TRPV4‐associated skeletal dysplasias

Abstract

Dominant mutations in the TRPV4 gene result in a bone dysplasia family and form a continuous phenotypic spectrum that includes, in decreasing severity, lethal, and nonlethal metatropic dysplasia (MD), spondylometaphyseal dysplasia Kozlowski type (SMDK), and autosomal dominant brachyolmia. Several rare variant phenotypes that have some overlap but deviate in some ways from the general pattern have also been described. The known variant phenotypes are spondyloepiphyseal dysplasia Maroteaux type (Pseudo-Morquio type 2), parastremmatic dysplasia, and familial digital arthropathy with brachydactyly. Interestingly, different TRPV4 mutations have been associated with dominantly inherited neurologic disorders such as congenital spinal muscular atrophy and hereditary motor and sensory neuropathy. Finally, a small number of patients have been identified in whom a TRPV4 mutation results in a phenotype combining skeletal dysplasia with peripheral neuropathy. The TRPV4 gene encodes a regulated calcium channel implicated in multiple and diverse cellular processes. Over 50 different TRPV4 mutations have been reported, with two codons appearing to be mutational hot spots: P799 in exon 15, mostly associated with MD, and R594 in exon 11, associated with SMDK. While most pathogenic mutations tested so far result in activation of the calcium channel in vitro, the mechanisms through which TRPV4 activation results in skeletal dysplasia and/or peripheral neuropathy remain unclear and the genotype-phenotype correlations in this group of disorders remains somewhat mysterious. Since the phenotypic expression of most mutations seems to be relatively constant, careful clinical and radiographic assessment is useful in directing molecular analysis.

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“…15). Most of the mutations are gain-of-function mutations, and the degree of channel overactivity seems to determine the severity of the disease (Loukin et al, 2010a,b) (for reviews, see Nilius and Owsianik, 2010a;Nishimura et al, 2012;Nilius and Voets, 2013).…”

Patient-Derived Skeletal Dysplasia Induced Pluripotent Stem Cells Display Abnormal Chondrogenic Marker Expression and Regulation byBMP2andTGFβ1

“…Heterozygous mutations in this gene result in a spectrum of dominantly inherited SD phenotypes [3][4][5][6][7][8]. TRPV4 is a tetrameric calcium-permeable ion channel that plays a role in chondrocyte differentiation [9][10][11][12][13].…”

“…However, reduced channel activity was reported for TRPV4 mutations in the mild disorder, familial digital arthropathybrachydactyly (FDAB), which is primarily characterized by osteoarthropathy in the hands [7]. TRPV4 mutations, sometimes in the same region of the gene, can show highly variable phenotypes that affect the skeleton, the peripheral nervous system, or both [6,8,13]. Several mechanisms for such phenotypes have been suggested, including: defects in Ca 2 + homeostasis in chondrocytes or in motor and sensory neurons, abnormal protein-protein interactions, or dysregulation of gene expression during chondrocyte differentiation [13].…”

Acidic microenvironment and bone pain in cancer-colonized bone

“…Recent studies revealed that mutations of TRPV4 are associated with varieties of skeletal dysplasia and osteoarthritis. 83 Different TRPV4 mutations cause dominantly inherited neurologic disorders such as congenital spinal muscular atrophy and hereditary motor and sensory neuropathy. Of interest, some patients with a TRPV4 mutation display skeletal dysplasia combined with peripheral neuropathy.…”