Sequence variations in the first exon of alpha-galactosidase A.

The alpha-galactosidase A gene (GALA), which is deficient in males with Anderson-Fabry disease, is shown to be remarkably polymorphic in the 5' untranslated region. GALA contains seven exons. The first exon contains 60 bp of 5' untranslated sequence before the methionine initiation codon. Single strand conformation polymorphism (SSCP) screening has shown three polymorphic variants from the published sequence within the 60 base pairs. The sequence changes involved are C to T at -10, G to A at -12 (which removes an MspI site), and G to A at -30 (which removes a SacII site). The combined frequency of these is 10%. A further insertion-deletion polymorphism is detected by SSCP of a 400 bp fragment including exon 3. Both polymorphisms can be easily detected using small polyacrylamide gels and ethidium bromide staining. Nine of 20 women were informative for one of these polymorphisms and this simple SSCP analysis should be of great assistance in family studies of Anderson-Fabry disease. Such a high level of polymorphism has not been previously reported in the 5' untranslated region of a human gene and is unusual in any such short stretch of DNA.