Comprehensive analysis of the TRPV4 gene in a large series of inherited neuropathies and controls.
ABSTRACT BACKGROUND: TRPV4 mutations have been identified in Charcot-Marie-Tooth type 2 (CMT2), scapuloperoneal spinal muscular atrophy and distal hereditary motor neuropathy (dHMN). OBJECTIVE: We aimed to screen the TRPV4 gene in 422 British patients with inherited neuropathy for potentially pathogenic mutations. METHODS: We sequenced TRPV4 coding regions and splice junctions in 271 patients with CMT2 and 151 patients with dHMN. Mutations were clinically and genetically characterised and screened in ≥345 matched controls. RESULTS: 13 missense and nonsense variants were identified, of which five were novel and absent from controls (G20R, E218K, N302Y, Y567X and T701I). N302Y and T701I mutations were present in typical CMT2 cases and are potentially pathogenic based on in silico analyses. G20R was detected in a patient with dHMN and her asymptomatic father and is possibly pathogenic with variable expressivity. The Y567X variant segregated with disease in a family with severe CMT2 but also with a MFN2 mutation reported to cause a mild CMT2 phenotype. Although Y567X caused nonsense mediated mRNA decay, the amount of TRPV4 protein on western blotting of patient lymphoblasts was no different to control. Y567X is therefore unlikely to be pathogenic. E218K is unlikely to be pathogenic based on segregation. CONCLUSIONS: In this comprehensive analysis of the TRPV4 gene, we identified mutations in <1% of patients with CMT2/dHMN. We found that TRPV4 likely harbours many missense and nonsense non-pathogenic variants that should be analysed in detail to prove pathogenicity before results are given to patients.
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Article: The puzzle of TRPV4 channelopathies.[Show abstract] [Hide abstract]
ABSTRACT: Hereditary channelopathies, that is, mutations in channel genes that alter channel function and are causal for the pathogenesis of the disease, have been described for several members of the transient receptor potential channel family. Mutations in the TRPV4 gene, encoding a polymodal Ca(2+) permeable channel, are causative for several human diseases, which affect the skeletal system and the peripheral nervous system, with highly variable phenotypes. In this review, we describe the phenotypes of TRPV4 channelopathies and overlapping symptoms. Putative mechanisms to explain the puzzle, and how mutations in the same region of the channel cause different diseases, are discussed and experimental approaches to tackle this surprising problem are suggested.EMBO Reports 01/2013; · 7.19 Impact Factor
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ABSTRACT: The importance of the TRPV4 channel for human physiology has been highlighted in recent years with the identification of an increasing number of hereditary diseases associated with mutations of this channel. However, the functional understanding of TRPV4 associated pathologies remains a puzzle due to incomplete understanding of the polymodal regulation of TRPV4 channels and lack of insight into the structure-function relationship of the channel. In this work, we identified a series of highly conserved aromatic residues in transmembrane (TM) helices 5-6 with profound importance for TRPV4 activity. Substituting F617, Y621 or F624 in TM5 with leucine reduced channel sensitivity to the agonist 4α-PDD and heat, yet two of these mutants–F617L and Y621L–showed increased activation in response to cell swelling. In TM6, a Y702L mutation significantly reduced sensitivity to all of the above stimuli. In conclusion, we have identified residues in TM5-6 which differentially affect heat and agonist activation, and we have demonstrated distinct activation pathways for 4α-PDD and osmolarityCell calcium 01/2013; · 4.29 Impact Factor