Late-onset G(m2) gangliosidosis: Ashkenazi Jewish family with an exon 5 mutation (Tyr(180)->His) in the Hex A alpha-chain gene

Late-onset G(M2) gangliosidosis is a variant form of Tay-Sachs disease characterized by onset of symptoms and signs in adolescence or in early adult life. The deficiency of beta-hexosaminidase A (Hex A) in this form of G(M2) gangliosidosis has been invariably associated with the presence of the Gly(269) --> Ser substitution in the alpha-chain. We found gangliosidosis who were negative for the two siblings of Ashkenazi Jewish descent diagnosed with late-onset G(M2) Gly(269) --> Ser mutation. Analysis of the HEXA. gene showed that they were compound heterozygotes for the functionally silent 4-bp insertion in exon 11, typical of the infantile form of the disease and for a novel mutation, T-538 --> C, resulting in the missense Tyr(180) --> His. Expression studies in COS-7 cells suggested that the effect of this mutation was to decrease the stability of the a-chain at physiologic temperatures and therefore to indirectly affect the formation of mature Hex A.