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 J. 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 C 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)

1 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
2 Institut de Myologie
3 Service de génétique médicale
4 Department of Neurology
5 IGBMC - Institut de génétique et biologie moléculaire et cellulaire
6 Applied human genetics
7 Département de Neurologie
8 Department of Medical and Clinical Genetics [Helsinki]
9 Department of Pediatrics
10 CNR
11 Hôpital Bicêtre
12 Division of human Genetics
13 Insitute of Neuroscience and Physiology
14 JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837
15 IRCAN - Institut de Recherche sur le Cancer et le Vieillissement
16 Service de Génétique Médicale [CHRU Nancy]
17 VEGATEC
18 Service de Neurologie
19 Department of Pediatrics
20 Dept. Medical Biochemistry, Biology and Physics
21 Service de génétique [Rouen]
22 LGMR - Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques
23 Department of Pediatrics
24 Unité UMR_S956
25 Entomology Research Unit, Department of Zoology
26 Collège de France - Chaire Génétique Humaine
27 Division of Genetics and Program in Genomics, The Manton Center for Orphan Disease Research,

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.

Domains: Computer Science [cs]; Bioinformatics [q-bio.QM]; Life Sciences [q-bio]; Genetics; Human genetics; Life Sciences [q-bio]; Biochemistry, Molecular Biology; Molecular biology

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, 2012, 33 (6), pp.949 - 959. ⟨10.1002/humu.22067⟩. ⟨hal-01681807⟩