Dominant mutations in the cation channel gene transient receptor potential vanilloid 4 cause an unusual spectrum of neuropathies

Abstract

Hereditary neuropathies form a heterogeneous group of disorders for which over 40 causal genes have been identified to date. Recently, dominant mutations in the transient receptor potential vanilloid 4 gene were found to be associated with three distinct neuromuscular phenotypes: hereditary motor and sensory neuropathy 2C, scapuloperoneal spinal muscular atrophy and congenital distal spinal muscular atrophy. Transient receptor potential vanilloid 4 encodes a cation channel previously implicated in several types of dominantly inherited bone dysplasia syndromes. We performed DNA sequencing of the coding regions of transient receptor potential vanilloid 4 in a cohort of 145 patients with various types of hereditary neuropathy and identified five different heterozygous missense mutations in eight unrelated families. One mutation arose de novo in an isolated patient, and the remainder segregated in families. Two of the mutations were recurrent in unrelated families. Four mutations in transient receptor potential vanilloid 4 targeted conserved arginine residues in the ankyrin repeat domain, which is believed to be important in protein-protein interactions. Striking phenotypic variability between and within families was observed. The majority of patients displayed a predominantly, or pure, motor neuropathy with axonal characteristics observed on electrophysiological testing. The age of onset varied widely, ranging from congenital to late adulthood onset. Various combinations of additional features were present in most patients including vocal fold paralysis, scapular weakness, contractures and hearing loss. We identified six asymptomatic mutation carriers, indicating reduced penetrance of the transient receptor potential vanilloid 4 defects. This finding is relatively unusual in the context of hereditary neuropathies and has important implications for diagnostic testing and genetic counselling.

CMT2C with vocal cord paresis associated with short stature and mutations in the TRPV4 gene

“…9,18 The family members were not described as being short, but a subsequent sporadic case was noted to have short stature (height not given) compatible with the more detailed findings of the present study. 12 In the present study, we enlarge and unify the phenotypic spectrum associated with mutations in Figure 3 Sequence chromatograms of portions of exons 6 and 10 of TRPV4 from affected individuals with CMT2C in 2 families (A) A heterozygous C to A transversion at nucleotide 1625 (in exon 10) in an affected subject in family 1. This change predicts amino acid alteration of S542Y.…”

“…Although the mutations responsible for skeletal dysplasias are scattered along the gene, 8 of 11 mutations are located in the transmembrane domain. It is interesting that the novel mutation S542Y found in our family 1 with CMT2C and short stature and the V620I mutation associated with distal weakness and short stature 12 are both in the transmembrane domain (figure 4). Correlation of the different phenotypes with the various mutations will require further evaluation.…”

“…However, more recently 4 separate groups reported additional families with 5 mutations in TRPV4 associated with CMT2C including a previously described syndrome of SPSMA and congenital distal SMA. [9][10][11][12] The SPSMA family had variable skeletal abnormalities that included congenital hip dysplasia, scoliosis, smaller hands with clinodactyly, and one arm or leg shorter than the other. 9,18 The family members were not described as being short, but a subsequent sporadic case was noted to have short stature (height not given) compatible with the more detailed findings of the present study.…”

“…[5][6][7][8] Recently a few groups have described several families with autosomal dominant CMT2C, scapuloperoneal spinal muscular atrophy (SPSMA), and congenital distal spinal muscular atrophy (SMA) having mutations in the calcium permeable ion channel gene (transient receptor potential cation channel, subfamily V, member 4; TRPV4). [9][10][11][12] Independently, 2 groups previously reported other mutations in the TRPV4 gene associated with the bone disorders spondylometaphyseal dysplasia, metatropic dysplasia, and brachyolmia 13,14 (recently further expanded 15 ). We now describe 2 families having both CMT2C and short stature caused by mutations in TRPV4 (one novel), thereby enlarging and unifying the phenotypic spectrum associated with mutations in this gene.…”

Axonal Neuropathy-associated TRPV4 Regulates Neurotrophic Factor-derived Axonal Growth

“…These neuropathies are classified as axonal, nondemyelinating degenerations of sensory and motor nerves because nerve conduction velocities are unchanged (1,2,4). Recent genetic linkage studies in patients indicate that mutations in the ankyrin repeat domains of TRPV4 are implicated in the neuropathies (5)(6)(7)(8). The gain-of-function mutations in the ankyrin repeat domain of TRPV4 are known to cause degenerative diseases involving peripheral nerves (6,7,9).…”