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
Division of Hematology and Oncology, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada.
Department of Pharmacology, University of Vermont, Burlington, Vermont, USA Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia, USA.
J Med Genet. 2016 Oct;53(10):705-9. doi: 10.1136/jmedgenet-2016-103829. Epub 2016 Jun 21.
Osteonecrosis of the femoral head is a debilitating disease that involves impaired blood supply to the femoral head and leads to femoral head collapse.
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.
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.
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.
股骨头坏死是一种使人衰弱的疾病，涉及股骨头血液供应受损并导致股骨头塌陷。
我们使用全外显子组测序和桑格测序分析一个患有遗传性股骨头坏死的家系，并通过荧光Ca(2+)成像对变异蛋白进行功能表征。
我们报告了一个有四名兄弟姐妹患遗传性股骨头坏死的家系，并在瞬时受体电位香草酸受体4（TRPV4）基因的一个等位基因中鉴定出c.2480_2483delCCCG移码缺失，随后是c.2486T>A替换。TRPV4编码一种Ca(2+)可渗透的阳离子通道，已知其在血管调节和破骨细胞分化中起作用。虽然致病性TRPV4突变会影响骨骼或神经系统，但与股骨头坏死的关联是新发现。通过对HEK293细胞和患者来源的皮肤成纤维细胞中通过突变TRPV4通道的Ca(2+)内流进行功能测量，确定了TRPV4功能获得。通过间接测量TRPV4通道簇内的TRPV4活性来确定通道开放时间，结果显示TRPV4功能获得是由更长的通道开放时间引起的。
这些发现确定了一种新的TRPV4突变，表明TRPV4和钙稳态改变在股骨头坏死发病机制中的作用，同时强化了TRPV4在骨疾病和血管内皮中的重要性。
