Dominant mutations in the cation channel gene transient receptor potential vanilloid 4 cause an unusual spectrum of neuropathies
Magdalena Zimoń,Jonathan Baets,Michaela Auer-Grumbach,José Berciano,Antonio G. García,Eduardo López-Laso,Luciano Merlini,David Hilton-Jones,Meriel McEntagart,Andrew H. Crosby,Nina Barišić,Eugen Boltshauser,Christopher Shaw,Guida Landouré,Christy L. Ludlow,Rachelle Gaudet,Henry Houlden,Mary M. Reilly,Kenneth H. Fischbeck,Charlotte J. Sumner,Vincent Timmerman,Albena Jordanova,Peter De Jonghe +22 more
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TLDR
The majority of patients displayed a predominantly, or pure, motor neuropathy with axonal characteristics observed on electrophysiological testing, which is relatively unusual in the context of hereditary neuropathies and has important implications for diagnostic testing and genetic counselling.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.read more
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Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine
Bernd Nilius,Arpad Szallasi +1 more
TL;DR: An overview of the functional properties of mammalian TRP channels is given, their roles in acquired and hereditary diseases are described, and their potential as drug targets for therapeutic intervention is discussed.
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The puzzle of TRPV4 channelopathies
Bernd Nilius,Thomas Voets +1 more
TL;DR: Putative mechanisms to explain the puzzle, and how mutations in the same region of the channel cause different diseases, are discussed and experimental approaches to tackle this surprising problem are suggested.
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Charcot-Marie-Tooth disease.
TL;DR: This review aims to provide a simple, pragmatic approach to diagnosing CMT from a clinician's perspective.
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Transient receptor potential (TRP) channels as drug targets for diseases of the digestive system
TL;DR: Transient receptor potential channels are identified as promising drug targets for the management of a number of gastrointestinal pathologies and major efforts are put into the development of selective TRP channel agonists and antagonists.
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The Polymodal Ion Channel Transient Receptor Potential Vanilloid 4 Modulates Calcium Flux, Spiking Rate, and Apoptosis of Mouse Retinal Ganglion Cells
Daniel A. Ryskamp,Paul Witkovsky,Peter Barabas,Wei Huang,Christopher L. Koehler,Nikolay P. Akimov,Suk Hee Lee,Shiwani Chauhan,Wei Xing,René C. Rentería,Wolfgang Liedtke,David Križaj +11 more
TL;DR: The results demonstrate functional TRPV4 expression in RGCs and suggest that its activation mediates response to membrane stretch leading to elevated [Ca2+]i and augmented excitability and is a component of the response mechanism to pathological elevations of intraocular pressure.
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