Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head. Issue 10 (21st June 2016)

• Record Type: Journal Article
• Authors: Mah, Wayne; Sonkusare, Swapnil K; Wang, Tracy; Azeddine, Bouziane; Pupavac, Mihaela; Carrot-Zhang, Jian; Hong, Kwangseok; Majewski, Jacek; Harvey, Edward J; Russell, Laura; Chalk, Colin; Rosenblatt, David S; Nelson, Mark T; Séguin, Chantal
• Is Part Of: Journal of medical genetics. Volume 53:Issue 10(2016)
• Page Start: 705
• Page End: 709
• Publication Date: 2016-06-21
• Subjects: TRPV4 -- osteonecrosis of the femoral head -- novel mutation -- calcium channel; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmedgenet-2016-103829
• Languages: English
• ISSNs: 1468-6244

Abstract

Abstract : 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 Ca 2+ 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 Ca 2+ -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 Ca 2+ 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.