Abstract
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.
Highlights
The Ehlers–Danlos syndromes (EDS) are a heterogeneous group of heritable disorders affecting connective tissue
We reported here three dogs with two different genetic variants in the COL5A1 gene affecting collagen synthesis and structure, analogous to classical EDS in human patients
A 4-month-old male intact Labrador was examined for several small skin lacerations of the distal normal skeletal development
Summary
The Ehlers–Danlos syndromes (EDS) are a heterogeneous group of heritable disorders affecting connective tissue. Variable clinical manifestations affecting primarily the skin, joints, ligaments, blood vessels, and internal organs have been reported. Abnormal collagen fibril formation is the hallmark of several types of human EDSs, including the classical form [19]. In the classical form of EDS, mutations in COL5A1 and COL5A2, which encode the α1- and α2-chain of type V collagen, have been reported [20,21,22,23,24,25,26]. Type V collagen is a quantitatively minor fibril-forming collagen. But the most widely distributed form is the [α1(V)]2 α2(V) heterotrimer that co-assembles with type I collagen into heterotypic type I/V collagen fibrils in the extracellular matrix. Type V collagen is thought to regulate the diameter of these fibrils by retention of its large N-propeptide domain, which projects above the surface of the collagen fibril [27]
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