Molecular Biology Understanding Tay Sachs Disease

Hex A is composed of two polypeptide subunits, one called a and one called 3 (Figure 1). One other form of the enzyme, Hex B, is composed of two 3 subunits. In Tay-Sachs disease, it is the a subunit that is mutated so that patients have a defective Hex A, while Hex B remains unaffected. However, Hex B is not active toward GM2 ganglioside and can not substitute for Hex A. Some patients have a disease similar to Tay-Sachs, with the absence of both Hex A and Hex B. This condition, now called Sandhoff disease, was first described by Konrad Sandhoff in the 1960s and is due to mutations in the 3 subunit.

One more protein is involved in the disease. It is called the GM2 activator and is essential to the breakdown of GM2 ganglioside. The protein forms a complex with the GM2 ganglioside, converting the GM2 from a hydrophobic, membrane-liking molecule to one that is hydrophilic (water loving) so that it can be successfully hydrolyzed by Hex A in the lysosome. Mutations in the GM2 activator gene, called GM2A, can also cause a Tay-Sachs-like disease, although it is exceedingly rare.

In sum, mutations in any of three genes can cause the disease: HEXA, HEXB, or GM2A. As a group, patients with any of these diseases are said to have GM2 gangliosidosis. Tay-Sachs disease refers specifically to the most common form of the disease, caused by mutations in the HEXA gene.

The HEXA gene is one of about 30,000 to 70,000 genes in the human genome. It is of average size at about 35,000 base pairs in length and contains fourteen exons. The remainder of the gene is made up of thirteen introns that separate the exons from one another. Extensive research has given us a clear picture how the enzyme is synthesized, processed through the endoplasmic reticulum and Golgi network of the cell, and sent to the lysosome. This understanding of the cell biology of Hex A has had an important impact on our understanding of mutations in Tay-Sachs disease. Some affect enzyme function, that is, they occur near the "active" site of the enzyme and block its activity, while others affect the biosynthetic processing of the protein. The latter type of mutations may not affect enzyme activity at all. but causes disease because the enzyme fails to reach the lysosome to carry out its biological role.

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