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OMIA 001483-9615 : Osteogenesis imperfecta, SERPINH1-related in Canis lupus familiaris

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 600943 , 613848

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:

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_006603.3 (23041649..23032761) SERPINH1 Homologene, Ensembl, NCBI gene

Variants

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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.

Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
Dachshund Osteogenesis imperfecta_Dachshund SERPINH1 missense CanFam3.1 21 g.23033735T>C c.977T>C p.L326P 2009 19629171 Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool
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References


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.
Schutz, E., Drogemuller, 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 Drogemuller, 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.

Edit History


  • Created by Frank Nicholas on 24 Feb 2010
  • Changed by Tosso Leeb on 01 Sep 2011
  • Changed by Frank Nicholas on 02 Sep 2011
  • Changed by Frank Nicholas on 28 Sep 2011
  • Changed by Frank Nicholas on 12 Dec 2011
  • Changed by Frank Nicholas on 17 Jan 2013
  • Changed by Tosso Leeb on 19 Apr 2013
  • Changed by Frank Nicholas on 23 Apr 2013
  • Changed by Tosso Leeb on 07 Aug 2015
  • Changed by Frank Nicholas on 13 Jul 2017