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Mutation spectrum in the large GTPase dynamin 2, and genotype-phenotype correlation in autosomal dominant centronuclear myopathy

Johann Böhm 1 Valérie Biancalana 1 Elizabeth T Dechene Marc Bitoun 2 Christophe Pierson Elise Schaefer 3 Hatice Karasoy 4 Melissa A Dempsey Fabrice Klein Nicolas Dondaine Christine Kretz 1 Nicolas Haumesser Claire Poirson Anne Toussaint 5 Rebecca S Greenleaf Melissa A Barger Lane J Mahoney Peter B Kang Edmar Zanoteli John Vissing 6 Nanna Witting Andoni Echaniz-Laguna 7 Carina Wallgren-Pettersson 8 James Dowling 9 Luciano Merlini 10 Anders Oldfors Lilian Bomme Ousager Judith Melki 11 Amanda Krause 12 Christina Jern 13 Acary S B Oliveira Florence Petit 14 Aurélia Jacquette 2 Annabelle Chaussenot 15 David Mowat Bruno Leheup 16 Michele Michel Juan José Poza Aldea Fabrice Michel 17 Alain Furby 18 Jose E Barcena Llona Rudy van Coster 19 Enrico Bertini 20 Jon Andoni Urtizberea Valérie Drouin-Garraud 21 Christophe Béroud 22 Bernard Prudhon 2 Melanie Bedford Katherine Mathews Lori a H Erby Stephen A Smith Jennifer Roggenbuck Carol A Crowe 23 Allison Brennan Spitale Sheila C Johal Anthony A Amato Laurie A Demmer Jessica Jonas Basil T Darras Thomas D Bird Mercy Laurino Selman I Welt Cynthia Trotter Pascale Guicheney 24 Soma Das 25 Jean-Louis Mandel 1, 26 Alan H Beggs Jocelyn Laporte 1 Elizabeth T. Dechene Melissa A. Dempsey Rebecca S. Greenleaf Melissa A. Barger Lane J. Mahoney Peter B. Kang Acary S. B. Oliveira Jose E. Barcena Llona Lori A. H. Erby Stephen A. Smith Carol A. Crowe Sheila C. Johal Anthony A. Amato Laurie A. Demmer Basil T. Darras Thomas D. Bird Selman I. Welt Alan H. Beggs 27
Abstract : Centronuclear myopathy (CNM) is a genetically heterogeneous disorder associated with general skeletal muscle weakness, type I fiber predominance and atrophy, and abnormally centralized nuclei. Autosomal dominant CNM is due to mutations in the large GTPase dynamin 2 (DNM2), a mechanochemical enzyme regulating cytoskeleton and membrane trafficking in cells. To date, 40 families with CNM-related DNM2 mutations have been described, and here we report 60 additional families encompassing a broad genotypic and phenotypic spectrum. In total, 18 different mutations are reported in 100 families and our cohort harbors nine known and four new mutations, including the first splice-site mutation. Genotype-phenotype correlation hypotheses are drawn from the published and new data, and allow an efficient screening strategy for molecular diagnosis. In addition to CNM, dissimilar DNM2 mutations are associated with Charcot-Marie-Tooth (CMT) peripheral neuropathy (CMTD1B and CMT2M), suggesting a tissue-specific impact of the mutations. In this study, we discuss the possible clinical overlap of CNM and CMT, and the biological significance of the respective mutations based on the known functions of dynamin 2 and its protein structure. Defects in membrane trafficking due to DNM2 mutations potentially represent a common pathological mechanism in CNM and CMT.
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Submitted on : Thursday, January 11, 2018 - 6:23:33 PM
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Johann Böhm, Valérie Biancalana, Elizabeth T Dechene, Marc Bitoun, Christophe Pierson, et al.. Mutation spectrum in the large GTPase dynamin 2, and genotype-phenotype correlation in autosomal dominant centronuclear myopathy. Human Mutation, Wiley, 2012, 33 (6), pp.949 - 959. ⟨10.1002/humu.22067⟩. ⟨hal-01681807⟩



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