OMIA:001483-9615 : Osteogenesis imperfecta, SERPINH1-related in Canis lupus familiaris
Categories: Skeleton phene (incl. short stature & teeth)
Links to MONDO diseases:
Mendelian trait/disorder: yes
Mode of inheritance: Autosomal recessive
Considered a defect: 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).
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|SERPINH1||serpin peptidase inhibitor, clade H (heat shock protein 47), member 1, (collagen binding protein 1)||Canis lupus familiaris||21||NC_051825.1 (23244497..23235602)||SERPINH1||Homologene, Ensembl , NCBI gene|
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WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.
Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.
|OMIA Variant ID||Breed(s)||Variant Phenotype||Gene||Allele||Type of Variant||Source of Genetic Variant||Reference Sequence||Chr.||g. or m.||c. or n.||p.||Verbal Description||EVA ID||Inferred EVA rsID||Year Published||PubMed ID(s)||Acknowledgements|
|25||Dachshund||Osteogenesis imperfecta_Dachshund||SERPINH1||missense||Naturally occurring variant||CanFam3.1||21||g.23033735A>G||c.977T>C||p.(L326P)||2009||19629171||Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool|
Cite this entry
Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
|2015||Lindert, U., Weis, M.A., Rai, J., Seeliger, F., Hausser, I., Leeb, T., Eyre, D., Rohrbach, M., Giunta, C. :|
|Molecular consequences of the SERPINH1/HSP47 mutation in the dachshund natural model of osteogenesis imperfecta. J Biol Chem 290:17679-89, 2015. Pubmed reference: 26004778 . DOI: 10.1074/jbc.M115.661025.|
|2013||Eckardt, J., Kluth, S., Dierks, C., Philipp, U., Distl, O. :|
|Population screening for the mutation associated with osteogenesis imperfecta in dachshunds. Vet Rec 172:364, 2013. Pubmed reference: 23315765 . DOI: 10.1136/vr.101122.|
|Eckardt, J., Kluth, S., Dierks, C., Philipp, U., Distl, O. :|
|Osteogenesis imperfecta in dachshunds. J. Eckardt, S. Kluth, C. Dierks, U. Philipp and O. Distl comment. Vet Rec 172:319, 2013. Pubmed reference: 23525818 . DOI: 10.1136/vr.f1870.|
|Schütz, E., Brenig, B., Scharfenstein, M., Drögemüller, C., Leeb, T. :|
|Osteogenesis imperfecta in dachshunds. Vet Rec 172:319, 2013. Pubmed reference: 23525816 . DOI: 10.1136/vr.f1823.|
|2012||Abitbol, M. :|
|[DNA testing for osteogenesis imperfecta in the Dachshund.] Point Veterinaire 43:6-7, 2012.|
|Schütz, E., Drögemüller, C., Scharfenstein, M., Brenig, B. :|
|[Osteogenesis imperfecta in the Dachshund]. Kleintierpraxis 57:57-62, 2012.|
|Widmer, C., Gebauer, J.M., Brunstein, E., Rosenbaum, S., Zaucke, F., Drögemüller, C., Leeb, T., Baumann, U. :|
|Molecular basis for the action of the collagen-specific chaperone Hsp47/SERPINH1 and its structure-specific client recognition. Proc Natl Acad Sci U S A 109:13243-7, 2012. Pubmed reference: 22847422 . DOI: 10.1073/pnas.1208072109.|
|2009||Drögemüller, C., Becker, D., Brunner, A., Haase, B., Kircher, P., Seeliger, F., Fehr, M., Baumann, U., Lindblad-Toh, K., Leeb, T. :|
|A missense mutation in the SERPINH1 gene in Dachshunds with osteogenesis imperfecta. PLoS Genet 5:e1000579, 2009. Pubmed reference: 19629171 . DOI: 10.1371/journal.pgen.1000579.|
|2003||Seeliger, F., Leeb, T., Peters, M., Brugmann, M., Fehr, M., Hewicker-Trautwein, M. :|
|Osteogenesis imperfecta in two litters of dachshunds. Vet Pathol 40:530-9, 2003. Pubmed reference: 12949410 .|
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