The molecular basis of null alleles was investigated by cDNA polymerase chain reaction (PCR) in seven Tay-Sachs patients. Although mRNAs were undetectable by Northern blot, cDNA-PCR amplification allowed us to get a sufficient amount of cDNA to characterize abnormal transcripts. In two French patients (one homozygote and one compound heterozygote with a 4-bp insertion in exon 11 of the second allele) suffering an infantile form of the disease, we detected abnormal RNAs with a 17-bp insertion due to a GT to AT transition at the donor site of intron 9, resulting in the activation of a cryptic donor site in the intron. This mutation has been found in 9 out of 82 Tay-Sachs chromosomes (11%) in association with alleles responsible from different clinical courses. In the other five patients we found the 4-bp insertion in exon 11 and two nonsense mutations.

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