Possibly relevant human trait(s) and/or gene(s) (MIM number): 600943

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2009

Mapping: By using homozygosity mapping in only 5 affected dogs, Drögemüller et al. (2009) narrowed the location of the causative mutation down to a 5.82 Mb region in chromosome CFA21.

Molecular basis: Drögemüller et al. (2009) showed that this disorder in Dachsunds is due to a missense variant (c.977T>C, p.Leu326Pro) in a conserved domain of the SERPINH1 gene. SERPINH1 acts as a chaperone to assist in the correct assembly of the nascent procollagen chains (Widmer et al. 2012). Lindert et al. (2015) investigated the functional impact of the SERPINH1 variant in detail by studying fibroblast cultures from affected and non-affected Dachshunds. The researchers found that "procollagen was retained intracellularly with concomitant dilation of ER cisternae and activation of the ER stress response markers GRP78 and phospho-eIF2α, thus suggesting a defect in procollagen processing." They further observed post-translational over-modification and abnormal cross-linking of the bone collagen.

Prevalence: Schutz et al. (2012) genotyped 591 German Dachshunds and estimated the frequency of the causative allele to be 8.86%. They also observed "a significantly increased mortality rate among the offspring of carriers".

Eckardt et al. (2013) reported the results of genotyping 1352 Dachshunds from 12 European countries for the causative mutation: "The overall frequency of OI [osteogenesis imperfecta] carriers was 12.9 per cent. Across all different size varieties, the SERPINH1 mutation was over-represented in wire-haired dachshunds with 17.3 per cent OI carriers. Among the different countries, the proportion of OI carriers was highest in Germany with 20.4 per cent." As noted by Schutz et al. (2013), this estimate is consistent with the allele-frequency estimate of Schutz et al. (2012).

Breed: Dachshund.

Associated gene: