Normal transcription of the beta-hexosaminidase alpha-chain gene in the Ashkenazi Tay-Sachs mutation.

Tay-Sachs disease is a biochemically heterogeneous lysosomal storage disorder caused by lack of the A isoenzyme of beta-hexosaminidase; the underlying defect is a mutation in the gene encoding the alpha-chain. It has been shown that fibroblasts isolated from Tay-Sachs patients of Ashkenazi Jewish origin contain no alpha-chain mRNA detectable on Northern blots. We now have compared run-on transcription in nuclei isolated from three strains of Ashkenazi Tay-Sachs fibroblasts and from a strain of normal (IMR90) cells. Using alpha-chain and beta-chain cDNAs as probes, we found no difference in the relative amount of [32P]ribonucleotide added to nascent transcripts; the average ratio of alpha/beta hybridizable radioactivity was 1.3 and 1.4 for mutant and normal cells, respectively. The identity of the Tay-Sachs alpha-chain transcript was confirmed by competition hybridization with excess alpha-chain mRNA. The results indicate that the Ashkenazi Tay-Sachs mutation permits a normal level of transcription of the alpha-chain gene and points to a posttranscriptional defect, such as RNA processing, transport, or stability.