Tay-Sachs disease

In 1991, with the use of a cDNA clone, it was determined the alpha chain gene is located at 15q23-q24(Nakai et al, 1991). All forms of Tay-Sachs disease are caused by mutations in the alpha chain of the enzyme(Navon et al, 1989). The alpha chain of B-hexosaminidase A is about 35 kilobases long and split into 14 exons(Proia and Soravia, 1987).
             There are at least thirty different mutations that cause Tay-Sachs disease. A majority of the classical (infantile) form of the disease that is found in the Ashkenazi Jewish population is caused by one of two different gene mutations( Triggs-Raine et al, 1990). .
             The first one, Tay Sachs disease [HexA, 4-BP INS, EX11] accounts for about 70% of heterozygous carriers in the Ashkenazi population. The mutation introduces a 4-basepair insertion into exon 11, which causes a premature termination signal. This results in a deficiency of mRNA. The 4-basepair insertion causes a frameshift which makes a termination codon 9 nucleotides down from the insertion (Myerowitz and Costigan, 1988). .
             This mutation is also prevelant in the southwest Louisiana Cajun population. In the last three decades, 8 infants from 6 unrelated families have been diagnosed with Tay-Sachs disease. With 12 heterozygous carriers in the 6 families identified, 11 were carriers of the exon 11 mutation. The other mutation was of a form of Tay-Sachs disease found in the French-Canadian populations. .
             The second mutation is Tay-Sachs disease [HexA, IVS< G-C, +1]. It is found in 20% of Ashkenazi patients and carriers. It is a G-C base substitution in the first nucleotide of intron 12. This results in defective splicing of the mRNA(Arpaia et al, 1988). .
             Another form of Tay-Sachs disease is Adult onset Tay-Sachs [HexA, GLY269SER]. This form of Tay-Sachs is caused by an amino acid substitution in the alpha chain of the B-hexosaminidase A molecule. Glycine is substituted serine at position 269 in the HexA subunit.