More overlap between HSP and CMT discovered

Posted - December 2015 in Research Highlights

New gene for HSP implicated

 

A gene previously associated with Charcot-Marie-Tooth disease (CMT) but not with HSP, Dynamin 2 (DNM2) has now been identified as a new link between them.

 

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.

 

SOURCE: BMC Neurol. 2015 Oct 30;15:223. doi: 10.1186/s12883-015-0481-3. PMID: 26517984 [PubMed – in process] PMCID: PMC4628244

 

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

 

Sambuughin N1, Goldfarb LG2, Sivtseva TM3, Davydova TK4, Vladimirtsev VA5, Osakovskiy VL6, Danilova AP7, Nikitina RS8, Ylakhova AN9, Diachkovskaya MP10, Sundborger AC11, Renwick NM12, Platonov FA13, Hinshaw JE14, Toro C15.

 

1Consortium for Health and Military Performance, Uniformed Services University, Bethesda, MD, 20814, USA. [email protected]

2National Institute of Neurological Disorders and Stroke, National Institute of Health, Bethesda, MD, 20892, USA. [email protected]

3Institute of Health, M.K. Ammosov North-Eastern Federal University, Sergelyakhskoe shosse 4 km, building C-2, Yakutsk, 677010, The Russian Federation. [email protected]

4Institute of Health, M.K. Ammosov North-Eastern Federal University, Sergelyakhskoe shosse 4 km, building C-2, Yakutsk, 677010, The Russian Federation. [email protected]

5Institute of Health, M.K. Ammosov North-Eastern Federal University, Sergelyakhskoe shosse 4 km, building C-2, Yakutsk, 677010, The Russian Federation. [email protected]

6Institute of Health, M.K. Ammosov North-Eastern Federal University, Sergelyakhskoe shosse 4 km, building C-2, Yakutsk, 677010, The Russian Federation. [email protected]

7Institute of Health, M.K. Ammosov North-Eastern Federal University, Sergelyakhskoe shosse 4 km, building C-2, Yakutsk, 677010, The Russian Federation. [email protected]

8Institute of Health, M.K. Ammosov North-Eastern Federal University, Sergelyakhskoe shosse 4 km, building C-2, Yakutsk, 677010, The Russian Federation. [email protected]

9Institute of Health, M.K. Ammosov North-Eastern Federal University, Sergelyakhskoe shosse 4 km, building C-2, Yakutsk, 677010, The Russian Federation. [email protected]

10Institute of Health, M.K. Ammosov North-Eastern Federal University, Sergelyakhskoe shosse 4 km, building C-2, Yakutsk, 677010, The Russian Federation. [email protected]

11National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Fishers Lane, Room 4S26, Bethesda, MD, 20892, USA. [email protected]

12Department of Pathology and Molecular Medicine, Queen’s University, Kingston General Hospital, Kingston, ON, K7L 3N6, Canada. [email protected]

13Institute of Health, M.K. Ammosov North-Eastern Federal University, Sergelyakhskoe shosse 4 km, building C-2, Yakutsk, 677010, The Russian Federation. [email protected]

14National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Fishers Lane, Room 4S26, Bethesda, MD, 20892, USA. [email protected]

15National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA. [email protected]

 

 

 

Add your comment on this story