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.

Overexpression of miR-29 Leads to Myopathy that Resemble Pathology of Ullrich Congenital Muscular Dystrophy

“…The Col6a1 mutant Landseer dogs can reproduce the human UCMD phenotype, and zebrafish model constructed by mutating Col6a1 can also mimic the human phenotype [34,35,36]. So far, no studies have been able to explain why Col6a1 mutations are so variable in different species [6].…”

COL6A1 related muscular dystrophy in Landseer dogs: A canine model for Ullrich congenital muscular dystrophy

“…We previously identified the presumed causative genetic defect in the COL6A1 gene in Landseer dogs with a severe muscular dystrophy and provided an initial limited characterization of the clinical and histopathological phenotype. All affected dogs were homozygous for the mutant allele at a nonsense variant in COL6A1 , p.Glu97* 24 …”

Tendon Extracellular Matrix Alterations in Ullrich Congenital Muscular Dystrophy

“…Animal models of COLVI myopathies have been developed in mice (Bonaldo et al, 1998 ; Pan et al, 2013 ) and zebrafish (Telfer et al, 2010 ; Zulian et al, 2014 ). Recently, a nonsense variant in COL6A1 −/− has been detected in Landseer dogs (Steffen et al, 2015 ). COL6A1 mice, a COLVI null model (Bonaldo et al, 1998 ), and COL6A3 deficient mice (Pan et al, 2013 ) develop a mild myopathy and tendon dysfunction possibly due to altered tendon fibrillogenesis (Izu et al, 2011 ; Pan et al, 2013 ).…”