title: Adult-onset autosomal dominant spastic paraplegia linked to a GTPase-effector domain mutation of dynamin 2.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Consortium for Health and Military Performance, Uniformed Services University, Bethesda, MD, 20814, USA. nyamkhishig.sambuughin.ctr@usuhs.edu.
authors.forename: Nyamkhishig
authors.initials: N
authors.lastname: Sambuughin
authors.affiliation: National Institute of Neurological Disorders and Stroke, National Institute of Health, Bethesda, MD, 20892, USA. GoldfarbL@ninds.nih.gov.
authors.forename: Lev G
authors.initials: LG
authors.lastname: Goldfarb
authors.affiliation: Institute of Health, M.K. Ammosov North-Eastern Federal University, Sergelyakhskoe shosse 4 km, building C-2, Yakutsk, 677010, The Russian Federation. sivtceva@list.ru.
authors.forename: Tatiana M
authors.initials: TM
authors.lastname: Sivtseva
authors.affiliation: Institute of Health, M.K. Ammosov North-Eastern Federal University, Sergelyakhskoe shosse 4 km, building C-2, Yakutsk, 677010, The Russian Federation. davtk@rambler.ru.
authors.forename: Tatiana K
authors.initials: TK
authors.lastname: Davydova
authors.affiliation: Institute of Health, M.K. Ammosov North-Eastern Federal University, Sergelyakhskoe shosse 4 km, building C-2, Yakutsk, 677010, The Russian Federation. sevelot@mail.ru.
authors.forename: Vsevolod A
authors.initials: VA
authors.lastname: Vladimirtsev
authors.affiliation: Institute of Health, M.K. Ammosov North-Eastern Federal University, Sergelyakhskoe shosse 4 km, building C-2, Yakutsk, 677010, The Russian Federation. iz_labgene@mail.ru.
authors.forename: Vladimir L
authors.initials: VL
authors.lastname: Osakovskiy
authors.affiliation: Institute of Health, M.K. Ammosov North-Eastern Federal University, Sergelyakhskoe shosse 4 km, building C-2, Yakutsk, 677010, The Russian Federation. danilova61@list.ru.
authors.forename: Al'bina P
authors.initials: AP
authors.lastname: Danilova
authors.affiliation: Institute of Health, M.K. Ammosov North-Eastern Federal University, Sergelyakhskoe shosse 4 km, building C-2, Yakutsk, 677010, The Russian Federation. nikitina_raisa@mail.ru.
authors.forename: Raisa S
authors.initials: RS
authors.lastname: Nikitina
authors.affiliation: Institute of Health, M.K. Ammosov North-Eastern Federal University, Sergelyakhskoe shosse 4 km, building C-2, Yakutsk, 677010, The Russian Federation. anesthesya@mail.ru.
authors.forename: Anastasia N
authors.initials: AN
authors.lastname: Ylakhova
authors.affiliation: Institute of Health, M.K. Ammosov North-Eastern Federal University, Sergelyakhskoe shosse 4 km, building C-2, Yakutsk, 677010, The Russian Federation. margarita.dyachkovskaya@mail.ru.
authors.forename: Margarita P
authors.initials: MP
authors.lastname: Diachkovskaya
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Fishers Lane, Room 4S26, Bethesda, MD, 20892, USA. anna.sundborger@nih.gov.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Sundborger
authors.affiliation: Department of Pathology and Molecular Medicine, Queen's University, Kingston General Hospital, Kingston, ON, K7L 3N6, Canada. neil.renwick@queensu.ca.
authors.forename: Neil M
authors.initials: NM
authors.lastname: Renwick
authors.affiliation: Institute of Health, M.K. Ammosov North-Eastern Federal University, Sergelyakhskoe shosse 4 km, building C-2, Yakutsk, 677010, The Russian Federation. platonovy@mail.ru.
authors.forename: Fyodor A
authors.initials: FA
authors.lastname: Platonov
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Fishers Lane, Room 4S26, Bethesda, MD, 20892, USA. jennyh@helix.nih.gov.
authors.forename: Jenny E
authors.initials: JE
authors.lastname: Hinshaw
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA. toroc@mail.nih.gov.
authors.forename: Camilo
authors.initials: C
authors.lastname: Toro
mesh_terms: D000328:Adult; D004252:DNA Mutational Analysis; D034285:Dynamin II; D034281:Dynamins / Q000235:genetics*; D059472:Exome; D005192:Family Health; D005260:Female; D020558:GTP Phosphohydrolases / Q000737:chemistry / Q000235:genetics*; D014644:Genetic Variation; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D012800:Siberia; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics*
chemical_list: D020558:GTP Phosphohydrolases; C000593490:DNM2 protein, human; D034285:Dynamin II; D034281:Dynamins