The GM2 gangliosidoses are a group of recessive disorders, which lead to the accumulation of GM2 ganglioside in neuronal cells. The genes responsible for these disorders are HEXA (Tay-Sachs disease and variants), HEXB (Sandhoff disease and variants) and GM2A (AB variant of GM2 gangliosidosis). We have established three relational locus-specific databases recording allelic variation at the HEXA, HEXB and GM2A genes, and these can be accessed through the G M2 Gangliosidoses home page (http://data.mch.mcgill.ca/gm2-gangliosidoses/). The purpose of these databases is to collect and distribute information on mutations in the genes responsible for GM2 gangliosidosis. These databases are available online for users to search and retrieve information about specific mutations either by mutation, phenotype or author(s). In addition, submission forms are available for the addition of new mutations to the databases. / In order to provide information concerning the effects of mutations on the manifestations of disease, we proceeded to model on the theoretical model of the alpha subunit a few missense mutations. (Abstract shortened by UMI.)

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The major beta-hexosaminidase isozymes in humans are Hex A (deficient in Tay-Sachs disease, TSD), an alphabeta heterodimer and Hex B (deficient in Sandhoff disease) a betabeta homodimer. Hex S, the alphaalpha homodimer is physiologically unstable. Mature alpha and beta subunits share 60% sequence identity. The beta subunit active site hydrolyzes neutral substrates. The alpha subunit active site hydrolyzes neutral (4MUG) and charged substrates (4MUGS, GM2 ganglioside). Only Hex A hydrolyzes the natural substrate, GM2 ganglioside, in the presence of the GM2 activator protein (AP). / We investigated regions of the alpha and beta subunits involved in AP binding, subunit dimerization, and substrate specificity. We constructed four chimeric cDNAs: alpha1--259beta292--544 , alpha1--118beta152--544, beta 1--418alpha387--529, and beta1--151 alpha119--259beta292--544 (subscripts refer to amino acid residues). Chimeric cDNAs were expressed in a TSD neuroglial cell line, which produces no endogenous alpha subunits. The chimeric isozymes were chromatofocused and assayed for hydrolysis of (a) 4MUG, (b) 4MUGS and (c) GM2 ganglioside. / Transfection of the cDNA constructs lead to expression of homodimeric and heterodimeric chimeric proteins, albeit at lower yields than transfection of wild alpha-cDNA. All of the chimeric proteins hydrolyzed 4MUG but none were active towards 4MUGS or GM2 ganglioside. These results suggest that (a) all constructs contained sufficient information to form both heterodimeric and homodimeric chimeric proteins, (b) the chimeras lacked the alpha-subunit sequence necessary for the hydrolysis of charged substrates.

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