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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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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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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DOI: https://doi.org/10.1038/ng1514
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