Identification of Two Independent COL5A1 Variants in Dogs with Ehlers-Danlos Syndrome.

Bauer, Anina; Bateman, John F; Lamandé, Shireen R; Hanssen, Eric; Kirejczyk, Shannon G M; Yee, Mark; Ramiche, Ali; Jagannathan, Vidya; Welle, Monika; Leeb, Tosso; Bateman, Fiona L (2019). Identification of Two Independent COL5A1 Variants in Dogs with Ehlers-Danlos Syndrome. Genes, 10(10) MDPI, Molecular Diversity Preservation International 10.3390/genes10100731

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The Ehlers-Danlos syndromes (EDS) are a heterogeneous group of heritable disorders affecting connective tissues. The mutations causing the various forms of EDS in humans are well characterized, but the genetic mutations causing EDS-like clinical pathology in dogs are not known, thus hampering accurate clinical diagnosis. Clinical analysis of two independent cases of skin hyperextensibility and fragility, one with pronounced joint hypermobility was suggestive of EDS. Whole-genome sequencing revealed de novo mutations of COL5A1 in both cases, confirming the diagnosis of the classical form of EDS. The heterozygous COL5A1 p.Gly1013ValfsTer260 mutation characterized in case 1 introduced a premature termination codon and would be expected to result in α1(V) mRNA nonsense-mediated mRNA decay and collagen V haploinsufficiency. While mRNA was not available from this dog, ultrastructural analysis of the dermis demonstrated variability in collagen fibril diameter and the presence of collagen aggregates, termed 'collagen cauliflowers', consistent with COL5A1 mutations underlying classical EDS. In the second case, DNA sequencing demonstrated a p.Gly1571Arg missense variant in the COL5A1 gene. While samples were not available for further analysis, such a glycine substitution would be expected to destabilize the strict molecular structure of the collagen V triple helix and thus affect protein stability and/or integration of the mutant collagen into the collagen V/collagen I heterotypic dermal fibrils. This is the first report of genetic variants in the COL5A1 gene causing the clinical presentation of EDS in dogs. These data provided further evidence of the important role of collagen V in dermal collagen fibrillogenesis. Importantly, from the clinical perspective, we showed the utility of DNA sequencing, combined with the established clinical criteria, in the accurate diagnosis of EDS in dogs.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) > Institute of Genetics
05 Veterinary Medicine > Research Foci > DermFocus
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Animal Pathology
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP)
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH)

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Bauer, Anina; Jagannathan, Vidya; Welle, Monika Maria and Leeb, Tosso

Subjects:

500 Science > 590 Animals (Zoology)
600 Technology > 630 Agriculture
500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

2073-4425

Publisher:

MDPI, Molecular Diversity Preservation International

Language:

English

Submitter:

Tosso Leeb

Date Deposited:

30 Sep 2019 13:30

Last Modified:

22 Oct 2019 19:14

Publisher DOI:

10.3390/genes10100731

PubMed ID:

31546637

Uncontrolled Keywords:

Canis familiaris Collagen Cutaneous asthenia Dermatology Dog Genodermatosis Precision medicine Rare disease Skin Whole-genome sequencing

BORIS DOI:

10.7892/boris.133541

URI:

https://boris.unibe.ch/id/eprint/133541

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