STRUCTURAL ORGANIZATION AND EXPRESSION OF THE MOUSE GENE ENCODING ALPHA-GALACTOSIDASE-A

alpha-Galactosidase A (alpha-D-galactoside galactohydrolase, EC 3.2.1. 22; alpha GalA) is a lysosomal enzyme that hydrolyses the alpha-D-gala ctosyl residues from glycosphingolipids. Fabry disease, an inherited X -linked recessive human metabolic disorder, results from a mutation in the alpha GalA gene at Xq22. As a prerequisite for generating a mouse model of Fabry disease by gene targeting, we have isolated and charac terized the mouse alpha GalA gene and cDNA. A cloned mouse alpha GalA cDNA encoded a putative precursor protein of 419 amino acids (aa), inc luding a 31-aa signal peptide (SP), The deduced aa sequence showed hig h homology (79%) with the human alpha GalA protein. Nucleotide sequenc e analysis of genomic clones revealed that the overall structure and o rganization of the gene was very similar to that of human alpha GalA. All exon-intron splice junctions conformed to the GT/AG consensus sequ ence. Comparison of genomic and cDNA sequences revealed the ocurrence of two putative polyadenylation signals whose alternative use results in the two mouse alpha GalA transcripts of 1.4 and 3.6 kb. The 5'-flan king region of mouse alpha GalA had no typical TATA box. Several putat ive promoter-associated elements including Sp1, AP1 and a potential cA MP-responsive element (CRE) were identified. Northern blot analysis re vealed the widespread tissue distribution of mouse alpha GalA transcri pts. Lower expression levels, however, were observed in some tissues, implying tissue-specific differences in alpha GalA promoter function.