Adult-onset autosomal dominant spastic paraplegia linked to a GTPase-effector domain mutation of dynamin 2

Nyamkhishig Sambuughin, Lev G. Goldfarb, Tatiana M. Sivtseva, Tatiana K. Davydova, Vsevolod A. Vladimirtsev, Vladimir L. Osakovskiy, Al'bina P. Danilova, Raisa S. Nikitina, Anastasia N. Ylakhova, Margarita P. Diachkovskaya, Anna C. Sundborger, Neil M. Renwick, Fyodor A. Platonov, Jenny E. Hinshaw, Camilo Toro

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


Background: Hereditary Spastic Paraplegia (HSP) represents a large group of clinically and genetically heterogeneous disorders linked to over 70 different loci and more than 60 recognized disease-causing genes. A heightened vulnerability to disruption of various cellular processes inherent to the unique function and morphology of corticospinal neurons may account, at least in part, for the genetic heterogeneity. Methods: Whole exome sequencing was utilized to identify candidate genetic variants in a four-generation Siberian kindred that includes nine individuals showing clinical features of HSP. Segregation of candidate variants within the family yielded a disease-associated mutation. Functional as well as in-silico structural analyses confirmed the selected candidate variant to be causative. Results: Nine known patients had young-adult onset of bilateral slowly progressive lower-limb spasticity, weakness and hyperreflexia progressing over two-to-three decades to wheel-chair dependency. In the advanced stage of the disease, some patients also had distal wasting of lower leg muscles, pes cavus, mildly decreased vibratory sense in the ankles, and urinary urgency along with electrophysiological evidence of a mild distal motor/sensory axonopathy. Molecular analyses uncovered a missense c.2155C > T, p.R719W mutation in the highly conserved GTP-effector domain of dynamin 2. The mutant DNM2 co-segregated with HSP and affected endocytosis when expressed in HeLa cells. In-silico modeling indicated that this HSP-associated dynamin 2 mutation is located in a highly conserved bundle-signaling element of the protein while dynamin 2 mutations associated with other disorders are located in the stalk and PH domains; p.R719W potentially disrupts dynamin 2 assembly. Conclusion: This is the first report linking a mutation in dynamin 2 to a HSP phenotype. Dynamin 2 mutations have previously been associated with other phenotypes including two forms of Charcot-Marie-Tooth neuropathy and centronuclear myopathy. These strikingly different pathogenic effects may depend on structural relationships the mutations disrupt. Awareness of this distinct association between HSP and c.2155C > T, p.R719W mutation will facilitate ascertainment of additional DNM2 HSP families and will direct future research toward better understanding of cell biological processes involved in these partly overlapping clinical syndromes.

Original languageEnglish (US)
Article number223
JournalBMC Neurology
Issue number1
StatePublished - Oct 30 2015

Bibliographical note

Funding Information:
We wish to thank Dr. C. Merrifield for providing the cloned wild-type human DNM2 and Dr. W. Gall for helpful comments and suggestions. The study was funded in part by the Ministry of Education and Science of the Russian Federation (project No. 3095). Research was supported by the Uniformed Services University (USU) R080148613 grant to N.S., Intramural Research Programs of the National Institute of Neurological Disorders and Stroke, the National Institute of Diabetes, Digestive and Kidney Diseases, and the National Human Genome Research Institute, NIH. Technical support was provided by the NIH Intramural Sequencing Center (NISC), Bioinformatics core of the NIH Undiagnosed Diseases Program, and the Biomedical Instrumentation Center of USU.

Publisher Copyright:
© 2015 Sambuughin et al.


  • DNM2
  • Dynamin
  • Endocytosis
  • Exome sequencing
  • HSP
  • Neuropathy
  • Paraplegia


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