Molecular genetics of GM₁β‐galactosidase

Abstract

The molecular genetics of GM1β‐galactosidase is reviewed. This enzyme exists in two forms, A and B. Form A is monomeric with a molecular weight of 72,000 and appears to be coded by a single autosomal locus. Form B is polymeric and cross‐reacts with anti‐A antibodies; it is coded wholly or in part by the same locus that codes for A. The simultaneous loss of A and B in GM1 gangliosidosis is explained. None of the other β‐galactosidases, including neutral β‐galactosidase, ceramide lactoside β‐galactosidase or cerebroside β‐galactosidase cross‐react with anti‐A antibodies, demonstrating that they are coded by loci separate from A. GM1, β‐galactosidase A is heterocatalytic, cleaving β‐Dgalactose from ganglioside GM1, lactose, N‐acetyllactosamine, and galactose‐containing glycoproteins such as asialofetuin, red cell stromal glycoproteins and keratan sulfate. The pleotropic effects of a single mutation affecting the locus for β‐galactosidase A can be explained by a one gene: one polypeptide: many substrates model. Phenotypic variability among β‐galactosidase A mutants may result from better residual activity of the mutant enzyme for one substrate than for another. Patients with normal intelligence and severe bony deformities, who are homozygous for a mutation affecting the enzyme, illustrate this point. Thus far all human mutants for GM1, β‐galactosidase studied are structural mutants, synthesizing nearly normal quantities of mutant enzyme; one is a proven Km mutant, the others are very likely so.

Spondyloepiphyseal dysplasia, corneal clouding, normal intelligence and acid β‐galactosidase deficiency

“…The clear inclusions noted in skin biopsies from patients with Type 1 GM1 gangliosidosis (O'Brien et al 1975) were not evident. These were U-shaped, round or irregular, some as large as 1 pm, and werc comprised of lamellae with alternating light and dense lines with a periodicity of 56 A.…”

“…Thus, a mutation giving rise to a profound deficiency of the enzyme can simul-taneously lead to the storage of multiple substrates (O'Brien 1975). In all, normal (3-galactosidase activities were found.…”

Mucolipidosis II and III: different residual activity of beta‐galactosidase in cultured fibroblasts*

“…The beta-galactosidase deficiency is apparently not the fundamental metabolic defect in ICD; this is because fibroblasts from obligatory heterozygotes have a normal instead of an intermediate activity of beta-galactosidase; and because this enzyme is only one of several acid hydrolases deficient in I-cells. data on GM,-gangliosidosis in a similar experimental format (O'Brien 1975, O'Brien et al 1976). This contention is supported by the correlation already discussed and by comparing the findings with the natural substrates with recent Table 3 Specific activity of beta-D-galactosidase in supernatants of fibroblast homogenates, assayed with artificial and natural substrates * Expressed as nrnol of p-nitrophenol released per mg proteinlh at 37°C.…”

Non‐progressive psychomotor retardation in a child with severe deficiency of arylsulphatase A activity

“…It is postulated that these pseudodeficiencies are the result of different mutations at the same gene locus, causing distinct clinical pictures (O'Brien 1975, Pennock & Barnes 1976.…”