Dominant mutations in the cation channel gene transient receptor potential vanil

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Brain. 2010 May 11.

Dominant mutations in the cation channel gene transient receptor potential

vanilloid 4 cause an unusual spectrum of neuropathies.

Zimon M, Baets J, Auer-Grumbach M, Berciano J, A, -Laso E, Merlini

L, Hilton- D, McEntagart M, Crosby AH, Barisic N, Boltshauser E, Shaw CE,

Landouré G, Ludlow CL, Gaudet R, Houlden H, Reilly MM, Fischbeck KH, Sumner CJ,

Timmerman V, Jordanova A, Jonghe PD.

1 Neurogenetics Group, VIB Department of Molecular Genetics, University of

Antwerp, 2610 Antwerpen, Belgium.

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.