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ABSTRACT

  • The GM2 gangliosidoses are a group of inherited disorders caused by excessive accumulation of ganglioside GM2 and related glycolipids in the lysosomes, mainly of neuronal cells. The enzymatic hydrolysis of ganglioside GM2 requires that it be complexed with a substrate-specific cofactor, the GM2 activator. There are two isoenzymes of β-hexosaminidase, Hex A, structure αβ, and Hex B, structure ββ where only Hex A can act on the ganglioside GM2/GM2 activator complex. Defects in any of three genes may lead to GM2 gangliosidosis: HEXA, which encodes the α-subunit of Hex A; HEXB, which encodes the β-subunit of Hex A and Hex B; or GM2A, which encodes the monomeric GM2 activator. There are three forms of GM2 gangliosidosis: (a) Tay-Sachs disease and variants, resulting from mutations of the HEXA gene, are associated with deficient activity of Hex A but normal Hex B; (b) Sandhoff disease and variants, resulting from mutations of the HEXB gene, are associated with deficient activity of both Hex A and Hex B; and (c) GM2 activator deficiency, due to mutation of the GM2A gene, is characterized by normal Hex A and Hex B but the inability to form a functional ganglioside GM2/GM2 activator complex. There are also pseudodeficient or clinically benign “disorders” characterized by biochemical defects of Hex A but functional activity toward ganglioside GM2. The gross pathology is very similar in Tay-Sachs disease, Sandhoff disease and GM2 activator deficiency, except that there is also involvement of the visceral organs in Sandhoff disease. The most pronounced cellular change is the presence of swollen neurons with storage material in lysosomes throughout the nervous system. Characteristic inclusions are the so-called membranous cytoplasmic bodies.

  • The hexosaminidases and GM2 activator are glycoproteins that are synthesized in the lumen of the endoplasmic reticulum (ER) and processed through the Golgi. They are transported to the lysosome via the mannose-6-phosphate receptor where they are processed further to their final “mature” forms. β-hexosaminidase A (Hex A) and β-hexosaminidase B (Hex B) hydrolyze a broad spectrum of substrates that are specific for terminal GlcNAc or GalNAc residues in β-linkage. Active site residues and the mechanism of catalysis are being revealed through mutagenesis, photoaffinity labeling with substrate analogs, and studies of chimeric α-β enzyme. In addition to the hydrolysis of ganglioside GM2 by only Hex A, both isoenzymes will catabolize glycoproteins, glycosaminoglycans, and glycolipids. They will also hydrolyze synthetic substrates of which the most sensitive and commonly used is β-GlcNAc derivative of 4-methylumbelliferone (4MUG). It is recognized by both Hex A and Hex B and does not require the GM2 activator. Using 4MUG, Hex A and Hex B can be distinguished by taking advantage of different thermal or other characteristics of the isoenzymes. A related compound cleaved by Hex A (and Hex S), but not Hex B, is 4-methylumbelliferyl-GlcNAc-6-sulfate (4MUGS). Substrate such as 4MUG or 4MUGS are ...

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