A novel mutation in the DNM2 gene impairs dynamin 2 localization in skeletal muscle of a patient with late onset centronuclear myopathy Biruta Kierdaszuk a , Mariusz Berdynski b , Justyna Karolczak c , Maria Jolanta Redowicz c , Cezary Zekanowski b , Anna M. Kaminska a,d,⇑ a Department of Neurology, Medical University of Warsaw, 1a Banacha St., 02-097 Warsaw, Poland b Department of Neurodegenerative Disorders, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego St., 02-106 Warszawa, Poland c Department of Biochemistry, Nencki Institute of Experimental Biology, 3 Pasteur St., 02-093 Warsaw, Poland d Neuromuscular Unit, Department of Neurosurgery, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego St., 02-106 Warszawa, Poland Received 15 June 2012; received in revised form 23 October 2012; accepted 13 December 2012 Abstract Centronuclear myopathies constitute a group of heterogeneous congenital myopathies characterized by the presence of abnormal, centrally located nuclei within muscle fibers. Centronuclear myopathies can be caused by mutations of several different genes, including DNM2, encoding dynamin 2 (DNM2) a large GTPase involved in membrane trafficking and endocytosis. We report a 52-year old female with slowly progressive muscle weakness, and a family history of the disease. Clinical, morphological, biochemical and genetic analyses of the proband and her family members were performed, including analyses of the proband’s muscle biopsy. A novel D614N mutation, located in the C-terminal region pleckstrin-homology (PH) domain of DNM2 was identified in the proband and four family members, who exhibited similar symptoms. The mutation was associated with profound changes in the localization of DNM2 in muscle fibers without significant changes in protein expression. Mutated DNM2 and proteins involved in the membrane trafficking or membrane compartments maintenance were dislocalized within the myofiber, and concentrated at centrally located nuclei. This novel causative mutation (D614N) within the DNM2 gene in a large Polish centronuclear myopathy family with a late age of overt clinical manifestation caused profound changes in DNM2 localization and impaired proper organization of myofibers, and skeletal muscle functioning. Ó 2012 Elsevier B.V. All rights reserved. Keywords: Centronuclear myopathy; Muscle biopsy; DNM2 gene; Dynamin, Myosin VI; Dystrophin 1. Introduction Centronuclear myopathies (CNMs) constitute a heterogeneous group of congenital myopathies characterized by abnormal, central localization of nuclei in muscle fibers [1,2]. Centronuclear myopathies can be classified into three main forms: recessive X-linked myotubular myopathy, caused by mutations in the myotubularin gene; autosomal recessive myopathy, caused by mutations in the amphiphysin 2 gene, and autosomal dominant myopathy. Autosomal dominant CNM is caused by mutations within the DNM2 gene encoding dynamin 2 (DNM2), a large GTPase involved in membrane trafficking and endocytosis. DNM2 is composed of five domains: an N-terminal GTPase domain, a middle domain (MD), a pleckstrin homology domain (PH), a GTPase effector domain (GED) and a C-terminal proline rich domain (PRD) (Fig. 1A). The pleckstrin homology domain is involved in targeting of dynamin to membranes via interaction with phosphoinositides [3], and 0960-8966/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.nmd.2012.12.007 ⇑ Corresponding author at: Department of Neurology, Medical University of Warsaw, 1a Banacha St., 02-097 Warsaw, Poland. Tel.: +48 22 599 28 58; fax: +48 22 599 18 57. E-mail address: amkaminska@wum.edu.pl (A.M. Kaminska). www.elsevier.com/locate/nmd Available online at www.sciencedirect.com Neuromuscular Disorders 23 (2013) 219–228