The genetic basis of Fabry disease

Abstract

The coding region of the α-galactosidase A gene (GLA) consists of 1290 base pairs, is divided into seven exons and defines a polypeptide of 429 amino acids. The great majority of disease-related GLA mutations are unique ('private'). We have compiled a list of 429 mutations of the GLA gene from the published literature, including 306 point mutations (missense, nonsense and those affecting splice sites), 115 'short-length' rearrangements (affecting fewer than 60 nucleotides) and eight gross rearrangements (affecting one or more exons). Based on the number of different changes at any nucleotide position, there is no obvious 'hot spot' for point mutations, although mutations of CpG dinucleotides account for the majority of recurrent point mutations seen in unrelated families with Fabry disease. Remarkably, about one-third of the short-length rearrangements occur in exon 7, which accounts for only 22% of the coding region, suggesting that this part of the gene is susceptible to rearrangement. The recent elaboration of a putative three-dimensional structure of α-galactosidase A by X-ray crystallography may provide a better insight into how the enzyme works at the molecular level. This knowledge has recently been used for computer modelling of the structure of α-galactosidase A mutants and may result in improved understanding of the molecular pathology of the mutated protein. It is hoped that an increased understanding of structure/function correlates will help to develop alternative therapies or adjuvant treatments for Fabry disease.