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

Abstract

BackgroundHereditary 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.MethodsWhole 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.ResultsNine 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.ConclusionThis 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.

Loss of Dynamin 2 GTPase function results in microcytic anaemia

“…In CMT, mutations almost always occur in the middle domain, whilst in CNM, they are predominantly found in the middle and PH domains (Bitoun et al, 2005;Zuchner et al, 2005). In contrast, recently described DNM2 mutations in HSP patients have thus far been detected in the GED domain (Sambuughin et al, 2015).…”

“…In CMT, mutations almost always occur in the middle domain, whilst in CNM, they are predominantly found in the middle and PH domains (Bitoun et al , ; Zuchner et al , ). In contrast, recently described DNM2 mutations in HSP patients have thus far been detected in the GED domain (Sambuughin et al , ). In vitro functional characterisation of mutant proteins from CMT and CMN suggests that these mutations behave in a dominant negative and disease‐specific manner (Durieux et al , ; Liu et al , ; Sidiropoulos et al , ).…”

Phenotype variability and histopathological findings in patients with a novel DNM2 mutation

“…Therefore, we present a case with intermediate CMT nerve pathological change co‐existing with chronic myopathy. Recently, adult‐onset autosomal dominant spastic paraplegia has been linked to a GTPase‐effector domain mutation of dynamin 2, which affects the function and morphology of corticospinal neurons . Therefore, the axonal neurotrophic disturbance due to cytoskeleton dysfunction by DNM2 mutations might contribute to the development of DNM2 ‐related neuromuscular diseases.…”

Allele‐specific silencing therapy for Dynamin 2‐related dominant centronuclear myopathy

“…Autosomal‐dominant centronuclear myopathy results from mutations in the DNM2 gene which encodes Dynamin 2 (DNM2) (Bitoun et al , ) also involved in rare cases of Charcot–Marie–Tooth disease (Zuchner et al , ) and hereditary spastic paraplegia (Sambuughin et al , ). DNM2 belongs to the superfamily of large GTPases (Heymann & Hinshaw, ) and acts as a mechanochemical scaffolding molecule that can deform biological membranes leading to the release of vesicles from distinct membrane compartments.…”