MUTATIONS IN THE LYSOSOMAL BETA-GALACTOSIDASE GENE THAT CAUSE THE ADULT FORM OF GMI GANGLIOSIDOSIS

Three adult patients with acid beta-galactosidase deficiency/GM1 gangl iosidosis who were from two unrelated families of Scandinavian descent were found to share a common point mutation in the coding region of t he corresponding gene. The patients share common clinical features, in cluding early dysarthria, mild ataxia, and bone abnormalities. When cD NA from the two patients in family 1 was PCR amplified and sequenced, most (39/41) of the clones showed a C-to-T transition (C --> T) at nuc leotide 245 (counting from the initiation codon). This mutation change s the codon for Thr(ACG) to Met(ATG). Mutant and normal sequences were also found in that position in genomic DNA, indicating the presence o f another mutant allele. Genomic DNA from the patient in family 2 reve aled the same point mutation in one allele. It was determined that in each family only the father carried the C --> T mutation. Expression s tudies showed that this mutation produced 3%-4% of beta-galactosidase activity, confirming its deleterious effects. The cDNA clones from the patients in family 1 that did not contain the C --> T revealed a 20-b p insertion of intronic sequence between nucleotides 75 and 76, the lo cation of the first intron. Further analysis showed the insertion of a T near the 5' splice donor site which led to the use of a cryptic spl ice site. It appears that the C --> T mutation results in enough funct ional enzyme to produce a mild adult form of the disease, even in the presence of a second mutation that likely produces nonfunctional enzym e.