title: A COL11A2 mutation in Labrador retrievers with mild disproportionate dwarfism.
abstract: We describe a mild form of disproportionate dwarfism in Labrador Retrievers, which is not associated with any obvious health problems such as secondary arthrosis. We designate this phenotype as skeletal dysplasia 2 (SD2). It is inherited as a monogenic autosomal recessive trait with incomplete penetrance primarily in working lines of the Labrador Retriever breed. Using 23 cases and 37 controls we mapped the causative mutation by genome-wide association and homozygosity mapping to a 4.44 Mb interval on chromosome 12. We re-sequenced the genome of one affected dog at 30x coverage and detected 92 non-synonymous variants in the critical interval. Only two of these variants, located in the lymphotoxin A (LTA) and collagen alpha-2(XI) chain gene (COL11A2), respectively, were perfectly associated with the trait. Previously described COL11A2 variants in humans or mice lead to skeletal dysplasias and/or deafness. The dog variant associated with disproportionate dwarfism, COL11A2:c.143G>C or p.R48P, probably has only a minor effect on collagen XI function, which might explain the comparatively mild phenotype seen in our study. The identification of this candidate causative mutation thus widens the known phenotypic spectrum of COL11A2 mutations. We speculate that non-pathogenic COL11A2 variants might even contribute to the heritable variation in height.
authors.affiliation: Vetsuisse Faculty, Institute of Genetics, University of Bern, Bern, Switzerland.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Frischknecht
authors.forename: Helena
authors.initials: H
authors.lastname: Niehof-Oellers
authors.forename: Vidhya
authors.initials: V
authors.lastname: Jagannathan
authors.forename: Marta
authors.initials: M
authors.lastname: Owczarek-Lipska
authors.forename: Cord
authors.initials: C
authors.lastname: Drögemüller
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Dietschi
authors.forename: Gaudenz
authors.initials: G
authors.lastname: Dolf
authors.forename: Bernd
authors.initials: B
authors.lastname: Tellhelm
authors.forename: Johann
authors.initials: J
authors.lastname: Lang
authors.forename: Katriina
authors.initials: K
authors.lastname: Tiira
authors.forename: Hannes
authors.initials: H
authors.lastname: Lohi
authors.forename: Tosso
authors.initials: T
authors.lastname: Leeb
mesh_terms: D000818:Animals; D002874:Chromosome Mapping / Q000662:veterinary; D024161:Collagen Type XI / Q000235:genetics*; D004283:Dog Diseases / Q000235:genetics* / Q000473:pathology*; D004285:Dogs; D004392:Dwarfism / Q000235:genetics / Q000473:pathology / Q000662:veterinary*; D005808:Genes, Recessive / Q000235:genetics; D055106:Genome-Wide Association Study / Q000662:veterinary; D005838:Genotype; D008233:Lymphotoxin-alpha / Q000235:genetics; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D017422:Sequence Analysis, DNA / Q000662:veterinary
chemical_list: D024161:Collagen Type XI; D008233:Lymphotoxin-alpha