Phenotypic variability of TRPV4 related neuropathies

Teresinha Evangelista,Boglarka Bansagi,Angela Pyle,Helen Griffin,Konstantinos Douroudis,Tuomo Polvikoski,Thalia Antoniadi,Kate Bushby,Volker Straub,Patrick F Chinnery,Hanns Lochmüller,Rita Horvath

doi:10.1016/j.nmd.2015.03.007

Teresinha Evangelista, Boglarka Bansagi + Show 10 more

Open Access

https://doi.org/10.1016/j.nmd.2015.03.007

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Abstract

Mutations in the transient receptor potential vanilloid 4 (TRPV4) gene have been associated with autosomal dominant skeletal dysplasias and peripheral nervous system syndromes (PNSS). PNSS include Charcot–Marie–Tooth disease (CMT) type 2C, congenital spinal muscular atrophy and arthrogryposis and scapuloperoneal spinal muscular atrophy. We report the clinical, electrophysiological and muscle biopsy findings in two unrelated patients with two novel heterozygous missense mutations in the TRPV4 gene. Whole exome sequencing was carried out on genomic DNA using Illumina TruseqTM 62Mb exome capture. Patient 1 harbours a de novo c.805C > T (p.Arg269Cys) mutation. Clinically, this patient shows signs of both scapuloperoneal spinal muscular atrophy and skeletal dysplasia. Patient 2 harbours a novel c.184G > A (p.Asp62Asn) mutation. While the clinical phenotype is compatible with CMT type 2C with the patient's muscle harbours basophilic inclusions. Mutations in the TRPV4 gene have a broad phenotypic variability and disease severity and may share a similar pathogenic mechanism with Heat Shock Protein related neuropathies.

Highlights

IntroductionTRPV4 (transient receptor potential vanilloid 4 channel; OMIM 605427) is a calcium permeable non-selective cation channel expressed in several tissues and cell types [1]
transient receptor potential vanilloid 4 (TRPV4) is a calcium permeable non-selective cation channel expressed in several tissues and cell types [1]
We report two patients, one manifesting a combination of scapuloperoneal spinal muscular atrophy and skeletal dysplasia while the other presented with a CMT2C phenotype and basophilic inclusions in the muscle biopsy

Summary

Introduction

TRPV4 (transient receptor potential vanilloid 4 channel; OMIM 605427) is a calcium permeable non-selective cation channel expressed in several tissues and cell types [1]. In bone it is expressed in osteoblasts, osteoclasts and chondrocytes and may be involved in bone remodelling. In the peripheral nervous system TRPV4 expression was demonstrated in the skin sensory receptors, in the dorsal root ganglia and to a lesser extent in the motor neurons [2]. The TRPV4 gene (NM_021625.4) is located on chromosome 12q23-q24.1 and is composed of 15 exons coding 5 different splice variants. The N-terminus is composed of six ankyrin repeats and the C-terminus consists of several calmodulin binding sites [4,5]

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