A point mutation in the coding sequence of the beta-hexosaminidase alpha gene results in defective processing of the enzyme protein in an unusual GM2-gangliosidosis variant.

cDNA clones were isolated from cultured fibroblasts of a patient previously reported as having GM2-gangliosidosis due to defective processing of the precursor beta-hexosaminidase alpha chain. Sequence analysis of a clone containing the entire protein coding sequence showed a single nucleotide substitution, from G to A, at nucleotide residue no. 1444, which resulted in a change in amino acid residue no. 482, from the normal glutamic acid to lysine. This transversion was confirmed in two other cDNAs from the same unamplified library. The results collectively indicate that the change from the strongly negative to strongly positive charge at amino acid residue no. 482 is responsible for the defective processing of the enzyme in this patient.