beta-Galactosidase gene mutations in patients with slowly progressive GM1 gangliosidosis.

Three unrelated North American cases with slowly progressive forms of GM1 gangliosidosis were found to have two unique point mutations and a 9 bp insertion in the coding region of the gene encoding beta-galactosidase. Case 1 was noted to have a 9 bp insertion ¿CAGAATTTT¿ on one allele between nucleotides 730 and 731 with no other mutations identified in the other allele. In case 2, two point mutations were found: a unique G-->A transition at nucleotide 602 causing an Arg-->His substitution in codon 201 (mutation R201H); and a previously identified G-->T transition at nucleotide 1527 causing a Trp-->Cys substitution in codon 509 (mutation W509C), which has been noted in adult and chronic forms of GM1 gangliosidosis. Case 3 had a unique point mutation (A-->G transition at nucleotide 797) resulting in a Asn-->Ser amino acid substitution in codon 266 (mutation N266S), with no other mutations found in the same or the other allele. Single-strand conformation polymorphism performed on over 100 controls did not demonstrate the presence of the point mutations R201H or N266S. Also, the mutant proteins coded by the two point mutations did not show enzymatic activity in the Cos-1 cell expression system confirming that these mutations are associated with low enzyme activity.