Mutations in the Gene Encoding the Calcium-Permeable Ion Channel TRPV4 Produce Spondylometaphyseal Dysplasia, Kozlowski Type and Metatropic Dysplasia

Abstract

The spondylometaphyseal dysplasias (SMDs) are a group of short-stature disorders distinguished by abnormalities in the vertebrae and the metaphyses of the tubular bones. SMD Kozlowski type (SMDK) is a well-defined autosomal-dominant SMD characterized by significant scoliosis and mild metaphyseal abnormalities in the pelvis. The vertebrae exhibit platyspondyly and overfaced pedicles similar to autosomal-dominant brachyolmia, which can result from heterozygosity for activating mutations in the gene encoding TRPV4, a calcium-permeable ion channel. Mutation analysis in six out of six patients with SMDK demonstrated heterozygosity for missense mutations in TRPV4, and one mutation, predicting a R594H substitution, was recurrent in four patients. Similar to autosomal-dominant brachyolmia, the mutations altered basal calcium channel activity in vitro. Metatropic dysplasia is another SMD that has been proposed to have both clinical and genetic heterogeneity. Patients with the nonlethal form of metatropic dysplasia present with a progressive scoliosis, widespread metaphyseal involvement of the appendicular skeleton, and carpal ossification delay. Because of some similar radiographic features between SMDK and metatropic dysplasia, TRPV4 was tested as a disease gene for nonlethal metatropic dysplasia. In two sporadic cases, heterozygosity for de novo missense mutations in TRPV4 was found. The findings demonstrate that mutations in TRPV4 produce a phenotypic spectrum of skeletal dysplasias from the mild autosomal-dominant brachyolmia to SMDK to autosomal-dominant metatropic dysplasia, suggesting that these disorders should be grouped into a new bone dysplasia family.

Inhibition of the cation channel TRPV4 improves bladder function in mice and rats with cyclophosphamide-induced cystitis

“…Mutations in the human TRPV4 gene have been identified as the direct cause of divergent hereditary diseases, including skeletal dysplasias, spinal muscular atrophy, and CharcotMarie-Tooth disease type 2C (36)(37)(38)(39)(40)(41). Although the exact role of TRPV4 in the etiology of these clinically diverse diseases is unknown, it appears that many disease-causing mutations lead to gain of TRPV4 function (41).…”

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).…”

“…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).…”

“…A gain-of-function characterized by increased constitutive activity and elevated channel activation by a variety of mechanisms has been suggested for the skeletal disorders. 5,6 One of the skeletal mutations predicts abolition of the normal C-terminal from P799 and substitution by a stretch of 63 missense amino acids; 8 as the C-terminus of TRPV4 is required for transport to the cell membrane, 11 it seems difficult to hypothesize that the gain-of-function mechanism alone could be responsible. Simple gain and loss of channel activity are also unlikely to explain the two distinct phenotypic groups.…”

A channelopathy mechanism revealed by direct calmodulin activation of TrpV4

“…E797K has been repeatedly discovered in different families (3,11). P799 appears to be a hot spot with several known alleles: P799A, P799S, P799R, and the first-reported P799L (11,12), causing different types of SD. Here, we scrutinized E797K, P799L, and several engineered mutations to further our understanding of TrpV4's Ca 2+ -CaM regulation and its relationship to channelopathy.…”