TY - JOUR
T1 - Dominant mutations in the cation channel gene transient receptor potential vanilloid 4 cause an unusual spectrum of neuropathies
AU - Zimoń, Magdalena
AU - Baets, Jonathan
AU - Auer-Grumbach, Michaela
AU - Berciano, José
AU - Garcia, Antonio
AU - Lopez-Laso, Eduardo
AU - Merlini, Luciano
AU - Hilton-Jones, David
AU - McEntagart, Meriel
AU - Crosby, Andrew H.
AU - Barisic, Nina
AU - Boltshauser, Eugen
AU - Shaw, Christopher E.
AU - Landouré, Guida
AU - Ludlow, Christy L.
AU - Gaudet, Rachelle
AU - Houlden, Henry
AU - Reilly, Mary M.
AU - Fischbeck, Kenneth H.
AU - Sumner, Charlotte J.
AU - Timmerman, Vincent
AU - Jordanova, Albena
AU - Jonghe, Peter De
N1 - Funding Information:
University of Antwerp, the Fund for Scientific Research (FWO-Flanders); Medical Foundation Queen Elisabeth (GSKE); ‘Association Belge contre les Maladies Neuromusculaires’ (ABMM);Interuniversity Attraction Poles P6/43 program of the Belgian Federal Science Policy Office (BELSPO); ‘Methusalem excellence grant’ of the Flemish Government; Austrian Science Fond (FWF; P19455-B05); McKnight Scholar Award and NIH grant (RG; R01GM081340); PhD fellowships of the FWO-Flanders to M.Z. and J.B.; Medical Research Council (MRC) and the Muscular Dystrophy Campaign support to M.M.R. and H.H. The work of M.M.R. and H.H. was undertaken at University College London Hospitals/University College London, which received a proportion of funding from the Department of Health’s National Institute for Health Research Biomedical Research Centres funding scheme; intramural research funds from NINDS.
PY - 2010/6
Y1 - 2010/6
N2 - 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.
AB - 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.
KW - Congenital distal spinal muscular atrophy
KW - Hereditary motor and sensory neuropathy type 2C
KW - Scapuloperoneal spinal muscular atrophy
KW - Skeletal dysplasia
KW - Transient receptor potential vanilloid 4 gene
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U2 - 10.1093/brain/awq109
DO - 10.1093/brain/awq109
M3 - Article
C2 - 20460441
AN - SCOPUS:77952959682
SN - 0006-8950
VL - 133
SP - 1798
EP - 1809
JO - Brain
JF - Brain
IS - 6
ER -