Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral headopen access
- 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.; Seguin, Chantal
- Issue Date
- Oct-2016
- Publisher
- BMJ PUBLISHING GROUP
- Keywords
- TRPV4; osteonecrosis of the femoral head; novel mutation; calcium channel
- Citation
- JOURNAL OF MEDICAL GENETICS, v.53, no.10, pp 705 - 709
- Pages
- 5
- Journal Title
- JOURNAL OF MEDICAL GENETICS
- Volume
- 53
- Number
- 10
- Start Page
- 705
- End Page
- 709
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/45660
- DOI
- 10.1136/jmedgenet-2016-103829
- ISSN
- 0022-2593
1468-6244
- 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 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.
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