Gandolfi B, Alamri S, Darby WG, et al. A dominant TRPV4 variant underlies osteochondrodysplasia in Scottish fold cats. Osteoarthritis Cartilage. 2016 Apr 6. pii: S1063-4584(16)30013-9.
Partially Funded by Winn Feline Foundation through Cat Health Network (D12FE-514)
Scottish fold cats, named for their unique ear shape, have a dominantly inherited osteochondrodysplasia involving malformation in the distal forelimbs, distal hindlimbs and tail, and progressive joint destruction. The aim of this study was to identify the gene and the underlying variant responsible for the osteochondrodysplasia.
Researchers from University of Sydney Veterinary Science Department, University of Missouri College of Veterinary Medicine and other collaborators used a feline DNA array and a case control genome–wide association analysis to genotype DNA samples from 44 Scottish fold and 54 control cats. A mutation in the gene encoding a calcium permeable ion channel, transient receptor potential cation channel, subfamily V, member 4 (TRPV4) was found to be responsible for the dominantly inherited folded ears and osteochondrodysplasia in Scottish fold cats. A T to G nucleotide mutation leads to a valine to phenylalanine amino acid substitution in mutant TRPV4. Researchers further performed a functional analysis of HEK293 cell line expressing either the wild-type or mutant TRPV4. Functional consequence of mutant TRPV4 relative to the wild-type TRPV4 is decreased expression of the calcium ion channel at the cell surface. Mutant TRPV4 channels also had a higher basal activity and an increased response to hypotonic conditions. TRPV4 is expressed in a range of tissues, including chondrocytes, osteoblasts and osteoclasts, where its correct activity is crucial for cell differentiation and tissue homeostasis; thus, mutant TRPV4 likely alters transduction of mechanical signals and influences chondrocyte intracellular responses and ultimately, the osteochondrodysplasia presentation. (GO)