Tay-Sachs disease: intron 7 splice junction mutation in two Portuguese patients

A single nucleotide transversion (G-->C) in the 5' donor site of intron 7 of the beta-hexosaminidase alpha-chain gene was identified in two Portuguese patients with infantile Tay-Sachs disease. One patient was found to be homozygous and the other a compound heterozygote with the four-base insertion in exon 11 on the other allele. In fibroblasts from the homozygous patient the beta-hexosaminidase alpha mRNA was observed as a nearly undetectable fast migrating band. Through cDNA-PCR amplification and hybridization with full length alpha cDNA several fragments of smaller size than the normal transcript were detected, most of them lacking exon 7. We propose that this point mutation in the 5' donor site of intron 7 of the beta-hexosaminidase alpha-chain gene is responsible for an inefficient and abnormal processing of the mutant transcript, resulting in functional abnormality.