TAY-SACHS DISEASE-CAUSING MUTATIONS AND NEUTRAL POLYMORPHISMS IN THE HEX-A GENE

Tay Sachs disease is an autosomal recessive disorder affecting the cen tral nervous system. The disorder results from mutations in the gene e ncoding the alpha-subunit of beta-hexosaminidase A, a lysosomal enzyme composed of alpha and beta polypeptides. Seventy eight mutations in t he Hex A gene have been described and include 65 single base substitut ions, one large and 10 small deletions, and two small insertions. Beca use these mutations cripple the catalytic activity of beta-hexosaminid ase to varying degrees, Tay Sachs disease displays clinical heterogene ity. Forty-five of the single base substitutions cause missense mutati ons; 39 of these are disease causing, three are benign but cause a cha nge in phenotype, and three are neutral polymorphisms. Six nonsense mu tations and 14 splice site lesions result from single base substitutio ns, 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 o f four bases within exon 11, is found in 80% of the carriers of Tay Sa chs 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, in cluding 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 a n 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 pro gnosis, In conjunction with a precise tertiary structure of the enzyme , these mutations could be used to gain insight into the structure-fun ction relationships of the lysosomal enzyme. (C) 1997 Wiley-Liss, Inc.