The major mutation among Japanese patients with infantile Tay-Sachs disease: a G-to-T transversion at the acceptor site of intron 5 of the beta-hexosaminidase alpha gene.

A G-to-T substitution at the 3'-splice site of intron 5 in the beta-hexosaminidase alpha-subunit gene has been identified among Japanese patients with infantile Tay-Sachs disease. Of the 24 patients from 24 unrelated families, 15 were homozygous and 8 were heterozygous for this mutation (38/48 mutant alleles). The mutation causes a splicing abnormality, and the resultant mRNA lacks the exon 6 sequence. Northern blot analysis showed a single band of mRNA, distinctly shorter in size and slightly smaller in quantity than normal. Since exon 6 consists of 102 nucleotides, the mRNA should generate a beta-hexosaminidase alpha-subunit missing 34 amino acids in the middle but otherwise normal in the primary structure. It must be catalytically inactive or unstable, or both. The high frequency of this mutation among the Japanese patients with the infantile form of Tay-Sachs disease and its apparent absence outside of Japan suggests that this mutation may have originated in Japan.