Identification of Two Independent COL5A1 Variants in Dogs with Ehlers–Danlos Syndrome
| Autor: | Ali Ramiche, V. Jagannathan, Fiona L Bateman, John F. Bateman, Shannon G.M. Kirejczyk, Monika Maria Welle, Eric Hanssen, Tosso Leeb, Shireen R. Lamandé, Mark Yee, Anina Bauer |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
lcsh:QH426-470 040301 veterinary sciences 610 Medicine & health Dermatology Biology medicine.disease_cause 0403 veterinary science 03 medical and health sciences Dermis Cutaneous asthenia Dog Genetics medicine Missense mutation Genodermatosis Genetics (clinical) Skin Whole-genome sequencing Mutation 630 Agriculture Precision medicine Fibrillogenesis Canis familiaris 04 agricultural and veterinary sciences medicine.disease Molecular biology 3. Good health lcsh:Genetics 030104 developmental biology medicine.anatomical_structure Ehlers–Danlos syndrome 590 Animals (Zoology) 570 Life sciences biology Collagen Haploinsufficiency Rare disease |
| Zdroj: | 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 Genes, Vol 10, Iss 10, p 731 (2019) Genes Volume 10 Issue 10 |
| ISSN: | 2073-4425 |
| DOI: | 10.3390/genes10100731 |
| Popis: | The Ehlers&ndash 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 &alpha 1(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 &lsquo collagen cauliflowers&rsquo 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. |
| Databáze: | OpenAIRE |
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