TY - JOUR
T1 - Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head
AU - Mah, Wayne
AU - Sonkusare, Swapnil K.
AU - Wang, Tracy
AU - Azeddine, Bouziane
AU - Pupavac, Mihaela
AU - Carrot-Zhang, Jian
AU - Hong, Kwangseok
AU - Majewski, Jacek
AU - Harvey, Edward J.
AU - Russell, Laura
AU - Chalk, Colin
AU - Rosenblatt, David S.
AU - Nelson, Mark T.
AU - Séguin, Chantal
PY - 2016/6/21
Y1 - 2016/6/21
N2 - 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 patientderived 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.
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 patientderived 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.
UR - http://www.scopus.com/inward/record.url?scp=84977599013&partnerID=8YFLogxK
U2 - 10.1136/jmedgenet-2016-103829
DO - 10.1136/jmedgenet-2016-103829
M3 - Article
AN - SCOPUS:84977599013
SN - 0022-2593
JO - Journal of Medical Genetics
JF - Journal of Medical Genetics
ER -