Mutational analysis suggests that outward rectification is governed by a gating mechanism independent of the main intracellular gate.
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It shows a very prominent outward rectification, rarely opening upon hyperpolarization. TRPV4 is a polymodal Ca 2+-permeable cation channel of 871 AA. The mechanism by which TRPV4 mutation causes skeletal dysplasia is unclear. This report covers only the mutations causing skeletal dysplasias and is not concerned with the four alleles causing neuromuscular disease nor the P19S polymorphism, which loosely correlate with serum hyponatremia and chronic obstructive pulmonary disease. Four mutations in two of the six N-terminal ankyrin repeats of TRPV4 have also recently been shown to cause a spectrum of late-onset neuromuscular diseases but not skeletal dysplasia, ,, indicating that SD and these neuromuscular diseases arise by different mechanisms. In most cases, mutations occurred de novo, often appearing to arise from gonadal mosaicism in the parent. Subsequent analysis of 59 genetically diverse and mostly unrelated MD and SMDK patients found that all but one resulted from dominant TRPV4 mutations, ,. That TRPV4 mutation causes SD was initially discovered through a pedigree analysis of autosomal dominant BO patients from two familial lines followed by position cloning. Most recently, TRPV4 mutations were also found to cause two other clinically distinguishable SD's: spondylo-epiphyseal dysplasia Maroteaux type (SDEM-PM2) and the rare parasymetric dysplasia (PD). Clinically distinguishable spondylometaphyseal dysplasia, Kozlowski type (SMDK) presents defects intermediate in severity. These range from mild autosomal-dominant brachyolmia (BO), diagnosed by a shortened spine with characteristic vertebral defects but only minor defects in the long bones to metatropic dysplasia (MD), ,, characterized by more prominent spine defects as well as pronounced abnormalities in articular skeleton resulting in short dumbbell-shaped long bones, which leads to prenatal lethality in its severest forms. Mutations in the transient receptor potential cation channel TRPV4 have been found to cause many different forms of skeletal dysplasias (SD), ,. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ĭompeting interests: The authors have declared that no competing interests exist. and Y.S.), NS067360 and GM047856 (to C.K.) and by the Vilas Trust of the University of Wisconsin, Madison. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.įunding: This work was supported by National Institutes of Health (NIH) grant GM054867 (to S.L. Received: JanuAccepted: ApPublished: May 5, 2011Ĭopyright: © 2011 Loukin et al. PLoS ONE 6(5):Įditor: Patrick Callaerts, VIB & Katholieke Universiteit Leuven, Belgium We discuss how the channel over-activity may lead to the “gain-of-function” phenotype and speculate that the function of wild-type TRPV4 may be secondary in normal bone development but crucial in an acute process such as fracture repair in the adult.Ĭitation: Loukin S, Su Z, Kung C (2011) Increased Basal Activity Is a Key Determinant in the Severity of Human Skeletal Dysplasia Caused by TRPV4 Mutations. Thus, while other factors are at play, our results are consistent with the increased TRPV4 basal activity being a critical determinant of the severity of skeletal dysplasia. The magnitude of this limitation revealed a clear correlation between the degree of over-activity (the molecular phenotype) and the severity of the disease over the entire spectrum (the biological phenotype).
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All mutant channels had higher basal open probabilities, which limited their further increase by agonist or hypotonicity. Expressed in Xenopus oocyte and without any stimulation, the wild-type channel had a ∼1% open probability (Po) while those of most of the lethal MD channels approached 100%.
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Here we report on a systematic examination of 14 TRPV4 mutant alleles covering the entire SD spectrum. Complexities of the results from fluorescence and electrophysiological studies have led to questions on whether channel activity is a good predictor of disease severity. The spectrum of these skeletal dysplasias (SD) ranges from dominantly inherited mild brachylomia (BO) to neonatal lethal forms of metatropic dysplasia (MD). To date, 33 mutations are known to affect human bone development to different extents. TRPV4 is a mechanically activated Ca 2+-passing channel implicated in the sensing of forces, including those acting on bones.