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  • Title: Ten novel mutations in the HEXA gene in non-Jewish Tay-Sachs patients.
    Author: Akli S, Chomel JC, Lacorte JM, Bachner L, Kahn A, Poenaru L.
    Journal: Hum Mol Genet; 1993 Jan; 2(1):61-7. PubMed ID: 8490625.
    Abstract:
    The heterogeneity of mutations causing Tay-Sachs disease in non-Jewish populations requires efficient techniques allowing the simultaneous screening for both known and novel mutations. beta-hexosaminidase mRNA isolated from cultured fibroblasts of 19 Tay-Sachs patients (7 with adult or late onset form of the disease and 12 with infantile Tay-Sachs disease) was amplified by cDNA-PCR in two overlapping segments spanning the entire coding sequence. We used chemical mismatch cleavage (CMC), denaturing gradient gel electrophoresis (DGGE) and direct sequencing of amplified fragments displaying a cleaved product or an altered melting behavior to screen the HEX A gene for mutations and to determine their distribution and frequency in the non-Jewish Tay-Sachs patients. These methods allowed us to identify 31 out of 38 alleles studied (82%). In addition to 9 previously described mutations (the 4 bp insertion in exon 11, G to A transitions at codons 170, 269, 482, 499 and 504, C to T transition at codon 499 and 504 and a GT to AT transition at the donor site of intron 9), we have identified 10 novel mutations. These include 1 donor splice site defect in intron 6, 8 missense mutations at non-randomly distributed conserved residues and a 2 bp deletion in exon 4. These results confirm the extreme molecular heterogeneity of mutations causing Tay-Sachs disease in non-Jewish population. The strategy used should be profitable for identifying mutations in large genes and for diagnostic purposes.
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