{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,19]],"date-time":"2026-07-19T01:52:58Z","timestamp":1784425978869,"version":"3.55.0"},"reference-count":25,"publisher":"Journal of Neurosurgery Publishing Group (JNSPG)","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,6,1]]},"abstract":"<jats:sec>\n<jats:title>OBJECTIVE<\/jats:title>\n<jats:p>The aim of this study was to characterize a novel pathogenic variant in the transient receptor potential vanilloid 4 (<jats:italic>TRPV4<\/jats:italic>) gene, causing familial nonsyndromic craniosynostosis (CS) with complete penetrance and variable expressivity.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>METHODS <\/jats:title>\n<jats:p>Whole-exome sequencing was performed on germline DNA of a family with nonsyndromic CS to a mean depth coverage of 300\u00d7 per sample, with greater than 98% of the targeted region covered at least 25\u00d7. In this study, the authors detected a novel variant, c.496C&gt;A in <jats:italic>TRPV4<\/jats:italic>, exclusively in the four affected family members. The variant was modeled using the structure of the TRPV4 protein from <jats:italic>Xenopus tropicalis<\/jats:italic>. In vitro assays in HEK293 cells overexpressing wild-type TRPV4 or TRPV4 p.Leu166Met were used to assess the effect of the mutation on channel activity and downstream MAPK signaling.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>RESULTS<\/jats:title>\n<jats:p>The authors identified a novel, highly penetrant heterozygous variant in <jats:italic>TRPV4<\/jats:italic> (NM_021625.4:c.496C&gt;A) causing nonsyndromic CS in a mother and all three of her children. This variant results in an amino acid change (p.Leu166Met) in the intracellular ankyrin repeat domain distant from the Ca<jats:sup>2+<\/jats:sup>-dependent membrane channel domain. In contrast to other TRPV4 mutations in channelopathies, this variant does not interfere with channel activity as identified by in silico modeling and in vitro overexpression assays in HEK293 cells.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>CONCLUSIONS<\/jats:title>\n<jats:p>Based on these findings, the authors hypothesized that this novel variant causes CS by modulating the binding of allosteric regulatory factors to TRPV4 rather than directly modifying its channel activity. Overall, this study expands the genetic and functional spectrum of TRPV4 channelopathies and is particularly relevant for the genetic counseling of CS patients.<\/jats:p>\n<\/jats:sec>","DOI":"10.3171\/2023.1.peds22287","type":"journal-article","created":{"date-parts":[[2023,3,11]],"date-time":"2023-03-11T06:44:06Z","timestamp":1678517046000},"page":"584-592","source":"Crossref","is-referenced-by-count":2,"title":["Association of novel mutation in TRPV4 with familial nonsyndromic craniosynostosis with complete penetrance and variable expressivity"],"prefix":"10.3171","volume":"31","author":[{"given":"Tenzin","family":"Gayden","sequence":"first","affiliation":[{"name":"Division of Experimental Medicine, McGill University, Montr\u00e9al;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Crevier-Sorbo","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Division of Neurosurgery, Montreal Children\u2019s Hospital, McGill University Health Centre Research Institute, Montr\u00e9al;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wajih","family":"Jawhar","sequence":"additional","affiliation":[{"name":"Division of Experimental Medicine, McGill University, Montr\u00e9al;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Saint-Martin","sequence":"additional","affiliation":[{"name":"Department of Radiology, Montreal Children\u2019s Hospital, McGill University, Montr\u00e9al;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Eveleigh","sequence":"additional","affiliation":[{"name":"Division of Experimental Medicine, McGill University, Montr\u00e9al;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirko S.","family":"Gilardino","sequence":"additional","affiliation":[{"name":"Division of Plastic and Reconstructive Surgery, McGill University, Montr\u00e9al;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natascia","family":"Anastasio","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Faculty of Medicine and Health Sciences, McGill University, Montr\u00e9al; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yannis","family":"Trakadis","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Faculty of Medicine and Health Sciences, McGill University, Montr\u00e9al; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelia V.","family":"Bassenden","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, McGill University, Montr\u00e9al, Qu\u00e9bec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert M.","family":"Berghuis","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, McGill University, Montr\u00e9al, Qu\u00e9bec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nada","family":"Jabado","sequence":"additional","affiliation":[{"name":"Division of Experimental Medicine, McGill University, Montr\u00e9al;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roy W. R.","family":"Dudley","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Division of Neurosurgery, Montreal Children\u2019s Hospital, McGill University Health Centre Research Institute, Montr\u00e9al;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1754","reference":[{"issue":"4","key":"b1","series-title":"Genet Med","first-page":"302","article-title":"Familial incidence and associated symptoms in a population of individuals with nonsyndromic craniosynostosis","volume":"16","author":"Greenwood J","year":"2014","unstructured":"Greenwood J, Flodman P, Osann K, Boyadjiev SA, Kimonis V. Familial incidence and associated symptoms in a population of individuals with nonsyndromic craniosynostosis. 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