Originally published as Genetics Published Articles Ahead of Print on June 8, 2005.

Genetics, Vol. 170, 1857-1861, August 2005, Copyright © 2005
doi:10.1534/genetics.105.042580

A Duplication in the Canine ß-Galactosidase Gene GLB1 Causes Exon Skipping and GM1-Gangliosidosis in Alaskan Huskies

Robert Kreutzer*, Tosso Leeb{dagger},1, Gundi Müller*, Andreas Moritz{ddagger} and Wolfgang Baumgärtner*

* Department for Pathology, University of Veterinary Medicine, 30559 Hannover, Germany
{dagger} Department for Animal Breeding and Genetics, University of Veterinary Medicine, 30559 Hannover, Germany
{ddagger} Clinic for Small Animals, Internal Medicine, Justus Liebig University, 35392 Giessen, Germany

1 Corresponding author: Department for Animal Breeding and Genetics, University of Veterinary Medicine, Bünteweg 17p, 30559 Hannover, Germany.
E-mail: tosso.leeb{at}tiho-hannover.de

GM1-gangliosidosis is a lysosomal storage disease that is inherited as an autosomal recessive disorder, predominantly caused by structural defects in the ß-galactosidase gene (GLB1). The molecular cause of GM1-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 GM1-gangliosidosis occurs.