An inversion of 25 base pairs causes feline GM2 gangliosidosis variant 0

Abstract

In GM2 gangliosidosis variant 0, a defect in the β-subunit of lysosomal β-N-acetylhexosaminidase (EC 3.2.1.52) causes abnormal accumulation of GM2 ganglioside and severe neurodegeneration. Distinct feline models of GM2 gangliosidosis variant 0 have been described in both domestic shorthair and Korat cats. In this study, we determined that the causative mutation of GM2 gangliosidosis in the domestic shorthair cat is a 25-base-pair inversion at the extreme 3′ end of the β-subunit (HEXB) coding sequence, which introduces three amino acid substitutions at the carboxyl terminus of the protein and a translational stop that is eight amino acids premature. Cats homozygous for the 25-base-pair inversion express levels of β-subunit mRNA approximately 190% of normal and protein levels only 10–20% of normal. Because the 25-base-pair inversion is similar to mutations in the terminal exon of human HEXB, the domestic shorthair cat should serve as an appropriate model to study the molecular pathogenesis of human GM2 gangliosidosis variant 0 (Sandhoff disease).