Fulltext

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

Zimoń, Magdalena ; Baets, Jonathan ; Auer-Grumbach, Michaela ; Berciano, José ; Garcia, Antonio ; Lopez-Laso, Eduardo ; Merlini, Luciano ; Hilton-Jones, David ; McEntagart, Meriel ; Crosby, Andrew H. ; Barisic, Nina ; Boltshauser, Eugen ; Shaw, Christopher E. ; Landouré, Guida ; Ludlow, Christy L. ; Gaudet, Rachelle ; Houlden, Henry ; Reilly, Mary M. ; Fischbeck, Kenneth H. ; Sumner, Charlotte J. ; Timmerman, Vincent ; Jordanova, Albena ; Jonghe, Peter De

In: Brain, 2010, vol. 133, no. 6, p. 1798-1809

Ajouter à la liste personnelle
    Titre
    • Dominant mutations in the cation channel gene transient receptor potential vanilloid 4 cause an unusual spectrum of neuropathies
    Auteur
    • Zimoń, Magdalena. 1 Neurogenetics Group, VIB Department of Molecular Genetics, University of Antwerp, 2610 Antwerpen, Belgium
    • Baets, Jonathan. 1 Neurogenetics Group, VIB Department of Molecular Genetics, University of Antwerp, 2610 Antwerpen, Belgium
    • Auer-Grumbach, Michaela. 4 Institute of Medical Biology and Department of Internal Medicine, Diabetes and Metabolism, Medical University Graz, 8010 Graz, Austria
    • Berciano, José. 5 Service of Neurology, University Hospital ‘Marqués de Valdecilla', ‘Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED)' and University of Cantabria (UC), 39008 Santander, Spain
    • Garcia, Antonio. 6 Service of Clinical Neurophysiology, University Hospital ‘Marqués de Valdecilla', ‘Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED)' and University of Cantabria (UC), 39008 Santander, Spain
    • Lopez-Laso, Eduardo. 7 Paediatric Neurology Unit, Department of Paediatrics, University Hospital Reina Sofia, University of Córdoba, 14005 Córdoba, Spain
    • Merlini, Luciano. 8 Muscle Unit, Division of Medical Genetics, Department of Experimental and Diagnostic Medicine, University of Ferrara, 44100 Ferrara, Italy
    • Hilton-Jones, David. 10 Department of Neurology, John Radcliffe Hospital, OX3 9DU Oxford, UK
    • McEntagart, Meriel. 11 Department of Medical Genetics, St. George's Hospital, Medical School, SW17 0RE London, UK
    • Crosby, Andrew H.. 11 Department of Medical Genetics, St. George's Hospital, Medical School, SW17 0RE London, UK
    • Barisic, Nina. 12 Department of Paediatrics, University of Zagreb, Medical School, University Hospital Centre Zagreb, 10000 Zagreb,Croatia
    • Boltshauser, Eugen. 13 Department of Paediatric Neurology, University of Zürich, Children's Hospital, CH-8032 Zürich, Switzerland
    • Shaw, Christopher E.. 14 MRC Centre for Neurodegeneration Research, Department of Clinical Neuroscience, King's College London, Institute of Psychiatry, SE5 8AF London, UK
    • Landouré, Guida. 15 University College London, Departments of Medicine and Neuroscience, WC1N 3BG London, UK
    • Ludlow, Christy L.. 17 Laboratory of Neural Bases of Communication and Swallowing, James Madison University, 22807 Harrisonburg, VA, USA
    • Gaudet, Rachelle. 18 Department of Molecular and Cellular Biology, Harvard University, 02138 Cambridge, MA, USA
    • Houlden, Henry. 19 Department of Molecular Neuroscience, UCL Institute of Neurology, WC1N 3BG London, UK
    • Reilly, Mary M.. 20 MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, WC1N 3BG London, UK
    • Fischbeck, Kenneth H.. 16 Neurogenetics Branch, NINDS, NIH, 3705 Bethesda, MD, USA
    • Sumner, Charlotte J.. 21 Department of Neurology, Johns Hopkins University, 21287 Baltimore, MD, USA
    • Timmerman, Vincent. 2 Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, 2610 Antwerpen, Belgium
    • Jordanova, Albena. 1 Neurogenetics Group, VIB Department of Molecular Genetics, University of Antwerp, 2610 Antwerpen, Belgium
    • Jonghe, Peter De. 1 Neurogenetics Group, VIB Department of Molecular Genetics, University of Antwerp, 2610 Antwerpen, Belgium
    Type de document
    • Postprint
    Langue
    • Anglais
    Publié dans
    • Brain, 2010, vol. 133, no. 6, p. 1798-1809. Oxford University Press
    Autre version électronique
    Identifiant OAI-PMH
    • oai:doc.rero.ch:296926
    Summary
    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