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. Osteogenesis imperfecta (OI) is a genetic condition of humans and dogs characterized by extremely fragile bones and teeth. Most human OI cases are caused by defects in one of two collagen genes. Mutations in two other genes related to collagen maturation can also lead to OI in some patients. We studied Dachshunds with OI and initially investigated the two known collagen genes that are normally mutated in OI but did not find a mutation. Subsequently, we performed a search for shared segments across the entire genome in five affected Dachshunds. This experiment revealed that the causative mutation for OI in Dachshunds is located on dog chromosome 21. The SERPINH1 gene known to be involved in collagen maturation is located in this shared genome region. We sequenced the SERPINH1 gene in healthy and affected Dachshunds and found a single mutation exclusively shared by all affected dogs but not by healthy controls. Thus we have identified SERPINH1 as a fifth OI gene and a mutation within this gene as the most likely cause of OI in Dachshunds. The knowledge of this mutation enables genetic testing and will allow breeders to eradicate the deleterious allele from the Dachshund breeding population. SERPINH1 mutations might also be responsible for some human OI forms, where the causative mutation has not yet been identified.