Alternative titles; symbols
HGNC Approved Gene Symbol: TRPV4
SNOMEDCT: 111304003, 22764001, 230248006, 717010007, 717264003, 719204007, 722210007, 763067000; ICD10CM: G12.1;
Cytogenetic location: 12q24.11 Genomic coordinates (GRCh38): 12:109,783,087-109,833,398 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q24.11 | ?Avascular necrosis of femoral head, primary, 2 | 617383 | Autosomal dominant | 3 |
| [Sodium serum level QTL 1] | 613508 | 3 | ||
| Brachyolmia type 3 | 113500 | Autosomal dominant | 3 | |
| Digital arthropathy-brachydactyly, familial | 606835 | Autosomal dominant | 3 | |
| Hereditary motor and sensory neuropathy, type IIc | 606071 | Autosomal dominant | 3 | |
| Metatropic dysplasia | 156530 | Autosomal dominant | 3 | |
| Neuronopathy, distal hereditary motor, autosomal dominant 8 | 600175 | Autosomal dominant | 3 | |
| Parastremmatic dwarfism | 168400 | Autosomal dominant | 3 | |
| Scapuloperoneal spinal muscular atrophy | 181405 | Autosomal dominant | 3 | |
| SED, Maroteaux type | 184095 | Autosomal dominant | 3 | |
| Spondylometaphyseal dysplasia, Kozlowski type | 184252 | Autosomal dominant | 3 |
The TRPV4 cation channel mediates calcium influx in response to physical, chemical, and hormonal stimuli in ciliated epithelial cells (Lorenzo et al., 2008).
By employing a candidate-gene approach based on genes encoding members of the TRP superfamily of ion channels, Liedtke et al. (2000) isolated cDNAs encoding the vanilloid receptor (VR1; 602076)-related osmotically activated channel, or VROAC, from rat, mouse, human, and chicken. The predicted 872-amino acid VROAC protein has a structure similar to VR1 and VR-like receptor-1 (VRL1, or TRPV2; 606676), with 6 predicted membrane-spanning domains and a putative pore loop. The N-terminal domain of VROAC bears 3 ankyrin repeats and, like its C terminus, is predicted to occur intracellularly. VROAC is a cation-selective channel that is gated by exposure to hypotonicity within the physiologic range. Northern blot analysis of rat tissues detected abundant expression of a 3.2-kb transcript in kidney, lung, spleen, testis, and fat, with lower expression in sensory ganglia. In situ hybridization showed that in the central nervous system, VROAC is expressed in neurons of the circumventricular organs, neurosensory cells responsive to systemic osmotic pressure. VROAC was also expressed in other neurosensory cells, including inner-ear hair cells, sensory neurons, and Merkel cells.
Strotmann et al. (2000) also cloned VROAC, which they termed OTRPC4 due to its similarity to other members of the Osm9 subfamily of transient receptor potential channels (e.g., VR1). In situ hybridization analysis revealed transcripts in the inner cortex and a punctate distribution in the outer cortex of mouse kidney.
Wissenbach et al. (2000) also cloned VROAC, which they called TRP12. The human protein is 96% identical to the mouse protein.
Using immunohistochemical analysis, Lorenzo et al. (2008) detected Trpv4 in mouse ciliated tracheal epithelial cells.
Lamande et al. (2011) analyzed Trpv4 expression in mice and observed that localization and expression are similar in knee and phalangeal joints. In the growth plate, Trpv4 was most highly expressed in the proliferative zone, whereas it was downregulated as chondrocytes matured in the prehypertrophic zone and was not detectable by immunohistochemistry in hypertrophic chondrocytes. Trpv4 was expressed at comparable levels in proliferative and articular chondrocytes.
Wissenbach et al. (2000) determined that the TRPV4 gene contains 15 exons.
By genomic sequence analysis, Liedtke et al. (2000) mapped the TRPV4 gene to chromosome 12q24.1. They mapped the mouse Trpv4 gene to distal chromosome 5 by radiation hybrid analysis.
Wissenbach et al. (2000) found that hypoosmotic conditions rapidly activated TRP12, while hyperosmotic conditions inhibited the activity.
Strotmann et al. (2000) showed that OTRPC4 was responsive to changes in extracellular osmolarity in the physiologically relevant range and was expressed in tissues exposed to changing osmotic environments.
Watanabe et al. (2003) demonstrated that the endocannabinoid anandamide and its metabolite arachidonic acid activate TRPV4 in an indirect way involving the cytochrome p450 epoxygenase (601258)-dependent formation of epoxyeicosatrienoic acids. Application of 5-prime,6-prime-epoxyeicosatrienoic acid at submicromolar concentrations activated TRPV4 in a membrane-delimited manner and caused calcium influx through TRPV4-like channels in vascular endothelial cells. Watanabe et al. (2003) concluded that activation of TRPV4 in vascular endothelial cells might contribute to the relaxant effects of endocannabinoids and their p450 epoxygenase-dependent metabolites on vascular tone.
Sidhaye et al. (2006) observed a dose-responsive decrease in Aqp5 (600442) abundance in mouse lung epithelial cells exposed to hypotonic medium. Hypotonic reduction of Aqp5 was augmented and reduced, respectively, by conditions that activated or inhibited Trpv4. Hypotonic reduction of Aqp5 required extracellular calcium and was associated with increased intracellular calcium. The response to hypotonicity was recapitulated by coexpression of TRPV4 and AQP5 in human embryonic kidney cells. Sidhaye et al. (2006) concluded that AQP5 abundance is tightly controlled along a spectrum of extracellular osmolalities and that its abundance in hypotonic conditions can be regulated by TRPV4 activation.
Using immunofluorescence analysis, Gevaert et al. (2007) detected Trpv4 expression in mouse and rat urothelium and vascular endothelium, but not in other bladder cell types. By measuring intracellular Ca(2+), they found that mouse urothelial cells displayed a Trpv4-dependent response to phorbol esters and to hypotonic cell swelling. Gevaert et al. (2007) concluded that TRPV4 has a role in bladder function.
The rate of mucociliary clearance in the airways is a function of ciliary beat frequency. Lorenzo et al. (2008) found that tracheal cells from wildtype mice, but not those from Trpv4 -/- mice, increased intracellular Ca(2+) concentration and ciliary beat frequency in response to chemical activation, mildly increased temperature, and ATP application. Both mutant and wildtype cells increased ciliary beat frequency in response to high viscosity solutions. Lorenzo et al. (2008) concluded that TRPV4 in tracheal epithelial cells transduces physical and chemical stimuli into a Ca(2+) signal that regulates ciliary beat frequency and mucociliary transport.
Landoure et al. (2010) found low levels of TRPV4 expression in human dorsal and ventral spinal cords, at approximately 95% lower levels compared to tracheal cartilage.
Sonkusare et al. (2012) identified local calcium ion signals, which they called sparklets, in the vascular endothelium of resistance arteries that represent calcium ion influx through single TRPV4 cation channels. Gating of individual TRPV4 channels within a 4-channel cluster was cooperative, with activation of as few as 3 channels per cell causing maximal dilation through activation of endothelial cell intermediate (IK)- and small-conductance (SK) calcium ion-sensitive potassium channels. Endothelial-dependent muscarinic receptor signaling also acted largely through TRPV4 sparklet-mediated stimulation of IK and SK channels to promote vasodilation. Sonkusare et al. (2012) concluded that their results supported the concept that calcium ion influx through single TRPV4 channels is leveraged by the amplifier effect of cooperative channel gating and the high calcium ion sensitivity of IK and SK channels to cause vasodilation.
Using various methods, Lanciotti et al. (2012) found that MLC1 (605908), TRPV4, HEPACAM (611642), syntrophin (see 601017), caveolin-1 (CAV1; 601047), Kir4.1 (KCNJ10; 602208), and AQP4 (600308) assembled into an Na,K-ATPase-associated multiprotein complex. In rat and human astrocyte cell lines, this Na,K-ATPase complex mediated swelling-induced cytosolic calcium increase and volume recovery in response to hyposmotic stress. MLC1 associated directly with the Na,K-ATPase beta-1 subunit (ATP1B1; 182330), and plasma membrane expression of MLC1 was required for assembly of the Na,K-ATPase complex. TRPV4 was required for calcium influx, and AQP4 was recruited to the complex following hyposmotic stress.
Skeletal Disorders
Rock et al. (2008) identified missense mutations in the TRPV4 gene in 2 families segregating autosomal dominant brachyolmia (BCYM3; 113500). Expression of the R616Q mutation (605427.0001) in human embryonic kidney cells yielded a much larger constitutive current before agonist application. The shape of the IV curve and the reversal potentials were not changed. Rock et al. (2008) demonstrated significantly increased constitutively activated current in the mutant. Similar data were obtained for the mutation encoding V620I (605427.0002), with a significantly increased constitutive current at +100 mV, albeit somewhat less increased than for the R616Q mutant. Thus, both missense mutations conferred a gain-of-function phenotype by significantly increasing the fraction of constitutively open channels and by potentiating agonist activation. Rock et al. (2008) suggested that the data presented in their paper contributed to evidence that TRPV4 is a key regulatory molecule in the growth plate.
In 6 patients with the Kozlowski type of spondylometaphyseal dysplasia (SMDK; 184252), Krakow et al. (2009) identified heterozygous mutations in the TRPV4 gene. Four of the patients had an R594H mutation (605427.0003) in the cytoplasmic S4 domain, which is associated with increased intracellular calcium ion concentration and activity.
In 2 patients with metatropic dysplasia (MTD; 156530), Krakow et al. (2009) identified heterozygous missense mutations in the TRPV4 gene: I331F (605427.0006) in the ankyrin-5 domain and a cytoplasmic mutation (P799L; 605427.0007). Both mutations occurred de novo. Because mutations in the TRPV4 gene produce a phenotypic spectrum of skeletal dysplasias from the mild autosomal dominant brachyolmia to Kozlowski-type SMD to autosomal dominant metatropic dysplasia, Krakow et al. (2009) suggested that these disorders should be grouped into a new bone dysplasia family.
Dai et al. (2010) analyzed the TRPV4 gene in 22 MTD probands and 20 SMDK probands, and identified heterozygous TRPV4 mutations in all, except for 1 MTD proband. In the MTD patients, the recurrent P799L mutation was found in 9 patients, and 4 more patients had 3 different substitutions at the pro799 codon (605427.0013-605427.0015). The remaining 8 MTD patients included 7 with novel missense mutations and 1 with a 3-bp deletion of a codon (F471del; 605427.0016), which the authors stated was the first mutation other than a missense mutation to be reported in the TRPV4 gene. In the SMDK patients, the recurrent R594H mutation was found in 12 patients, and 8 had novel missense mutations (see, e.g., 605427.0017 and 605427.0018). Dai et al. (2010) designated pro799 in exon 15 of the TRPV4 gene as a 'hot codon' for MTD mutations and arg594 in exon 11 as a hotspot for SMDK mutations. Dai et al. (2010) noted that although some radiologic signs are shared by both disorders, the presence or absence of dumbbell-shaped femurs ascertained distinction between MTD and SMDK, respectively.
In 6 patients with the Maroteaux type of spondyloepiphyseal dysplasia (184095), Nishimura et al. (2010) identified heterozygous mutations in the TRPV4 gene (see, e.g., 605427.0019-605427.0021), 2 of which had previously been identified in patients with MTD (605427.0007) and SMDK (605427.0018). In a patient with parastremmatic dwarfism (168400), they identified heterozygosity for a missense mutation in TRPV4 (R594H; 605427.0003) that had previously been found in patients with SMDK (184252). Nishimura et al. (2010) noted that genotype/phenotype correlations did not appear to be robust, and suggested that in the presence of a TRPV4 mutation, modulation of the clinical phenotype by other genes and/or by nongenetic factors might occur.
Camacho et al. (2010) reported 10 patients with varying severity of metatropic dysplasia, all of whom carried a heterozygous mutation in the TRPV4 gene (see, e.g., 605427.0006-605427.0007, 605427.0023-605427.0024). Five patients had a lethal form of the disorder with death in the neonatal period or infancy, whereas 5 had a nonlethal disorder classified as mild, moderately severe, or severe. There was no clear relationship between the severity of the disorder and type of mutation or domain affected, but Camacho et al. (2010) suggested that the degree of constitutive activation of the mutant channels likely correlates with disease severity. Histologic studies of bone derived from 2 lethal cases showed abnormally thick cartilage with nodular proliferation, short diaphyses, and abnormal bone formation, indicating disrupted endochondral ossification. There was also evidence of abnormal chondrogenesis and abnormal differentiation of mesenchymal progenitors as well as lack of normal columns of chondrocytes. Camacho et al. (2010) suggested that the mechanism of disease may result from increased calcium in chondrocytes.
Unger et al. (2011) reported 4 patients, including a pair of monozygotic twins, with a severe lethal form of metatropic dysplasia associated with fetal akinesia. Three of the 4 were found to have absent movements, severe contractures, and features of metatropic dysplasia on prenatal ultrasound, and the pregnancies were terminated. The fourth patient presented with multiple joint contractures and absent limb movements at birth, consistent with fetal akinesia. Features of severe metatropic dysplasia in these patients included short long bones, cartilaginous joint expansion, narrow thorax, flat vertebral bodies, and sacrococcygeal tail. The fourth patient had a normal neonatal neurologic examination, although movement was restricted, but electromyography at age 3 months showed an absence of voluntary activity in the lower limbs. There was some residual activity in the upper limbs, and there were signs of a chronic axonal denervating process. These results were considered to be indicative of a neuropathic disorder. The baby died of respiratory complications at age 4 months. Genetic analysis of the 4 patients identified 3 different heterozygous de novo missense mutations in the TRPV4 gene (605427.0027-605427.0029). Unger et al. (2011) noted that skeletal dysplasias do not generally cause arthrogryposis multiplex, as seen in these patients, and since electrophysiologic studies of 1 indicated a neuropathic process, these TRPV4 mutations may cause a combination of a severe skeletal dysplasia and a neurologic phenotype causing fetal akinesia.
In a cohort of 26 patients diagnosed with various skeletal dysplasias, including 15 with MTD, 9 with SMDK, and 2 with brachyolmia, Andreucci et al. (2011) sequenced the TRPV4 gene and identified heterozygosity for missense mutations in 21 of them, including 14 patients with a diagnosis of MTD and 7 patients with SMDK (see, e.g., 605427.0003, 605427.0007, 605427.0014). In addition, 1 patient (case 17) with SMDK was heterozygous for a 3-bp duplication (L523dup). The 4 patients in whom no mutation was detected in the TRPV4 gene all exhibited atypical features for their respective clinical diagnoses.
In a large Swedish family in which 11 individuals over 4 generations had brachyolmia, Grigelioniene et al. (2014) identified heterozygosity for the previously reported R616Q substitution in the TRPV4 gene (605427.0001), which segregated fully with disease.
In 4 sibs from a Greek family with avascular necrosis of the femoral head (ANFH2; 617383), Mah et al. (2016) identified heterozygosity for a truncating mutation in the TRPV4 gene (V829WfsX3; 605427.0034). The mutation was not found in an unaffected brother or in public variant databases, but DNA from the sibs' parents was unavailable for study. Functional analysis in patient fibroblasts and transduced HEK293 cells indicated that the mutation results in a gain of function of TRPV4 channels by impeding channel closure. Mah et al. (2016) noted that only 2 of the previously reported TRPV4 mutations are truncating, and none are located beyond residue 799.
In a patient with nonlethal MTD, Weinstein et al. (2016) identified somatic mosaicism for a leu618-to-pro substitution (L618P; 605427.0035) in the TRPV4 gene that had previously been identified in heterozygosity by Camacho et al. (2010) in a patient with lethal MTD.
Neuromuscular Disorders
Auer-Grumbach et al. (2010) reported a large 5-generation family in which 10 individuals with a neuromuscular disease carried the same heterozygous mutation in the TRPV4 gene (R315W; 605427.0008). Four patients had hereditary motor and sensory neuropathy type IIC (HMSN2C; 606071), 1 had congenital spinal muscular atrophy (HMND8; 600175), and 2 had scapuloperoneal spinal muscular atrophy (SPSMA; 181405). Inheritance was autosomal dominant. The R315W mutation was also identified in an unrelated family in which 6 members had HMSN2C (originally reported by McEntagart et al., 2005). Auer-Grumbach et al. (2010) identified 2 additional TRPV4 mutations (R269H, 605427.0009 and R316C, 605427.0010) in affected members of 3 additional families with these 3 phenotypes, indicating that they are allelic disorders. All 3 mutations occurred at the outer helices of the ANK4 and ANK5 domains, in the N-terminal cytoplasmic domain. In vitro functional expression studies in HeLa cells showed that the mutant protein formed cytoplasmic aggregates and had reduced surface expression, as well as an impaired response to stimulus-dependent channel activity. These studies suggested that the mutations interfered with normal channel trafficking and function, resulting in haploinsufficiency.
Independently, Deng et al. (2010) and Landoure et al. (2010) identified some of the same mutations as Auer-Grumbach et al. (2010) in additional families with either SPSMA or HMSN2C, including the original families reported with the disorders (Delong and Siddique, 1992 and Dyck et al., 1994, respectively). Landoure et al. (2010) identified a novel mutation (R269C; 605427.0011) in the same protein region in another family with HMSN2C. In contrast to Auer-Grumbach et al. (2010), functional studies by Deng et al. (2010) and Landoure et al. (2010) indicated that the mutant proteins were trafficked normally, appeared at the plasma membrane, and resulted in increased calcium channel activity consistent with a gain of function. Commenting on the divergent functional findings of Auer-Grumbach et al. (2010) and Deng et al. (2010) and Landoure et al. (2010), Nilius and Owsianik (2010) suggested that the discrepancies were related to differences in experimental protocols.
In a family and an unrelated patient with CMT2C, Klein et al. (2011) identified 2 different heterozygous mutations in the TRPV4 gene (R232C, 605427.0025 and R316H, 605427.0026, respectively) in conserved residues in the ankyrin-repeat domain. In vitro functional expression studies showed that both mutant proteins had the same subcellular localization as wildtype in HEK293 cells and localized to the plasma membrane similar to wildtype in HeLa cells. In HEK293 cells, the mutant proteins caused increased agonist-induced channel activity and increased basal intracellular calcium concentrations compared to wildtype. HeLa cells expressing the mutant protein showed increased cell death, which could be suppressed by the TRPV antagonist ruthenium red. Klein et al. (2011) concluded that CMT2C-related mutations in this gene cause a dominant gain of function rather than haploinsufficiency.
By direct screening of the TRPV4 gene in 169 French patients with inherited axonal sensorimotor or motor peripheral neuropathy, Echaniz-Laguna et al. (2014) identified pathogenic heterozygous mutations in 12 (7%) patients. However, these 12 patients accounted for 16% of 74 patients from the entire cohort who had neuropathy with vocal cord paresis and/or skeletal dysplasia; no mutations were found in 95 patients with pure CMT2. All 12 patients had childhood-onset motor neuropathy with a variety of associated findings, including foot deformities (100%), kyphoscoliosis (100%), increased serum creatine kinase (100%), vocal cord paralysis (94%), scapular winging (53%), respiratory insufficiency (29%), hearing loss (24%), skeletal dysplasia (18%), and arthrogryposis (12%). Six mutations occurred de novo, and 2 asymptomatic carriers were observed. The diagnoses included dHMN8 (HMND8; 600175; 7 patients), congenital spinal muscular atrophy with arthrogryposis (2 patients), scapuloperoneal spinal muscular atrophy, and CMT2C. Several of the mutations had previously been reported in patients with a spectrum of axonal neuropathies; functional studies were not performed.
Serum Sodium Level Quantitative Trait Locus
Tian et al. (2009) demonstrated that the rs3742030 SNP in the TRPV4 gene (P19S; 605427.0012) was significantly associated with serum sodium concentration (613508) and with hyponatremia, defined as serum sodium less than 135 mEq/L, in 2 non-Hispanic Caucasian male populations. In heterologous expression studies in HEK293 cells, P19S mutant channels showed diminished response to hypotonic stress and to the osmotransducing lipid epoxyeicosatrienoic acid compared to wildtype channels. Tian et al. (2009) suggested that the P19S polymorphism affects TRPV4 function in vivo and likely influences systemic water balance on a population-wide basis.
Digital Arthropathy-Brachydactyly
In 2 families with digital arthropathy-brachydactyly mapping to chromosome 12q24 (FDAB; 606835), Lamande et al. (2011) sequenced the candidate gene TRPV4 and identified 2 different heterozygous missense mutations that segregated with disease in each family (605427.0030 and 605427.0031). In a sporadic patient with digital arthropathy-brachydactyly, heterozygosity for a third missense mutation was identified (605427.0032). All 3 arthropathy-associated substitutions are located at highly conserved residues in TRPV4 finger loop 3 and reduce channel activity, in contrast to gain-of-function TRPV4 mutations causing skeletal dysplasias and peripheral neuropathies.
Suzuki et al. (2003) generated Trpv4-knockout mice by homologous recombination. The Trpv4-null mice showed reduced sensitivity of the tail to pressure and acidic nociception. Their threshold to noxious stimuli and the conduction velocity of myelinated nerve responding to stimuli were impaired, but they retained olfaction, taste sensation, and heat avoidance. The Trpv4 channel expressed in vitro in CHO cells was opened by low pH, citrate, and inflation but not by heat or capsaicin. These data identified the TRPV4 channel as essential for the normal detection of pressure and as a receptor of the high-threshold mechanosensory complex.
Gevaert et al. (2007) found that Trpv4 -/- mice had an incontinent phenotype, with a lower frequency of voiding contractions and a higher frequency of nonvoiding contractions. Relative to controls, explanted bladder strips from Trpv4 -/- mice showed reduced amplitude of spontaneous contractions, and whole bladders from Trpv4 -/- mice showed decreased intravesical stretch-evoked ATP release.
In a 5-generation pedigree segregating autosomal dominant brachyolmia type 3 (BCYM3; 113500), Rock et al. (2008) identified a c.1847G-A transition in the TRPV4 gene, resulting in an arg616-to-gln (R616Q) substitution in the fifth transmembrane region. This change was not present among 107 alleles of ancestry-matched unaffected individuals and was present in heterozygosity in all affected members of the pedigree. The mutation results in a gain of function and constitutive activation of the TRPV4 channel. R616 is conserved among human, rat, mouse, chicken, stickleback, and zebrafish proteins.
In a large Swedish family in which 11 individuals over 4 generations had brachyolmia, Grigelioniene et al. (2014) identified heterozygosity for the previously reported R616Q substitution in the TRPV4 gene, which segregated fully with disease.
In a family segregating autosomal dominant brachyolmia type 3 (BCYM3; 113500), Rock et al. (2008) identified heterozygosity for an c.858G-A transition in the TRPV4 gene, resulting in a val620-to-ile (V620I) substitution. V620 is conserved among human, rat, mouse, chicken, stickleback, and zebrafish proteins. Rock et al. (2008) found that the V620I substitution results in constitutive activation of the TRPV4 channel.
Spondylometaphyseal Dysplasia, Kozlowski Type
In 4 unrelated patients with the Kozlowski type of spondylometaphyseal dysplasia (SMDK; 184252), Krakow et al. (2009) identified a c.1781G-A transition in exon 11 of the TRPV4 gene, resulting in an arg594-to-his (R594H) substitution in the cytoplasmic S4 domain. In 2 of the 4 families, the mutation was not found in DNA from the unaffected parents, establishing the change as de novo. The mutation was associated with increased basal intracellular calcium ion concentration and intracellular calcium activity. The mutation occurs in a highly conserved residue and was not identified in at least 214 control chromosomes.
In 12 probands with SMDK, Dai et al. (2010) identified heterozygosity for the R594H mutation and concluded that arg594 is a hotspot for mutation in SMDK. One of the patients did not show overt metaphyseal changes on x-ray and was considered to have a phenotype of intermediate severity between SMDK and brachyolmia (113500).
Parastremmatic Dwarfism
In a 7-year-old girl with parastremmatic dwarfism (168400), Nishimura et al. (2010) identified heterozygosity for the R594H mutation in the TRPV4 gene.
Metatropic Dysplasia
In a mother and 2 sons (patients 5, 6, and 7) and 2 unrelated patients (10 and 11, previously reported by Kannu et al., 2007) with metatropic dysplasia (MTD; 156530), Andreucci et al. (2011) identified heterozygosity for the R594H mutation in the TRPV4 gene. Andreucci et al. (2011) noted that the 2 sons exhibited intrafamilial variability, with one showing radiographic features that were more consistent with MTD and the other showing features more consistent with SMDK. The authors also identified heterozygosity for the R594H variant in 3 unrelated patients (patients 15, 16, and 22) clinically diagnosed with SMDK.
In a patient with the Kozlowski type of spondylometaphyseal dysplasia (SMDK; 184252), Krakow et al. (2009) identified heterozygosity for a c.992A-G transition in exon 6 of the TRPV4 gene, resulting in an asp333-to-gly (N333G) substitution in the ankyrin-5 domain. The mutation, which was inherited from the proband's affected mother, was associated with increased basal intracellular calcium ion concentration and intracellular calcium activity. The mutation occurs in a highly conserved residue and was not identified in at least 214 control chromosomes.
In a patient with spondylometaphyseal dysplasia of the Kozlowski type (SMDK; 184252), Krakow et al. (2009) identified heterozygosity for a c.2146G-T transversion in exon 13 of the TRPV4 gene, resulting in an ala716-to-ser (A716S) substitution in the cytoplasmic S6 domain. The mutation occurred de novo and was not associated with increased basal intracellular calcium ion concentration or intracellular activity when compared with wildtype. The mutation occurs in a highly conserved residue and was not found in at least 214 control chromosomes.
In a patient with metatropic dysplasia (MTD; 156530), Krakow et al. (2009) identified heterozygosity for a c.1080A-T transversion in exon 6 of the TRPV4 gene, resulting in an ile331-to-phe (I331F) substitution in the ankyrin-5 domain. The mutation occurs in a highly conserved residue and was not identified in the unaffected parents or in at least 214 control chromosomes.
Variant Function
By in vitro functional expression studies in HEK cells, Camacho et al. (2010) showed that the I331F-mutant protein had larger basal currents with constitutive open channels compared to wildtype. Treatment with agonists resulted in even larger calcium currents and increased intracellular calcium levels.
Metatropic Dysplasia
In a patient with metatropic dysplasia (MTD; 156530), Krakow et al. (2009) identified heterozygosity for a c.2396C-T transition in exon 15 of the TRPV4 gene, resulting in a pro799-to-leu substitution in the cytoplasmic domain. The mutation, which occurs in a highly conserved residue, was not identified in the unaffected parents or in at least 214 control chromosomes.
In 9 probands with MTD, Dai et al. (2010) identified heterozygosity for the P799L mutation. Four more MTD patients had 3 different substitutions at pro799 (see 605427.0013-605427.0015), leading Dai et al. (2010) to designate it as a 'hot codon' for MTD mutations.
Camacho et al. (2010) reported 2 unrelated patients with metatropic dysplasia who were heterozygous for the P799L mutation. Each had a nonlethal but moderately severe form of the disorder, with scoliosis, platyspondyly with irregular endplates, widened irregular metaphyses, and marked epiphyseal delay. In vitro functional expression studies in HEK cells showed that the P799L-mutant protein had larger basal currents with constitutive open channels compared to wildtype. Treatment with agonists resulted in even larger calcium currents and increased intracellular calcium levels.
In 5 patients with MTD (patients 2, 3, 4, 12, and 13), including 3 patients previously reported by Kannu et al. (2007) (patients 2, 3, and 4), Andreucci et al. (2011) identified heterozygosity for the P799L variant in the TRPV4 gene. Patients 2 and 3 were a father/daughter pair; the father was originally described by Beck et al. (1983).
Spondyloepiphyseal Dysplasia, Maroteaux Type
In 2 unrelated patients with the Maroteaux type of spondyloepiphyseal dysplasia (184095), 1 of whom was a girl previously reported by Megarbane et al. (2004), Nishimura et al. (2010) identified heterozygosity for the P799L mutation in the TRPV4 gene.
Auer-Grumbach et al. (2010) reported a large 5-generation family in which 10 individuals with a neuromuscular disease carried the same heterozygous c.943C-T transition in exon 6 of the TRPV4 gene, resulting in an arg315-to-trp (R315W) substitution. Four patients had hereditary motor and sensory neuropathy type IIC (HMSN2C; 606071), 1 had distal hereditary motor neuropathy, type VIII (HMND8; 600175), and 2 had scapuloperoneal spinal muscular atrophy (SPSMA; 181405). Inheritance was autosomal dominant. The R315W mutation was also identified in an unrelated family in which 6 members had HMSN2C (McEntagart et al., 2005). The mutation was not found in 304 control individuals. The R315W mutation occurred at the outer helices of the ANK4 and ANK5 domains in the N-terminal cytoplasmic domain. In vitro functional expression studies in HeLa cells showed that the mutant protein formed cytoplasmic aggregates and had reduced surface expression. In cotransfection studies, both mutant and wildtype proteins were detected in cytoplasmic aggregates. Mutant TRPV4 cells showed an impaired response to stimulus-dependent channel activity. The studies indicated that the mutation interferes with normal channel trafficking and function. Haploinsufficiency was proposed as the most likely underlying mechanism, although a gain of function could not be fully excluded.
Chen et al. (2010) identified a heterozygous R315W mutation in a 47-year-old mother and her 26-year-old daughter with HMSN2C and vocal cord paresis; the family had originally been reported by Dyck et al. (1994). Both patients had onset in infancy and developed a relatively severe form of distal muscle weakness and distal sensory loss, as well as short stature.
Aharoni et al. (2011) reported a 3-generation family of Ashkenazi/Sephardic Jewish origin with variable expression of HMSN2C due to a heterozygous R315W TRPV4 mutation. Five mutation carriers in 1 family were studied. The proband was a girl who presented at birth with inspiratory stridor, clubfeet, congenital hip dislocation, and knee contractures. She had absent reflexes and bilateral vocal cord paresis requiring tracheostomy. In childhood, she showed delayed motor development, progressive distal amyotrophy and weakness, weakness of the shoulder girdle, scoliosis, and pectus excavatum. Neurophysiologic studies showed an axonal sensorimotor neuropathy. Two of her affected brothers also presented with stridor in infancy and showed a similar phenotype, but without electrophysiologic examination. The mother showed a milder phenotype; she reported being unathletic as a child and having a hoarse voice. In her thirties, she developed slowly progressive fatigue associated with mild distal muscle atrophy in the lower limbs. She had poor reflexes and minimal distal temperature sensitivity. Electrophysiologic studies showed a sensorimotor neuropathy. One mutation carrier in this family was clinically unaffected at age 14 years, although deep tendon reflexes were difficult to elicit.
Distal Hereditary Motor Neuropathy 8, Autosomal Dominant
In affected members of a large family in which 20 individuals had autosomal dominant distal hereditary motor neuropathy-8 (HMND8; 600175), Auer-Grumbach et al. (2010) identified a heterozygous c.806G-A transition in exon 5 of the TRPV4 gene, resulting in an arg269-to-his (R269H) substitution. The family had originally been reported by Fleury and Hageman (1985). The mutation was not found in 162 European control individuals. The mutation occurred at the outer helices of the ANK4 and ANK5 domains. In vitro functional expression studies in HeLa cells showed that the mutant protein formed cytoplasmic aggregates and had significantly reduced surface expression. In cotransfection studies, both mutant and wildtype proteins were detected in cytoplasmic aggregates. Mutant TRPV4 cells showed an impaired response to stimulus-dependent channel activity. The studies suggested that the mutation interferes with normal channel trafficking and function, which the authors predicted would result in haploinsufficiency.
Hereditary Motor and Sensory Neuropathy Type IIC
In affected members of the family with hereditary motor and sensory neuropathy type IIC (HMSN2C; 606071) reported by Dyck et al. (1994), Deng et al. (2010) and Landoure et al. (2010) independently identified a heterozygous R269H mutation in the TRPV4 gene. Deng et al. (2010) did not find the mutation in over 700 control samples. Studies in transiently transfected HEK293 cells showed that the mutant protein was expressed at the plasma membrane, suggesting no defect in channel assembly or intracellular trafficking. Functional studies suggested that the mutation resulted in increased constitutive calcium channel activity, both under basal conditions and in response to stimuli, compared to wildtype. Deng et al. (2010) postulated a gain-of-function mechanism. The studies of Landoure et al. (2010) showed that the mutant protein caused cell death in cultured neuronal cells and in HEK293 cells, where cell death was associated with increased intracellular calcium. Further studies in Xenopus oocytes showed that the mutant channel was expressed normally at the cell surface and had increased current activity compared to wildtype. Mutant TRPV4 expressed in HeLa and HEK293 cells showed similar spatial distributions of the channel at the plasma membrane. Another pathogenic mutation was identified in this same codon (R269C; 605427.0011).
Variant Function
Commenting on the divergent functional findings of Auer-Grumbach et al. (2010) and Deng et al. (2010) and Landoure et al. (2010), Nilius and Owsianik (2010) suggested that the discrepancies were related to differences in experimental protocols.
By in vitro functional expression studies, Klein et al. (2011) showed that the mutant R269H protein caused increased agonist-induced channel activity and increased basal intracellular calcium concentrations in HEK293 cells compared to wildtype. HeLa cells expressing the mutant protein showed increased cell death, which could be suppressed by the TRPV antagonist ruthenium red. The findings were consistent with a pathogenic gain of function.
Hereditary Motor and Sensory Neuropathy Type IIC
In 3 affected members of a family with hereditary motor and sensory neuropathy type IIC (HMSN2C; 606071), Auer-Grumbach et al. (2010) identified a heterozygous c.946C-T transition in exon 6 of the TRPV4 gene, resulting in an arg316-to-cys (R316C) substitution. The mean age at onset was 3 years, with distal lower limb muscle weakness and wasting, areflexia, and vocal cord paralysis. The R316C mutation was also found in 3 affected individuals in another family: 1 had a phenotype of HMSN2C and 2 others had a phenotype consistent with scapuloperoneal spinal muscular atrophy (181405). The mean age at onset was 29.2 years, with distal upper and lower limb muscle weakness, atrophy, and areflexia. One patient had scoliosis, 1 had proximal muscle involvement, 1 had sensory symptoms, and 1 had vocal cord paresis. The mutation was not found in 304 European control individuals. The mutation occurs at the outer helices of the ANK4 and ANK5 domains. In vitro functional expression studies in HeLa cells showed that the mutant protein formed cytoplasmic aggregates and had significantly reduced surface expression. In cotransfection studies, both mutant and wildtype proteins were detected in cytoplasmic aggregates. Mutant TRPV4 cells showed an impaired response to stimulus-dependent channel activity. The studies suggested that the mutation interferes with normal channel trafficking and function, which the authors predicted would result in haploinsufficiency.
Scapuloperoneal Spinal Muscular Atrophy
Deng et al. (2010) identified a heterozygous R316C mutation in affected members of a large family with autosomal dominant scapuloperoneal spinal muscular atrophy reported by DeLong and Siddique (1992). The mutation was not found in 600 control samples. Studies in transiently transfected HEK293 cells showed that the mutant protein was expressed at the plasma membrane, suggesting no defect in channel assembly or intracellular trafficking. Functional studies suggested that the mutation resulted in increased constitutive calcium channel activity, both under basal conditions and in response to stimuli, compared to wildtype. Deng et al. (2010) postulated a gain-of-function mechanism.
Variant Function
Commenting on the divergent functional findings of Auer-Grumbach et al. (2010) and Deng et al. (2010) and Landoure et al. (2010), Nilius and Owsianik (2010) suggested that the discrepancies were related to differences in experimental protocols.
In affected members of a family with hereditary motor and sensory neuropathy IIC (HMSN2C; 606071), Landoure et al. (2010) identified a heterozygous c.805C-T transition in exon 5 of the TRPV4 gene, resulting in an arg269-to-cys (R269C) substitution. In vitro functional expression studies showed that the mutant protein caused cell death in cultured neuronal cells and in HEK293 cells, where cell death was associated with increased intracellular calcium. Further studies in Xenopus oocytes showed that the mutant channel was expressed normally at the cell surface and had increased current activity compared to wildtype. Mutant TRPV4 expressed in HeLa and HEK293 cells showed similar spatial distributions of the channel at the plasma membrane. Another pathogenic mutation was identified in this same codon (R269H; 605427.0009).
Scapuloperoneal Spinal Muscular Atrophy and Autosomal Dominant Distal Hereditary Motor Neuropathy 8
Berciano et al. (2011) reported a family in which 2 of 5 individuals carrying the same heterozygous R269C mutation had different phenotypes: a 44-year-old woman had scapuloperoneal spinal muscular atrophy (SPSMA; 181405) and her 7-year-old daughter had autosomal dominant distal hereditary motor neuropathy-8 (HMND8; 600175). The 3 other individuals with the mutation were clinically and electrophysiologically asymptomatic 9, 40, and 70 years of age, respectively, consistent with incomplete penetrance. The mother had sloped shoulders since childhood and later developed progressive lower leg muscle weakness and atrophy. She also had transient dysphonia. Muscle biopsy showed evidence of chronic denervation and renervation, and electrophysiologic studies showed reduced compound muscle action potentials with normal nerve conduction velocities, consistent with a motor axonal neuropathy. The daughter was born with congenital arthrogryposis and showed delayed motor development and laryngomalacia with stridor and vocal cord paresis necessitating intermittent tracheostomy placement. She was wheelchair-bound at age 7 due to limited joint mobility and lower limb muscle weakness, and also had weakness and atrophy of the shoulder girdle muscles.
In 2 cohorts of elderly individuals, Tian et al. (2009) found that a pro19-to-ser (P19S) polymorphism in the TRPV4 gene (rs3742030) was significantly associated with serum sodium concentration (613508) and with hyponatremia, defined as serum sodium less than 135 mEq/L, in non-Hispanic Caucasian males. Mean serum sodium concentration was lower among subjects with the 19S allele relative to the wildtype 19P allele, and subjects with the minor allele were 2.4 to 6.4 times as likely to exhibit hyponatremia as subjects without the minor allele. Heterologous expression studies in HEK293 cells showed that P19S mutant channels showed diminished response to hypotonic stress and to the osmotransducing lipid epoxyeicosatrienoic acid compared to wildtype channels.
In a patient with metatropic dysplasia (MTD; 156530), Dai et al. (2010) identified heterozygosity for a c.2395C-G transversion in exon 15 of the TRPV4 gene, resulting in a pro799-to-ala (P799A) substitution at an evolutionarily conserved residue in the cytoplasmic domain. Dai et al. (2010) noted that pro799 appeared to be a 'hot codon' for MTD mutations (see 605427.0007, 605427.0014, and 605427.0015).
In a patient with metatropic dysplasia (MTD; 156530), Dai et al. (2010) identified heterozygosity for a c.2395C-T transition in exon 15 of the TRPV4 gene, resulting in a pro799-to-ser (P799S) substitution at an evolutionarily conserved residue in the cytoplasmic domain. Dai et al. (2010) noted that pro799 appeared to be a 'hot codon' for MTD mutations (see 605427.0007, 605427.0013, and 605427.0015).
In a female infant (patient 8) who died at age 4.5 months with MTD, Andreucci et al. (2011) identified heterozygosity for the P799S variant in the TRPV4 gene. The patient was hospitalized immediately after birth due to skeletal malformations and respiratory difficulties. She had severe cervical instability, and her death was believed to be caused by medullary compression and respiratory decompensation.
In a patient with metatropic dysplasia (MTD; 156530), Dai et al. (2010) identified heterozygosity for a c.2396C-G transversion in exon 15 of the TRPV4 gene, resulting in a pro799-to-arg (P799R) substitution at an evolutionarily conserved residue in the cytoplasmic domain. Dai et al. (2010) noted that pro799 appeared to be a 'hot codon' for MTD mutations (see 605427.0007, 605427.0013, and 605427.0014).
In a patient with metatropic dysplasia (MTD; 156530), Dai et al. (2010) identified heterozygosity for a 3-bp deletion (c.1411delTTC) in exon 8 of the TRPV4 gene, resulting in deletion of phe471 (F471del) from the S1 domain. The authors stated that this was the first reported mutation other than a missense mutation in the TRPV4 gene.
In a patient with lethal infantile metatropic dysplasia, Camacho et al. (2010) identified heterozygosity for the F471del mutation, which they described as affecting nucleotides 1412 to 1414.
In 2 patients with the Kozlowski type of spondylometaphyseal dysplasia (SMDK; 184252), Dai et al. (2010) identified heterozygosity for an c.832G-A transition in exon 5 of the TRPV4 gene, resulting in a glu278-to-lys (E278K) substitution at an evolutionarily conserved residue in the ANK3 domain.
Spondylometaphyseal Dysplasia, Kozlowski Type
In a patient with the Kozlowski type of spondylometaphyseal dysplasia (SMDK; 184252), Dai et al. (2010) identified heterozygosity for a c.2389G-A transition in exon 15 of the TRPV4 gene, resulting in a glu797-to-lys (E797K) substitution at an evolutionarily conserved residue in the cytoplasmic domain. The authors noted that this was the first SMDK patient to be reported with a mutation in exon 15, which otherwise appears to be a hotspot for mutations causing metatropic dysplasia (MTD; 156530).
Spondylometaphyseal Dysplasia, Maroteaux Type
In an adult woman with the Maroteaux type of spondyloepiphyseal dysplasia (184095), Nishimura et al. (2010) identified heterozygosity for the E797K mutation in the TRPV4 gene.
Metatropic Dysplasia
Camacho et al. (2010) identified a heterozygous E797K mutation in a patient with a mild form of metatropic dysplasia (MTD; 156530), with little or no scoliosis, mild platyspondyly, mild metaphyseal widening, and carpal ossification delay.
In a Japanese woman with the Maroteaux type of spondyloepiphyseal dysplasia (184095), previously reported by Nishimura et al. (2003), Nishimura et al. (2010) identified heterozygosity for a 17-bp deletion (c.2396del17) in the TRPV4 gene.
In a Japanese man with the Maroteaux type of spondyloepiphyseal dysplasia (184095), previously reported by Nishimura et al. (2003), Nishimura et al. (2010) identified heterozygosity for a c.647G-A transition in exon 3 of the TRPV4 gene, resulting in a glu183-to-lys (E183K) substitution.
In a 6.5-year-old boy from a 4-generation family with the Maroteaux type of spondyloepiphyseal dysplasia (184095), Nishimura et al. (2010) identified heterozygosity for a c.1805A-G transition in exon 11 of the TRPV4 gene, resulting in a tyr602-to-cys (Y602C) substitution. His mother, maternal grandfather, and great-grandmother were also affected.
In affected members of a large family with hereditary motor and sensory neuropathy type IIC (HMSN2C; 606071), Chen et al. (2010) identified a heterozygous c.1625C-A transversion in exon 10 of the TRPV4 gene, resulting in a ser542-to-tyr (S542Y) substitution in the transmembrane domain. The mutation was not found in 400 control chromosomes. The distal sensory loss and muscle weakness in this family was relatively mild, and all but 1 patient had vocal cord paresis. In addition, affected individuals had proportional short stature, which was more pronounced in females, and 1 had dolichocephaly.
In a patient with lethal neonatal metatropic dysplasia (MTD; 156530), Camacho et al. (2010) identified heterozygosity for a c.366C-T transition in exon 2 of the TRPV4 gene, resulting in a thr89-to-ile (T89I) substitution in the N-terminal cytoplasmic domain.
In a patient with lethal infantile metatropic dysplasia (MTD; 156530), Camacho et al. (2010) identified heterozygosity for a c.590A-G transition in exon 4 of the TRPV4 gene, resulting in a lys197-to-arg (K197R) substitution in the ANK2 domain.
Hereditary Motor and Sensory Neuropathy Type IIC
In a family with hereditary motor and sensory neuropathy type IIC (HMSN2C; 606071) originally reported by Donaghy and Kennett (1999), Klein et al. (2011) identified a heterozygous c.694C-T transition in exon 4 of the TRPV4 gene, resulting in an arg232-to-cys (R232C) substitution in a conserved residue in the ankyrin-repeat domain. In vitro functional expression studies showed that the mutant protein had the same subcellular localization as wildtype in HEK293 cells and localized to the plasma membrane similar to wildtype in HeLa cells. In HEK293 cells, the mutant protein caused increased agonist-induced channel activity and increased basal intracellular calcium concentrations compared to wildtype. HeLa cells expressing the mutant protein showed increased cell death, which could be suppressed by the TRPV antagonist ruthenium red. The mutation was not found in 800 controls.
Distal Hereditary Motor Neuronopathy 8, Autosomal Dominant
Astrea et al. (2012) identified an R232C mutation in an 11-year-old girl with autosomal dominant distal hereditary motor neuropathy-8 (HMND8; 600175). She had proximal and distal muscle weakness, atrophy of the distal leg muscles, and clubfoot. MRI of the thighs and calf muscles showed extensive fatty atrophy with preservation of the biceps femoris in the lateral thighs and of the medial gastrocnemius in the posteromedial calves. This pattern was distinct when compared to a patient with non-TRPV4 spinal muscular atrophy.
In a 30-year-old man with HMSN2C (606071), Klein et al. (2011) identified a de novo heterozygous c.947G-A transition in exon 6 of the TRPV4 gene, resulting in an arg316-to-his (R316H) substitution in a conserved residue in the ankyrin-repeat domain. In vitro functional expression studies showed that the mutant protein had the same subcellular localization as wildtype in HEK293 cells and localized to the plasma membrane similar to wildtype in HeLa cells. In HEK293 cells, the mutant protein caused increased agonist-induced channel activity and increased basal intracellular calcium concentrations compared to wildtype. HeLa cells expressing the mutant protein showed increased cell death, which could be suppressed by the TRPV antagonist ruthenium red. The mutation was not found in 800 controls.
In a 21-week-old fetus with severe metatropic dysplasia (MTD; 156530) and fetal akinesia, Unger et al. (2011) identified a de novo heterozygous mutation in the TRPV4 gene, resulting in a gly78-to-trp (G78W) substitution in a conserved residue. Prenatal ultrasound at age 20 weeks' gestation showed short long bones, narrow bell-shaped thorax, finger contractures, and undetectable fetal movements. After termination, the fetus was found to have short long bones with mildly accentuated metaphyses, cartilaginous expansions of the elbow, wrist, and knee joints, relatively long hands and feet, and flattened vertebral bodies. Unger et al. (2011) noted that skeletal dysplasias do not generally cause arthrogryposis multiplex, as seen in this patient, and suggested that this TRPV4 mutation may cause a combination of a severe skeletal dysplasia and a neurologic phenotype causing fetal akinesia.
In a pair of 20-week-old monozygotic twins with severe metatropic dysplasia (MTD; 156530) and fetal akinesia, Unger et al. (2011) identified a de novo heterozygous mutation in the TRPV4 gene, resulting in a thr740-to-ile (T740I) substitution in a conserved residue. Absence of fetal movements with arthrogryposis was detected on prenatal ultrasound. Both fetuses had short long bones, thoracic hypoplasia, a sacrococcygeal tail, and contractures. Unger et al. (2011) noted that skeletal dysplasias do not generally cause arthrogryposis multiplex, as seen in these patients, and suggested that this TRPV4 mutation may cause a combination of a severe skeletal dysplasia and a neurologic phenotype causing fetal akinesia.
In a male infant, born of consanguineous Algerian parents, with severe metatropic dysplasia (MTD; 156530), Unger et al. (2011) identified a de novo heterozygous mutation in the TRPV4 gene, resulting in a lys276-to-glu (K276E) substitution in a conserved residue. The mother noted diminished fetal movements during pregnancy, which was confirmed by ultrasound. At birth the infant was noted to have severe contractures consistent with fetal akinesia syndrome, thoracic hypoplasia, clubfeet, camptodactyly, and enlarged joints. Radiographs confirmed metatropic dysplasia. The legs could not be straightened and remained in a flexed and adducted position. Although neonatal neurologic examination was normal, except for restricted movements, electromyography at age 3 months showed an absence of voluntary activity in the lower limbs. There was some residual activity in the upper limbs, and there were signs of a chronic axonal denervating process. These results were considered to be indicative of a neuropathic disorder. The baby died of respiratory complications at age 4 months. Unger et al. (2011) noted that skeletal dysplasias do not generally cause arthrogryposis multiplex, as seen in this patient, and since electrophysiologic studies indicated a neuropathic process, this TRPV4 mutation may cause a combination of a severe skeletal dysplasia and a neurologic phenotype causing fetal akinesia.
In all affected members of a family with digital arthropathy-brachydactyly (FDAB; 606835), originally reported by Amor et al. (2002), Lamande et al. (2011) identified heterozygosity for an c.819C-G transversion in exon 5 of the TRPV4 gene, resulting in a phe273-to-leu (F273L) substitution at a highly conserved residue within finger loop 3. The mutation was not found in 264 control alleles. Functional analysis revealed that the mutant protein was poorly expressed on the cell surface, and although a small increase in constitutive activity of the mutant channel compared to wildtype was observed, the mutant channel showed a significantly reduced response to agonists and the hypotonicity response was ablated.
In all 5 affected members of a family with digital arthropathy-brachydactyly (FDAB; 606835), Lamande et al. (2011) identified heterozygosity for an c.812G-C transversion in exon 5 of the TRPV4 gene, resulting in an arg271-to-pro (R271P) substitution at a highly conserved residue within finger loop 3. The mutation was not found in 264 control alleles. Functional analysis revealed that the mutant protein was poorly expressed on the cell surface, and although a small increase in constitutive activity of the mutant channel compared to wildtype was observed, the mutant channel showed a significantly reduced response to agonists and the hypotonicity response was ablated.
In a man with digital arthropathy-brachydactyly (FDAB; 606835), Lamande et al. (2011) identified heterozygosity for an c.809G-T transversion in exon 5 of the TRPV4 gene, resulting in a gly270-to-val (G270V) substitution at a highly conserved residue within finger loop 3. The mutation was not found in the patient's unaffected sister or in 264 control alleles. Functional analysis revealed that the mutant protein was poorly expressed on the cell surface, and although a small increase in constitutive activity of the mutant channel compared to wildtype was observed, the mutant channel showed a significantly reduced response to agonists and the hypotonicity response was ablated.
Hereditary Motor and Sensory Neuropathy Type IIC
In 3 members of a family with HMSN2C (606071), Landoure et al. (2012) identified a heterozygous c.557G-A transition in the TRPV4 gene, resulting in an arg186-to-gln (R186Q) substitution at a highly conserved residue situated on the convex face of the ankyrin repeat domain (ARD). The mutation was found by exome sequencing and confirmed by Sanger sequencing. This family had previously been reported as family 3 in Landoure et al. (2010), but the primers used in that study did not identify the TRPV4 mutation. Functional expression studies in HEK293 cells showed that the R186Q mutant protein resulted in increased calcium levels and increased cell death, suggesting abnormal constitutive TRPV4 activity, as observed with the R269C (605427.0011) mutant. The patients had progressive distal limb muscle weakness and atrophy, hoarse voice, and stridor on exertion. Nerve conduction studies confirmed an axonal neuropathy with phrenic nerve involvement. Two patients had scoliosis and 1 had sensorineural hearing loss, but none had skeletal dysplasia.
Distal Hereditary Motor Neuronopathy Type VIII
Echaniz-Laguna et al. (2014) identified a heterozygous R186Q mutation in a child with autosomal dominant distal hereditary motor neuropathy-8 (HMND8; 600175). The patient's unaffected mother also carried the mutation, consistent with incomplete penetrance.
In 4 sibs from a Greek family with avascular necrosis of the femoral head (ANFH2; 617383), Mah et al. (2016) identified heterozygosity for a 4-bp deletion (c.2480_2483delCCCG, NM_021625.4) followed by a c.2486T-A transversion (c.2486T-A, NM_021625.4) in a highly conserved region of the TRPV4 gene, causing a frameshift that results in a premature termination codon (Val829TrpfsTer3). The mutation was not found in an unaffected brother, or in the 1000 Genomes or Exome Variant Server databases; parental DNA was unavailable, but the sibs' father reportedly had symptoms of joint pain that were never evaluated. Functional analysis in patient fibroblasts and transduced HEK293 cells indicated that the mutation results in a gain-of-function of TRPV4 channels by impeding channel closure.
In a patient (R09-035) with a neonatal lethal form of metatropic dysplasia (MTD; 156530), Camacho et al. (2010) identified heterozygosity for an c.1853T-C transition in exon 12 of the TRPV4 gene that resulted in a leu618-to-pro (L618P) substitution at a highly evolutionarily conserved amino acid residue in transmembrane segment 5 (TM5).
In a patient (R09-440A) with nonlethal MTD, Weinstein et al. (2016) detected somatic mosaicism for the L618P mutation in TRPV4 previously identified by Camacho et al. (2010). Sanger sequencing was negative for mutations in all of the coding exons of TRPV4, as well as of other genes consistent with the phenotype. Subsequent exome sequencing detected a c.1853T-C transition in 16 of 71 reads, consistent with somatic mosaicism. Parental exomes were negative for the mutation. Comparison of the levels of the mutant allele in this patient with those of the patient of Camacho et al. (2010) showed that 15% of alleles in blood cells contained the mutation, implying that about 30% of cells in the patient would be expected to be heterozygous for the L618P allele. However, the level of mosaicism in the target tissue (cartilage) could not be assessed directly because a sample was not available. Weinstein et al. (2016) noted that high-throughput sequencing can have higher sensitivity for the detection of mosaicism than Sanger sequence analysis.
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