title: An inversion of 25 base pairs causes feline GM2 gangliosidosis variant.
abstract: In G(M2) gangliosidosis variant 0, a defect in the beta-subunit of lysosomal beta-N-acetylhexosaminidase (EC 3.2.1.52) causes abnormal accumulation of G(M2) ganglioside and severe neurodegeneration. Distinct feline models of G(M2) gangliosidosis variant 0 have been described in both domestic shorthair and Korat cats. In this study, we determined that the causative mutation of G(M2) gangliosidosis in the domestic shorthair cat is a 25-base-pair inversion at the extreme 3' end of the beta-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 beta-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 G(M2) gangliosidosis variant 0 (Sandhoff disease).
authors.affiliation: Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL 36849-5525, USA. martidr@auburn.edu
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Martin
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Krum
authors.forename: G S
authors.initials: GS
authors.lastname: Varadarajan
authors.forename: Terri L
authors.initials: TL
authors.lastname: Hathcock
authors.forename: Bruce F
authors.initials: BF
authors.lastname: Smith
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Baker
mesh_terms: D000818:Animals; D000918:Antibody Specificity; D001483:Base Sequence; D015153:Blotting, Western; D002415:Cats; D002478:Cells, Cultured; D007446:Chromosome Inversion; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D054819:Hexosaminidase B; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008969:Molecular Sequence Data; D021122:Protein Subunits / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012497:Sandhoff Disease / Q000235:genetics*; D001619:beta-N-Acetylhexosaminidases / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D021122:Protein Subunits; D054819:Hexosaminidase B; D001619:beta-N-Acetylhexosaminidases