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

Johann Böhm, Valerie Biancalana, Elizabeth T. DeChene, Marc Bitoun, Christopher R. Pierson, Elise Schaefer, Hatice Karasoy, Melissa A. Dempsey, Fabrice Klein, Nicolas Dondaine, Christine Kretz, Nicolas Haumesser, Claire Poirson, Anne Toussaint, Rebecca S. Greenleaf, Melissa A. Barger, Lane J. Mahoney, Peter B. Kang, Edmar Zanoteli, John VissingNanna Witting, Andoni Echaniz-Laguna, Carina Wallgren-Pettersson, James Dowling, Luciano Merlini, Anders Oldfors, Lilian Bomme Ousager, Judith Melki, Amanda Krause, Christina Jern, Acary S.B. Oliveira, Florence Petit, Aurélia Jacquette, Annabelle Chaussenot, David Mowat, Bruno Leheup, Michele Cristofano, Juan José Poza Aldea, Fabrice Michel, Alain Furby, Jose E.Barcena Llona, Rudy Van Coster, Enrico Bertini, Jon Andoni Urtizberea, Valérie Drouin-Garraud, Christophe Bé roud, Bernard Prudhon, Melanie Bedford, Katherine Mathews, Lori A.H. Erby, Stephen A. Smith, Jennifer Roggenbuck, Carol A. Crowe, 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, Soma Das, Jean Louis Mandel, Alan H. Beggs, Jocelyn Laporte

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)949-959
Number of pages11
JournalHuman mutation
Volume33
Issue number6
DOIs
StatePublished - Jun 2012

Keywords

  • ADCNM
  • BIN1
  • CMT2M
  • CMTD1B
  • Centronuclear myopathy
  • Charcot-marie-tooth neuropathy
  • Congenital myopathy
  • DNM2
  • Di-CMTB
  • Endocytosis
  • HMSNII
  • Hereditary motor and sensory neuropathy type II
  • MTM1
  • Myotubular myopathy
  • RYR1

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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