Categories: Skeleton phene (incl. short stature & teeth)

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 600943 (gene) , 613848 (trait)

Links to relevant human diseases in MONDO:

• MONDO:0013459: osteogenesis imperfecta type 10

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2009

Species-specific name: Brittle bone disease

Species-specific description: Several forms of osteogenesis imperfecta have been identified so far in dogs. See also 'OMIA000754-9615 Osteogenesis imperfecta, generic', 'OMIA002126-9615 Osteogenesis imperfecta, type III, COL1A1-related' and 'OMIA 002112-9615 Osteogenesis imperfecta, COL1A2-related'

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.

Clinical features: Clinical features include reduced agility, pain, spontaneous and intrauterine bone and teeth fractures, joint hyperlaxity, brittle, thin-walled primary teeth, and reduced bone density on radiography (Seeliger et al., 2003). Low bone mass and reduced bone strength leading to bone fragility and deformity can be observed (Lindert et al., 2015). other clinical signs include blue-grey sclera, progressive hearing loss, dwarfism, and other developmental complications (Drögemüller et al., 2009). Stillbirths have been reported to occur as part of this condition (Schütz et al., 2013). [IT thanks DVM student Carol Bency, who provided the basis of this contribution in April 2022]

Pathology: Histologically collagen fibres are reduced in number but regularly patterned. Insufficient conversion of cartilage and connective tissue to bone is resulting in reduced bone mass and absence of mature bone tissue in both medullary and cortical regions. The dentine layer of the teeth is thin and missing a normal tubular pattern. The bone marrow has slightly increased density of all cell lines (Seeliger et al., 2003) [IT thanks DVM student Carol Bency, who provided the basis of this contribution in April 2022]

Prevalence: Schütz 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 Schütz et al. (2013), this estimate is consistent with the allele-frequency estimate of Schütz et al. (2012).

Breed: Dachshund (Dog) (VBO_0200406).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: