17. Naturally occurring mutations in GM2 gangliosidosis: A compendium

Abstract

This chapter includes a discussion on naturally occurring mutations in G M2 gangliosidois: a compendium. The characterization of complementary DNA clones encoding the subunits of α-hexosaminidase (Hex) set the stage for delineating the mutation basis. Guided by elegant biochemical and genetic studies, these analyses rapidly progressed to other populations and individuals with variant forms of both Tay-Sachs and Sandhoff diseases. Two of the genes, Hex A (αβ) and Hex B (ββ) encode α and β subunits. The third gene, G M2 A, encodes the G M2 activator. Only Hex acting on the G M2 ganglioside–G M2 activator complex, hydrolyze the terminal N-acetylgalactosamine of G M2 ganglioside. Mutations in the Hex A gene, leading to deficiency of Hex A activity, cause Tay-Sachs disease or less severely affected variants. Mutations in the Hex B gene, leading to deficiency of both Hex A and Hex B activities, cause Sandhoff disease or its variants. Mutations in the G M2 A gene, leading to defects of the G M2 activator while retaining functional Hex A and Hex B, result in the AB variant of G M2 gangliosidosis. Other studies have described genetic and biochemical heterogeneity that has been largely accounted for the discovery of allelic diversity.