A Missense Mutation in the SERPINH1 Gene in Dachshunds with Osteogenesis Imperfecta

Abstract

Osteogenesis imperfecta (OI) is a hereditary disease occurring in humans and dogs. It is characterized by extremely fragile bones and teeth. Most human and some canine OI cases are caused by mutations in the COL1A1 and COL1A2 genes encoding the subunits of collagen I. Recently, mutations in the CRTAP and LEPRE1 genes were found to cause some rare forms of human OI. Many OI cases exist where the causative mutation has not yet been found. We investigated Dachshunds with an autosomal recessive form of OI. Genotyping only five affected dogs on the 50 k canine SNP chip allowed us to localize the causative mutation to a 5.82 Mb interval on chromosome 21 by homozygosity mapping. Haplotype analysis of five additional carriers narrowed the interval further down to 4.74 Mb. The SERPINH1 gene is located within this interval and encodes an essential chaperone involved in the correct folding of the collagen triple helix. Therefore, we considered SERPINH1 a positional and functional candidate gene and performed mutation analysis in affected and control Dachshunds. A missense mutation (c.977C>T, p.L326P) located in an evolutionary conserved domain was perfectly associated with the OI phenotype. We thus have identified a candidate causative mutation for OI in Dachshunds and identified a fifth OI gene.

Molecular Consequences of the SERPINH1/HSP47 Mutation in the Dachshund Natural Model of Osteogenesis Imperfecta

“…Its pivotal role in bone formation became evident when it was shown to cause a recessive form of OI in the dachshund (15) and then in humans (17). However, the disease mechanism is not well understood.…”

“…In dachshunds, a p.L326P mutation in HSP47 was found to cause a severe recessive form of OI characterized by marked osteopenia, thin bones with inhomogeneous and shallow trabeculation in the entire foreleg, joint hyperlaxity and undermineralization of the teeth (dentinogenesis imperfecta) (15). Previous clinical and histological investigations in OI dachshunds, performed before the mutation had been identified, have revealed bone fragility due to a paucity of cancellous and cortical lamellar bone (16).…”

A preliminary proteomic evaluation of smooth muscle cells in thoracic aortic aneurysms

“…Our data present evidence of a reduction in collagen protein levels (Col1A2, Table 1) that is accompanied by a reduction in SerpinH1/HSP47 levels, a protein involved in the correct folding of the collagen triple helix (Nagai et al, 2000). Although complete knockout of this gene is embryonically lethal (Nagai et al, 2000), mutations in SerpinH1 have been associated with other connective tissue disorders (Drogemuller et al, 2009;Christiansen et al, 2010). The proposed mechanism of action for SerpinH1 is via its interactions with triple-helical procollagen molecules that are distinct from protein disulfide isomerase (PDIA3), another molecule observed to be diminished in our study.…”

Genetics: Pet project

“…GWAS have proved successful in finding the genes for several dog traits that are relevant to human diseases, including the bone disorder osteogenesis imperfecta -pinned to the gene causing stubby legs in dachshunds 8 -and the autoimmune disease systemic lupus erythematosus, which was shown in a study published this year to be controlled by five separate genes in Nova Scotia duck-tolling retrievers 9 . And more are coming.…”