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Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.

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.

SUBMITTER: Mah W

PROVIDER: S-EPMC5035228 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.

Mah Wayne W Sonkusare Swapnil K SK Wang Tracy T Azeddine Bouziane B Pupavac Mihaela M Carrot-Zhang Jian J Hong Kwangseok K Majewski Jacek J Harvey Edward J EJ Russell Laura L Chalk Colin C Rosenblatt David S DS Nelson Mark T MT Séguin Chantal C

Journal of medical genetics 20160621 10

<h4>Background</h4>Osteonecrosis of the femoral head is a debilitating disease that involves impaired blood supply to the femoral head and leads to femoral head collapse.<h4>Methods</h4>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.<h4>Results</h4>We report a family with four siblings affected with inherited osteonecrosis of the femoral head a ...[more]

PMID: 27330106

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Project description:BackgroundGlucocorticoid usage and alcohol abuse are the most widely accepted risk factors for nontraumatic osteonecrosis of femoral head (ONFH). Despite distinct etiologies between glucocorticoid-associated ONFH (GONFH) and alcohol-associated ONFH (AONFH), little is known about the differences of the microarchitectural and histomorphologic characteristics between these subtypes of ONFH.PurposesTo investigate bone microarchitecture, bone remodeling activity and histomorphology characteristics of different regions in femoral heads between GONFH and AONFH.MethodsFrom September 2015 to October 2020, 85 patients diagnosed with GONFH and AONFH were recruited. Femoral heads were obtained after total hip replacement. Femoral head specimens were obtained from 42 patients (50 hips) with GONFH and 43 patients (50 hips) with AONFH. Micro-CT was utilized to assess the microstructure of 9 regions of interest (ROIs) in the femoral head. Along the supero-inferior orientation, the femoral head was divided into necrotic region, reactive interface, and normal region; along the medio-lateral orientation, the femoral head was divided into medial region, central region and lateral region. Decalcified and undecalcified bone histology was subsequently performed to evaluate histopathological alterations and bone remodeling levels.ResultsIn the necrotic region, most of the microarchitectural parameters did not differ significantly between GONFH and AONFH, whereas both the reactive interface and normal region revealed a less sclerotic microarchitecture but a higher bone remodeling level in GONFH than AONFH. Despite similar necrotic pathological manifestations, subchondral trabecular microfracture in the necrotic region was more severe and vasculature of the reactive interface was more abundant in GONFH.ConclusionsGONFH and AONFH shared similar microarchitecture and histopathological features in the necrotic region, while GONFH exhibited a less sclerotic microarchitecture and a more active bone metabolic status in both the reactive interface and normal region. These differences between GONFH and AONFH in bone microarchitectural and histopathological characteristics might contribute to the development of disease-modifying prevention strategies and treatments for ONFH, taking into etiologies.

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Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.

Publications

Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head.

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