Tay-Sachs Disease

To date, nearly 100 mutations have been identified in Tay-Sachs disease. Ashkenazi Jews have two common mutations that cause the severe, infantile form of the disease. One, accounting for 80 percent of mutant alleles carried in the population, is the loss of four nucleotides in exon 11 of the gene. This causes a "frameshift" in the reading of the genetic code and the inability to generate a complete protein. The second mutation, accounting for about 15 to 18 percent of mutations, is a splice junction mutation, a defect in processing nuclear RNA to form the mature messenger RNA that makes its way to the cytoplasm to direct protein synthesis. When this mutation is present, splicing of intron 12 fails to occur properly, and a functional protein fails to be synthesized. In both cases, the result is the absence of the α subunit and hence Hex A.

Ashkenazi Jews and other populations also have mutations that cause amino acid substitutions. One such mutation, accounting for about 3 percent of mutations in Ashkenazi Jews, results in a glycine to serine substitution in exon 7. This mutant α subunit is synthesized and an abnormal Hex A is produced. It is sufficiently active so that patients with this mutation as one of their two mutant alleles have sufficient "residual" Hex A activity to produce a mild, adult form of the disease.

This finding of three predominant mutations causing Ashkenazi Jewish Tay-Sachs disease was unexpected. Most medical scientists thought a single mutation would have acted as a "founder" mutation and over time increased in frequency to the level at which it is found today. It is believed that the first Tay-Sachs mutation may have entered the population about 1000 years ago. It increased in frequency either by random genetic drift or possibly through selection for presence of the gene in heterozygous carriers. This latter interpretation is controversial, but it has been suggested that carriers might have been more resistant to tuberculosis than normal individuals so that they had a greater chance of surviving the epidemics of centuries ago, thereby resulting in a steady increase in the frequency of the mutant allele in Ashkenazi Jews. Another group with a founder mutation, a large deletion of the 5′ ("five prime," or front) end of the gene, are French Canadians from the Lac Saint-Jean region of Quebec.