title: A Nonsense Variant in COL6A1 in Landseer Dogs with Muscular Dystrophy.
abstract: A novel canine muscular dystrophy in Landseer dogs was observed. We had access to five affected dogs from two litters. The clinical signs started at a few weeks of age, and the severe progressive muscle weakness led to euthanasia between 5 and 15 months of age. The pedigrees of the affected dogs suggested a monogenic autosomal-recessive inheritance of the trait. Linkage and homozygosity mapping indicated two potential genome segments for the causative variant on chromosomes 10 and 31 harboring a total of 4.8 Mb of DNA or 0.2% of the canine genome. Using the Illumina sequencing technology, we obtained a whole-genome sequence from one affected Landseer. Variants were called with respect to the dog reference genome and compared with the genetic variants of 170 control dogs from other breeds. The affected Landseer dog was homozygous for a single, private nonsynonymous variant in the critical intervals, a nonsense variant in the COL6A1 gene (Chr31:39,303,964G>T; COL6A1:c.289G>T; p.E97*). Genotypes at this variant showed perfect concordance with the muscular dystrophy phenotype in all five cases and more than 1000 control dogs. Variants in the human COL6A1 gene cause Bethlem myopathy or Ullrich congenital muscular dystrophy. We therefore conclude that the identified canine COL6A1 variant is most likely causative for the observed muscular dystrophy in Landseer dogs. On the basis of the nature of the genetic variant in Landseer dogs and their severe clinical phenotype these dogs represent a model for human Ullrich congenital muscular dystrophy.
authors.affiliation: Neurology Service, Department of Small Animals, Vetsuisse Faculty, University of Zurich, Winterthurerstrasse 260, 8057 Zurich, Switzerland.
authors.forename: Frank
authors.initials: F
authors.lastname: Steffen
authors.affiliation: Institute of Neuropathology, University Hospital Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bilzer
authors.affiliation: Institute of Neuropathology, University Hospital Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Brands
authors.affiliation: Neurology Service, Department of Small Animals, Vetsuisse Faculty, University of Zurich, Winterthurerstrasse 260, 8057 Zurich, Switzerland.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Golini
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland.
authors.forename: Vidhya
authors.initials: V
authors.lastname: Jagannathan
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland.
authors.forename: Michaela
authors.initials: M
authors.lastname: Wiedmer
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland.
authors.forename: Michaela
authors.initials: M
authors.lastname: Drögemüller
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland.
authors.forename: Cord
authors.initials: C
authors.lastname: Drögemüller
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland Tosso.Leeb@vetsuisse.unibe.ch.
authors.forename: Tosso
authors.identifier: http://orcid.org/0000-0003-0553-4880
authors.initials: T
authors.lastname: Leeb
mesh_terms: D000818:Animals; D002874:Chromosome Mapping; D018389:Codon, Nonsense; D024142:Collagen Type VI / Q000235:genetics*; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D056726:Genetic Association Studies; D008040:Genetic Linkage; D016678:Genome; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009136:Muscular Dystrophies / Q000175:diagnosis / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D024142:Collagen Type VI
keywords: Mendelian traits; animal model; dog; veterinary genetics; whole-genome sequencing