Abstract
Heterozygous mutations in dynamin 2 (DNM2) have been linked to dominant Charcot-Marie-Tooth neuropathy and centronuclear myopathy. We report the first homozygous mutation in the DNM2 protein p.Phe379Val, in three consanguineous patients with a lethal congenital syndrome associating akinesia, joint contractures, hypotonia, skeletal abnormalities, and brain and retinal hemorrhages. In vitro membrane tubulation, trafficking and GTPase assays are consistent with an impact of the DNM2p.Phe379Val mutation on endocytosis. Although DNM2 has been previously implicated in axonal and muscle maintenance, the clinical manifestation in our patients taken together with our expression analysis profile during mouse embryogenesis and knockdown approaches in zebrafish resulting in defects in muscle organization and angiogenesis support a pleiotropic role for DNM2 during fetal development in vertebrates and humans.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Michalk A, Stricker S, Becker J et al: Acetylcholine receptor pathway mutations explain various fetal akinesia deformation sequence disorders. Am J Hum Genet 2008; 82: 464–476.
Ravenscroft G, Sollis E, Charles AK, North KN, Baynam G, Laing NG : Fetal akinesia: review of the genetics of the neuromuscular causes. J Med Genet 2011; 48: 793–801.
Sewry CA, Jimenez-Mallebrera C, Muntoni F : Congenital myopathies. Curr Opin Neurol 2008; 21: 569–575.
Bitoun M, Maugenre S, Jeannet PY et al: Mutations in dynamin 2 cause dominant centronuclear myopathy. Nat Genet 2005; 37: 1207–1209.
Bohm J, Biancalana V, Dechene ET et al: Mutation spectrum in the large GTPase dynamin 2, and genotype-phenotype correlation in autosomal dominant centronuclear myopathy. Hum Mutat 2012; 33: 949–959.
Zuchner S, Noureddine M, Kennerson M et al: Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth disease. Nat Genet 2005; 37: 289–294.
Stoetzel C, Muller J, Laurier V et al: Identification of a novel BBS gene (BBS12) highlights the major role of a vertebrate-specific branch of chaperonin-related proteins in Bardet-Biedl syndrome. Am J Hum Genet 2007; 80: 1–11.
Pareyson D, Marchesi C : Diagnosis, natural history, and management of Charcot-Marie-Tooth disease. Lancet Neurol 2009; 8: 654–667.
Bitoun M, Durieux AC, Prudhon B et al: Dynamin 2 mutations associated with human diseases impair clathrin-mediated receptor endocytosis. Hum Mutat 2009; 30: 1419–1427.
Damke H, Baba T, Warnock DE, Schmid SL : Induction of mutant dynamin specifically blocks endocytic coated vesicle formation. J Cell Biol 1994; 127: 915–934.
van der Bliek AM, Meyerowitz EM : Dynamin-like protein encoded by the Drosophila shibire gene associated with vesicular traffic. Nature 1991; 351: 411–414.
Chappie JS, Acharya S, Leonard M, Schmid SL, Dyda F : G domain dimerization controls dynamin's assembly-stimulated GTPase activity. Nature 2010; 465: 435–440.
Praefcke GJ, McMahon HT : The dynamin superfamily: universal membrane tubulation and fission molecules? Nat Rev Mol Cell Biol 2004; 5: 133–147.
Cao H, Thompson HM, Krueger EW, McNiven MA : Disruption of Golgi structure and function in mammalian cells expressing a mutant dynamin. J Cell Sci 2000; 113 (Part 11): 1993–2002.
Thompson HM, Cao H, Chen J, Euteneuer U, McNiven MA : Dynamin 2 binds gamma-tubulin and participates in centrosome cohesion. Nat Cell Biol 2004; 6: 335–342.
Schaeren-Wiemers N, Gerfin-Moser A : A single protocol to detect transcripts of various types and expression levels in neural tissue and cultured cells: in situ hybridization using digoxigenin-labelled cRNA probes. Histochemistry 1993; 100: 431–440.
Ferguson SM, Raimondi A, Paradise S et al: Coordinated actions of actin and BAR proteins upstream of dynamin at endocytic clathrin-coated pits. Dev Cell 2009; 17: 811–822.
Ferguson SM, De Camilli P : Dynamin, a membrane-remodelling GTPase. Nat Rev Mol Cell Biol 2012; 13: 75–88.
Cowling BS, Toussaint A, Amoasii L et al: Increased expression of wild-type or a centronuclear myopathy mutant of dynamin 2 in skeletal muscle of adult mice leads to structural defects and muscle weakness. Am J Pathol 2011; 178: 2224–2235.
Durieux AC, Vignaud A, Prudhon B et al: A centronuclear myopathy-dynamin 2 mutation impairs skeletal muscle structure and function in mice. Hum Mol Genet 2010; 19: 4820–4836.
Koutsopoulos OS, Koch C, Tosch V, Bohm J, North KN, Laporte J : Mild functional differences of dynamin 2 mutations associated to centronuclear myopathy and Charcot-Marie Tooth peripheral neuropathy. PLoS One 2011; 6: e27498.
Liu YW, Lukiyanchuk V, Schmid SL : Common membrane trafficking defects of disease-associated dynamin 2 mutations. Traffic 2011; 12: 1620–1633.
Sidiropoulos PN, Miehe M, Bock T et al: Dynamin 2 mutations in Charcot-Marie-Tooth neuropathy highlight the importance of clathrin-mediated endocytosis in myelination. Brain 2012; 135: 1395–1411.
Acknowledgements
We thank Pietro De Camilli, Joelle Morvan, Nicolas Vitale, Dominique Massotte, Valérie Biancalana and Michel Koenig for reagents and discussion, Fabrice Klein Marc Koch, Olivia Wendling, Frederic Humbert, Emilie Peter and Isabelle Kolb-Cheynel for technical assistance, Frederic Plewniak for the homoSNP linkage program and Sjoerd van Duinen for histology images. Some control cell lines were established by the Généthon DNA and Cell Bank (Evry, France). This study was supported by grants from the Institute National de la Santé et de la Recherche Médicale, the Center National de la Recherche Scientifique, University of Strasbourg, Collège de France, the Association Française contre les Myopathies, Fondation Recherche Médicale, Agence Nationale de la Recherche and the E-rare program.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies the paper on European Journal of Human Genetics website
Supplementary information
Rights and permissions
About this article
Cite this article
Koutsopoulos, O., Kretz, C., Weller, C. et al. Dynamin 2 homozygous mutation in humans with a lethal congenital syndrome. Eur J Hum Genet 21, 637–642 (2013). https://doi.org/10.1038/ejhg.2012.226
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/ejhg.2012.226
Keywords
This article is cited by
-
Differential impact of ubiquitous and muscle dynamin 2 isoforms in muscle physiology and centronuclear myopathy
Nature Communications (2022)
-
A meta-analysis of prognostic biomarkers in neonatal retinal hemorrhage
International Ophthalmology (2022)
-
Mutational and clinical spectrum of centronuclear myopathy in 9 cases and a literature review of Chinese patients
Neurological Sciences (2022)
-
A review of Dynamin 2 involvement in cancers highlights a promising therapeutic target
Journal of Experimental & Clinical Cancer Research (2021)
-
A new mutation in DNM2 gene in a large Italian family
Neurological Sciences (2021)
