Abstract
TRPV4 is a mechanically activated Ca2+-passing channel implicated in the sensing of forces, including those acting on bones. To date, 33 mutations are known to affect human bone development to different extents. The spectrum of these skeletal dysplasias (SD) ranges from dominantly inherited mild brachylomia (BO) to neonatal lethal forms of metatropic dysplasia (MD). Complexities of the results from fluorescence and electrophysiological studies have led to questions on whether channel activity is a good predictor of disease severity. Here we report on a systematic examination of 14 TRPV4 mutant alleles covering the entire SD spectrum. 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%. All mutant channels had higher basal open probabilities, which limited their further increase by agonist or hypotonicity. 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). 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. 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.
Highlights
IntroductionMutations in the transient receptor potential cation channel TRPV4 have been found to cause many different forms of skeletal dysplasias (SD) [1,2,3,4,5]
Mutations in the transient receptor potential cation channel TRPV4 have been found to cause many different forms of skeletal dysplasias (SD) [1,2,3,4,5]. These range from mild autosomaldominant brachyolmia (BO) [5], diagnosed by a shortened spine with characteristic vertebral defects but only minor defects in the long bones [6] to metatropic dysplasia (MD) [2,3,4], characterized by more prominent spine defects as well as pronounced abnormalities in articular skeleton resulting in short dumbbellshaped long bones [7], which leads to prenatal lethality in its severest forms [8]
Four mutations in two of the six N-terminal ankyrin repeats of TRPV4 have recently been shown to cause a spectrum of late-onset neuromuscular diseases but not skeletal dysplasia [11,12,13], indicating that SD and these neuromuscular diseases arise by different mechanisms [14]
Summary
Mutations in the transient receptor potential cation channel TRPV4 have been found to cause many different forms of skeletal dysplasias (SD) [1,2,3,4,5]. These range from mild autosomaldominant brachyolmia (BO) [5], diagnosed by a shortened spine with characteristic vertebral defects but only minor defects in the long bones [6] to metatropic dysplasia (MD) [2,3,4], characterized by more prominent spine defects as well as pronounced abnormalities in articular skeleton resulting in short dumbbellshaped long bones [7], which leads to prenatal lethality in its severest forms [8]. 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 [15] and chronic obstructive pulmonary disease [16]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
