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Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth disease

Nature Genetics volume 37, pages 289–294 (2005)Cite this article

Abstract

Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous group of peripheral neuropathies. Different chromosomal loci have been linked with three autosomal dominant, 'intermediate' types of CMT: DI-CMTA1, DI-CMTB2 and DI-CMTC3. We refined the locus associated with DI-CMTB on chromosome 19p12–13.2 to 4.2 Mb in three unrelated families with CMT originating from Australia, Belgium and North America. After screening candidate genes, we identified unique mutations in dynamin 2 (DNM2) in all families. DNM2 belongs to the family of large GTPases and is part of the cellular fusion-fission apparatus4. In transiently transfected cell lines, mutations of DNM2 substantially diminish binding of DNM2 to membranes by altering the conformation of the β3/β4 loop of the pleckstrin homology domain. Additionally, in the Australian and Belgian pedigrees, which carry two different mutations affecting the same amino acid, Lys558, CMT cosegregated with neutropenia, which has not previously been associated with CMT neuropathies.

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Figure 1: Physical map of the locus associated with DI-CMTB, the structure of DNM2 and the mutations identified in three multigenerational families with DI-CMTB.
Figure 2: Illustration of the mutation identified in family DUK1118 leading to the unusual case of three resulting protein products.
Figure 3: Morphology of transiently transfected cell lines.
Figure 4: Confocal microscopic analysis of transiently transfected COS7 cells stained with antibody to His, to detect the DNM2 construct, and antibody to tubulin, a marker against microtubules.
Figure 5: Colocalization analysis of transiently transfected COS7 cells with antibody to clathrin, a marker for clathrin-coated vesicles.
Figure 6: Neuro2a cells transiently transfected with mutant DNM2 lack colocalization of DNM2 and transferrin-containing vesicles after 15 min of incubation with transferrin.

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Acknowledgements

We thank the affected individuals and their families for their participation in this study, M. Van Hul for technical assistance, M. Gardner and S. Robertson for assisting the family investigations, A. Krüttgen for critical comments on the design of the cell culture experiments and S. Garvey for help with the expression experiments. This research project was supported by the Association Belge contre les Maladies Neuromusculaires, the Fund for Scientific Research-Flanders, the Interuniversity Attraction Poles program P5/19 of the Belgian Federal Science Office, the Medical Foundation Queen Elisabeth, the Muscular Dystrophy Association, National Health and Medical Research Council of Australia, US National Institutes of Health, Special Research Fund of the University of Antwerp, University of Sydney and donations from family members and friends of families with CMT to the Center for Human Genetics. S.Z. was supported by a fellowship of the Deutsche Forschungsgemeinschaft. K.V. was supported by a postdoctoral fellowship of the Fund for Scientific Research-Flanders.

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Authors and Affiliations

  1. Center for Human Genetics, Duke University Medical Center, Durham, North Carolina, USA

    Stephan Züchner, Maher Noureddine, Sofia A Oliveira, Marcy C Speer, Judith E Stenger, Margaret A Pericak-Vance & Jeffery M Vance

  2. Department of Neuropathology, University Hospital, RWTH Aachen, Pauwelsstrasse 30, Aachen, 52074, Germany

    Stephan Züchner

  3. Northcott Neuroscience Laboratory, ANZAC Research Institute, New South Wales, Australia

    Marina Kennerson, Gina Walizada, Danqing Zhu & Garth Nicholson

  4. Molecular Medicine Laboratory, Concord Hospital, Concord, New South Wales, Australia

    Marina Kennerson, Kristien Verhoeven & Garth Nicholson

  5. Molecular Genetics Department, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Antwerp, Belgium

    Kristl Claeys, Peter De Jonghe & Vincent Timmerman

  6. Division of Neurology, University Hospital Antwerpen, Antwerpen, Belgium

    Kristl Claeys & Peter De Jonghe

  7. Department of Neurology, Heidelberg Repatriation Hospital, West Heidelberg, Victoria, 3081, Australia

    John Merory

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Supplementary information

Supplementary Fig. 1

Expression of DNM2 in the nervous system. (PDF 493 kb)

Supplementary Fig. 2

Design of the constructs used in cell transfection experiments. (PDF 30 kb)

Supplementary Fig. 3

Colocalization of mutant DNM2 aggregates with the Golgi marker ceramide in COS7 cells. (PDF 54 kb)

Supplementary Fig. 4

Molecular modeling of β3/β4 loops (PDF 31 kb)

Supplementary Table 1

Clinical and genetic data from affected individuals of three DI-CMTB families. (PDF 336 kb)

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Züchner, 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 37, 289–294 (2005). https://doi.org/10.1038/ng1514

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