RT Journal Article SR Electronic T1 Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 705 OP 709 DO 10.1136/jmedgenet-2016-103829 VO 53 IS 10 A1 Wayne Mah A1 Swapnil K Sonkusare A1 Tracy Wang A1 Bouziane Azeddine A1 Mihaela Pupavac A1 Jian Carrot-Zhang A1 Kwangseok Hong A1 Jacek Majewski A1 Edward J Harvey A1 Laura Russell A1 Colin Chalk A1 David S Rosenblatt A1 Mark T Nelson A1 Chantal Séguin YR 2016 UL http://jmg.bmj.com/content/53/10/705.abstract AB Background Osteonecrosis of the femoral head is a debilitating disease that involves impaired blood supply to the femoral head and leads to femoral head collapse.Methods We use whole-exome sequencing and Sanger sequencing to analyse a family with inherited osteonecrosis of the femoral head and fluorescent Ca2+ imaging to functionally characterise the variant protein.Results We report a family with four siblings affected with inherited osteonecrosis of the femoral head and the identification of a c.2480_2483delCCCG frameshift deletion followed by a c.2486T>A substitution in one allele of the transient receptor potential vanilloid 4 (TRPV4) gene. TRPV4 encodes a Ca2+-permeable cation channel known to play a role in vasoregulation and osteoclast differentiation. While pathogenic TRPV4 mutations affect the skeletal or nervous systems, association with osteonecrosis of the femoral head is novel. Functional measurements of Ca2+ influx through mutant TRPV4 channels in HEK293 cells and patient-derived dermal fibroblasts identified a TRPV4 gain of function. Analysis of channel open times, determined indirectly from measurement of TRPV4 activity within a cluster of TRPV4 channels, revealed that the TRPV4 gain of function was caused by longer channel openings.Conclusions These findings identify a novel TRPV4 mutation implicating TRPV4 and altered calcium homeostasis in the pathogenesis of osteonecrosis while reinforcing the importance of TRPV4 in bone diseases and vascular endothelium.