| Autor: |
Bauer A; Institute of Genetics, University of Bern, 3012 Bern, Switzerland. anina.bauer@vetsuisse.unibe.ch.; Dermfocus, University of Bern, 3012 Bern, Switzerland. anina.bauer@vetsuisse.unibe.ch., Bateman JF; Murdoch Children's Research Institute, Parkville, Victoria 3052, Australia. john.bateman@mcri.edu.au.; Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria 3010, Australia. john.bateman@mcri.edu.au., Lamandé SR; Murdoch Children's Research Institute, Parkville, Victoria 3052, Australia. shireen.lamande@mcri.edu.au.; Department of Paediatrics, University of Melbourne, Parkville, Victoria 3010, Australia. shireen.lamande@mcri.edu.au., Hanssen E; Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria 3010, Australia. ehanssen@unimelb.edu.au.; Melbourne Advanced Microscopy Facility, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia. ehanssen@unimelb.edu.au., Kirejczyk SGM; College of Veterinary Medicine, Department of Pathology, The University of Georgia, Athens, GA 30602, USA. skirejc@emory.edu., Yee M; Torquay Animal Hospital, Torquay, Victoria 3228, Australia. info@torquayvets.com.au., Ramiche A; Veterinary Practice, Agadir 86603, Morocco. ali.ramiche@umontreal.ca., Jagannathan V; Institute of Genetics, University of Bern, 3012 Bern, Switzerland. vidhya.jagannathan@vetsuisse.unibe.ch.; Dermfocus, University of Bern, 3012 Bern, Switzerland. vidhya.jagannathan@vetsuisse.unibe.ch., Welle M; Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria 3010, Australia. monika.welle@vetsuisse.unibe.ch.; Institute of Animal Pathology, University of Bern, 3012 Bern, Switzerland. monika.welle@vetsuisse.unibe.ch., Leeb T; Institute of Genetics, University of Bern, 3012 Bern, Switzerland. tosso.leeb@vetsuisse.unibe.ch.; Dermfocus, University of Bern, 3012 Bern, Switzerland. tosso.leeb@vetsuisse.unibe.ch., Bateman FL; Murdoch Children's Research Institute, Parkville, Victoria 3052, Australia. fibatema@gmail.com.; College of Veterinary Medicine, Small Animal Medicine and Surgery, The University of Georgia, Athens, GA 30602, USA. fibatema@gmail.com. |
| Abstrakt: |
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. |
