title: A duplication in the canine beta-galactosidase gene GLB1 causes exon skipping and GM1-gangliosidosis in Alaskan huskies.
abstract: GM(1)-gangliosidosis is a lysosomal storage disease that is inherited as an autosomal recessive disorder, predominantly caused by structural defects in the beta-galactosidase gene (GLB1). The molecular cause of GM(1)-gangliosidosis in Alaskan huskies was investigated and a novel 19-bp duplication in exon 15 of the GLB1 gene was identified. The duplication comprised positions +1688-+1706 of the GLB1 cDNA. It partially disrupted a potential exon splicing enhancer (ESE), leading to exon skipping in a fraction of the transcripts. Thus, the mutation caused the expression of two different mRNAs from the mutant allele. One transcript contained the complete exon 15 with the 19-bp duplication, while the other transcript lacked exon 15. In the transcript containing exon 15 with the 19-bp duplication a premature termination codon (PTC) appeared, but due to its localization in the last exon of canine GLB1, nonsense-mediated RNA decay (NMD) did not occur. As a consequence of these molecular events two different truncated GLB1 proteins are predicted to be expressed from the mutant GLB1 allele. In heterozygous carrier animals the wild-type allele produces sufficient amounts of the active enzyme to prevent clinical signs of disease. In affected homozygous dogs no functional GLB1 is synthesized and G(M1)-gangliosidosis occurs.
authors.affiliation: Department for Pathology, University of Veterinary Medicine, 30559 Hannover, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Kreutzer
authors.forename: Tosso
authors.initials: T
authors.lastname: Leeb
authors.forename: Gundi
authors.initials: G
authors.lastname: Müller
authors.forename: Andreas
authors.initials: A
authors.lastname: Moritz
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baumgärtner
mesh_terms: D000483:Alleles; D000818:Animals; D001483:Base Sequence; D004285:Dogs; D005091:Exons; D016537:Gangliosidosis, GM1 / Q000209:etiology* / Q000235:genetics*; D020131:Genes, Duplicate; D012333:RNA, Messenger / Q000378:metabolism; D001616:beta-Galactosidase / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; D001616:beta-Galactosidase