TRPV4, KRAS, and FGFR1 Gain-of-function Mutations Drive Giant Cell Lesions of the Jaw

Carolina Cavalieri Gomes1,2, Tenzin Gayden1, Andrea Bajic1, Osama F. Harraz3, Jonathan Pratt1, Hamid Nikbakht1,4, Eric Bareke1,4, Marina Gonçalves Diniz5, Wagner Henriques Castro5, Pascal St-Onge6, Daniel Sinnett6,7, Leonie G. Mikael8, Nicolas De Jay1, Claudia L. Kleinman1,9, Elvis Terci Valera1,10, Angelia V. Bassenden11, Albert M. Berghuis11, Jacek Majewski1,4, Mark T. Nelson3,12, Ricardo Santiago Gomez1,5, Nada Jabado1,8

1. Department of Human Genetics, McGill University, Montreal, QC, Canada; 2. Department of Pathology, Biological Sciences Institute, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; 3. Department of Pharmacology, Larner College of Medicine, University of Vermont, Burlington, VT, USA; 4. McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada; 5. Department of Oral Surgery and Pathology, Faculty of Dentistry, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; 6. CHU Sainte-Justine Research Center, University of Montreal, Montreal, QC, Canada; 7. Department of Pediatrics, University of Montreal, QC, Canada; 8.Department of Pediatrics, McGill University and McGill University Heath Centre Research Institute, Montreal, QC, Canada; 9. Lady Davis Research Institute, Jewish General Hospital, Montreal, QC, Canada; 10. Department of Pediatrics, Ribeirão Preto Medical School, Universidade de São Paulo, São Paulo, Brazil; 11. Department of Biochemistry, McGill University, Montreal, QC, Canada; 12. Institute of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom

Giant cell lesions of the jaw (GCLJ) are debilitating tumors of unknown origin that can cause extensive bone resorption, morbidities, and facial deformities. We report somatic, gain-of-function mutations in TRPV4, KRAS, and FGFR1 in 67% (39/58) of GCLJ. Novel mutations in TRPV4 gene, encoding a calcium-permeable channel, led to increased channel activity and cell death when overexpressed in HEK293 cells. This effect could be prevented using TRPV4 antagonists. Our data extend the spectrum of TRPV4 channelopathies and provide rationale for the use of TRPV4 and RAS/MAPK antagonists at the bedside.