2. Academic Validation
  3. Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head

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

  • J Med Genet. 2016 Oct;53(10):705-9. doi: 10.1136/jmedgenet-2016-103829.
Wayne Mah 1,  Swapnil K Sonkusare 2,  Tracy Wang 1,  Bouziane Azeddine 1,  Mihaela Pupavac 3,  Jian Carrot-Zhang 4,  Kwangseok Hong 5,  Jacek Majewski 4,  Edward J Harvey 6,  Laura Russell 3,  Colin Chalk 7,  David S Rosenblatt 3,  Mark T Nelson 8,  Chantal Séguin 1
Affiliations

Affiliations

  • 1 Division of Hematology and Oncology, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada.
  • 2 Department of Pharmacology, University of Vermont, Burlington, Vermont, USA Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia, USA.
  • 3 Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
  • 4 Department of Human Genetics, McGill University, Montreal, Quebec, Canada Department of Human Genetics, McGill University and Genome Québec Innovation Centre, Montreal, Quebec, Canada.
  • 5 Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia, USA.
  • 6 Department of Surgery, Division of Orthopaedic Surgery, McGill University Health Centre, Montreal, Quebec, Canada.
  • 7 Department of Neurology & Neurosurgery, McGill University, Montreal, Quebec, Canada.
  • 8 Department of Pharmacology, University of Vermont, Burlington, Vermont, USA Institute of Cardiovascular Sciences, University of Manchester, Manchester, UK.
PMID: 27330106 DOI: 10.1136/jmedgenet-2016-103829
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.

Keywords

TRPV4; calcium channel; novel mutation; osteonecrosis of the femoral head.

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