Molecular Genetics of β-N-Acetylhexosaminidase α Subunit Mutations

Abstract

Tay-Sachs disease is the prototype of human sphingolipidoses. Since the description of the disease a century ago, many other disorders have been added to the list. Generally, investigations of genetic sphingolipidoses have progressed through several distinct stages; clinicopathological descriptions, identification of the chemical nature of affected lipids, identification of the underlying enzymatic defects, and most recently characterization of the diseases on the level of nucleic acids. In Tay- Sachs disease, the second stage arrived when Klenk discovered the new class of lipids, gangliosides, in brains of patients [1], although the exact structure of GM2-ganglioside (Tay-Sachs ganglioside) was not established for thirty more years [2,3]. The primary genetic defect was traced to deficient activity of N-acetyl β-hexosaminidase A (hexosaminidase A) in 1969 [4,5]. Studies on the subunit structure of hexosaminidase A and B clarified that hexosaminidase A is a heterodimer consisting of the a and β subunits and that the genetic defect in Tay-Sachs disease resides in the a subunit. Detailed enzymological studies began to show heterogenous nature of the a mutation. For example, a patient with a juvenile form of the disease was shown to have a partial defect of hexosaminidase A with a disproportionate loss of activity toward the natural substrate, GM2-ganglioside [6-8]. By that time, both hexosaminidase isozymes were purified and immunological investigations with antibodies further indicated complex heterogeneity of the so-called Tay-Sachs disease. The classical Tay-Sachs disease prevalent among the Ashkenazi Jewish population and some other severe infantile forms were shown to lack immunologically reactive hexosaminidase a protein, while some variant forms proved to produce immunoloigically detectable but catalytically defective enzyme protein [9]. It became clear that these phenotypic complexities can only be understood definitively when abnormalities in the hexosaminidase a subunit are clarified on the level of the nucleic acids.