from six deletion‐ and two insertion‐type lesions. One of these insertions, consisting of four bases within exon 11, is found in 80% of the carriers of Tay‐Sachs disease from the Ashkenazi Jewish population, an ethnic group that has a 10‐fold higher gene frequency for a severe form of the disorder than the general population. A very large deletion, 7.5 kilobases, including all of exon 1 and portions of DNA upstream and downstream from that exon, is the major mutation found in Tay‐Sachs disease carriers from the French Canadian population, a geographic isolate displaying an elevated carrier frequency. Most of the other mutations are confined to single pedigrees. Identification of these mutations has permitted more accurate carrier information, prenatal diagnosis, and disease prognosis. In conjunction with a precise tertiary structure of the enzyme, these mutations could be used to gain insight into the structure‐function relationships of the lysosomal enzyme. Hum Mutat 9:195–208, 1997. © 1997 Wiley‐Liss, Inc.