Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family

Abstract

Background Mutations in TRPV4, a gene that encodes a Ca 2+ permeable non-selective cation channel, have recently been found in a spectrum of skeletal dysplasias that includes brachyolmia, spondylometaphyseal dysplasia, Kozlowski type (SMDK) and metatropic dysplasia (MD). Only a total of seven missense mutations were detected, however. The full spectrum of TRPV4 mutations and their phenotypes remained unclear. Objectives and methods To examine TRPV4 mutation spectrum and phenotypeÀgenotype association, we searched for TRPV4 mutations by PCR-direct sequencing from genomic DNA in 22 MD and 20 SMDK probands. Results TRPV4 mutations were found in all but one MD subject. In total, 19 different heterozygous mutations were identified in 41 subjects; two were recurrent and 17 were novel. In MD, a recurrent P799L mutation was identified in nine subjects, as well as 10 novel mutations including F471del, the first deletion mutation of TRPV4. In SMDK, a recurrent R594H mutation was identified in 12 subjects and seven novel mutations. An association between the position of mutations and the disease phenotype was also observed. Thus, P799 in exon 15 is a hot codon for MD mutations, as four different amino acid substitutions have been observed at this codon; while R594 in exon 11 is a hotspot for SMDK mutations. Conclusion The TRPV4 mutation spectrum in MD and SMDK, which showed genotypeÀphenotype correlation and potential functional significance of mutations that are non-randomly distributed over the gene, was presented in this study. The results would help diagnostic laboratories establish efficient screening strategies for genetic diagnosis of the TRPV4 dysplasia family diseases.

Calcium/calmodulin-signaling supports TRPV4 activation in osteoclasts and regulates bone mass

“…The pathologies of patients with genetic mutations in TRPV4 have recently been reported, (8)(9)(10)(11)(12)(13) and certain features of their skeletal muscles were identified. (8,9) Thus, physiological targets of this channel are being sought.…”

A channelopathy mechanism revealed by direct calmodulin activation of TrpV4

“…This inhibitory interaction apparently also requires a subsequent kink in the backbone structure as evidenced that P799L is also in a constitutively CaMactivated state (Fig. 3 A and B) and several other substitutions of this proline also cause disease (22). binding (states a to b to d) allowing channels to open (d to e).…”

TRPV4-pathy, a novel channelopathy affecting diverse systems

“…4 Mutations in TRPV4 had originally been found in a different category of disorders; autosomal-dominant skeletal dysplasias that includes brachyolmia, spondylometaphyseal dysplasia, Kozlowski type and metatropic dysplasia. [5][6][7] Recently, we have found TRPV4 mutations in two additional skeletal dysplasias, spondyloepiphyseal dysplasia, type Maroteaux (or pseudo-Morquio, type 2) and parastremmatic dysplasia. 8 Altogether, 29 different mutations have been found in the 'family' of skeletal dysplasias composed of these overlapping, but distinctive entities [5][6][7][8] ( Figure 1).…”

“…Four missense mutations at three distinct positions in the TRPV4 protein have been identified in the neuromuscular disorders, all four mutations are within the ankyrin (ANK) repeats of TRPV4, and all involve substitutions of arginine residues. 1-3 Although most 'skeletal' TRPV4 mutations are also missense mutations, they also include a single amino-acid deletion 7 and a frame-shift mutation 8 (Figure 1). The clustering of 'neuropathic' mutations in the ANK domain is emphasized in the Nature Genetics papers, 1,3 but ANK mutations have been observed in many 'skeletal' phenotypes as well (Figure 1).…”

“…It seems equally unlikely that substitution of arginine may have a special significance, as R594H is a very frequent mutation in the skeletal group. 6,7 Moreover, arginine residues in the ANK domains are not conserved between human TRPV proteins, whereas many of surrounding residues are conserved (Supplementary Figure 1). Interestingly, the residues corresponding to arginine 269 of TRPV4 are histidine in TRPV1 and cysteine in TRPV2-precisely the substitutions observed by the papers (R269H and R269C).…”