The+HEXA+Gene

The HEXA gene, is located on the long arm (also called the q arm) of human chromosome 15 (as seen below) at the cytogenetic location 15q24.1 (notice the 15 refers to the chromosome and the q refers to the arm of the chromosome). The gene is 32742 base pairs long ("Genetics Home Reference-HEXA," 2008).



The HEXA gene codes for one part of the hexosaminidase A protein, called the alpha subunit. Mutations in the HEXA gene can lead to production of a deficient alpha subunit, which is required for hydrolysis of GM2 gangliosides in neuronal lysosomes. There are more than 120 identified mutations that lead to Tay-Sachs disease. Many mutations have been found to be highly conserved in certain populations. For example, over 90% of North American Ashkenazi Jew carriers have been found to carry only two of the 120 mutations, either a splice site mutation between exon 12 and intron 12 of HEXA, or a 4 base pair insertion in exon 11, a nonsense mutation which codes for a premature STOP codon Landels, E.C., et. al, 1991).

The fact that the genetic mutations are highly conserved in specific populations may lead to inferences of a heterozygous advantage, which is a phenomenon in which a deleterious, or "bad" trait, is actually selected for in heterozygous individuals, meaning that the homozygous genotype will result in a lethal phenotype (in which the individual will have NO selective advantage because they will die before reproductive age, as with TSD), but the heterozygous genotype, which results in a largely normal (at least non-lethal) phenotypic expression, leads to a selective advantage in some other way. The popular hypothesis of heterozygous advantage explaining the increased prevalence of the mutated allele in the Ashkenazi Jewish populations in North America was that it led to a selective advantage against tuberculosis. Although this hypothesis is hard to examine, chi-square and other statistical studies of these populations and their mortality rates over defined areas and periods of time show no significant advantage against tuberculosis (Spyropoulos, B., Moens, P.B., Davidson, J., & Lowden, J.A., 1981).

Instead, the conservation of these deleterious alleles in the given populations is more likely caused by a combination of founder effect and genetic drift.

GM2 gangliosidosis can also be caused by mutations of two other genes, HEXB and GM2A, both located on chromosome 5. These genes code for the beta subunit of hexosaminidase A and the GM2 activating cofactor, respectively. Although they result in clinically indistinguishable symptoms, they result in Sandhoff disease and AB variant, both of which were diagnosed as Tay-Sachs until modern molecular biology and genetic screening techniques were developed.





Back to Tay-Sachs (Home)

Hexosaminidase A

HEXA Gene and Hexosaminidase A Protein--Phylogenetic Analysis

HEXA Protein Interactions

Tay Sachs Overview and History

GM2 Gangliosidosis Symptoms

GM2 Gangliosides and Sphingolipidoses Pathway

Materials and Methods

References