Wang, H;
Kaçar Bayram, A;
Sprute, R;
Ozdemir, O;
Cooper, E;
Pergrande, M;
Efthymiou, S;
Nedic, I;
Mazaheri, N;
Stumpfe, K;
et al.
Wang, H; Kaçar Bayram, A; Sprute, R; Ozdemir, O; Cooper, E; Pergrande, M; Efthymiou, S; Nedic, I; Mazaheri, N; Stumpfe, K; AziziMalamiri, R; Shariati, G; Zeighami, J; Bayram, N; Naghibzadeh, K; Tajik, M; Yaşar, M; Sami Güven, A; Bibi, F; Sultan, T; Salpietro, V; Houlden, H; Per, H; Galehdari, H; Shalbafan, B; Jamshidi, Y; Cirak, S
(2019)
Genotype-Phenotype Correlations in Charcot-Marie-Tooth Disease Due to MTMR2 Mutations and Implications in Membrane Trafficking.
Frontiers in Neuroscience, 13.
p. 974.
ISSN 1662-453X
https://doi.org/10.3389/fnins.2019.00974
SGUL Authors: Jamshidi, Yalda
Abstract
Charcot-Marie-Tooth type 4 (CMT4) is an autosomal recessive severe form of neuropathy with genetic heterogeneity. CMT4B1 is caused by mutations in the myotubularin-related 2 (MTMR2) gene and as a member of the myotubularin family, the MTMR2 protein is crucial for the modulation of membrane trafficking. To enable future clinical trials, we performed a detailed review of the published cases with MTMR2 mutations and describe four novel cases identified through whole-exome sequencing (WES). The four unrelated families harbor novel homozygous mutations in MTMR2 (NM_016156, Family 1: c.1490dupC; p.Phe498IlefsTer2; Family 2: c.1479+1G>A; Family 3: c.1090C>T; p.Arg364Ter; Family 4: c.883C>T; p.Arg295Ter) and present with CMT4B1-related severe early-onset motor and sensory neuropathy, generalized muscle atrophy, facial and bulbar weakness, and pes cavus deformity. The clinical description of the new mutations reported here overlap with previously reported CMT4B1 phenotypes caused by mutations in the phosphatase domain of MTMR2, suggesting that nonsense MTMR2 mutations, which are predicted to result in loss or disruption of the phosphatase domain, are associated with a severe phenotype and loss of independent ambulation by the early twenties. Whereas the few reported missense mutations and also those truncating mutations occurring at the C-terminus after the phosphatase domain cause a rather mild phenotype and patients were still ambulatory above the age 30 years. Charcot-Marie-Tooth neuropathy and Centronuclear Myopathy causing mutations have been shown to occur in proteins involved in membrane remodeling and trafficking pathway mediated by phosphoinositides. Earlier studies have showing the rescue of MTM1 myopathy by MTMR2 overexpression, emphasize the importance of maintaining the phosphoinositides equilibrium and highlight a potential compensatory mechanism amongst members of this pathway. This proved that the regulation of expression of these proteins involved in the membrane remodeling pathway may compensate each other's loss- or gain-of-function mutations by restoring the phosphoinositides equilibrium. This provides a potential therapeutic strategy for neuromuscular diseases resulting from mutations in the membrane remodeling pathway.
Item Type: |
Article
|
Additional Information: |
Copyright © 2019 Wang, Kaçar Bayram, Sprute, Ozdemir, Cooper, Pergande, Efthymiou, Nedic, Mazaheri, Stumpfe, Azizi Malamiri, Shariati, Zeighami, Bayram, Naghibzadeh, Tajik, Yaşar, Sami Güven, Bibi, Sultan, Salpietro, Houlden, Per, Galehdari, Shalbafan, Jamshidi and Cirak. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
Keywords: |
1109 Neurosciences, 1702 Cognitive Science |
SGUL Research Institute / Research Centre: |
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) |
Journal or Publication Title: |
Frontiers in Neuroscience |
ISSN: |
1662-453X |
Dates: |
Date | Event |
---|
14 October 2019 | Published | 30 August 2019 | Accepted |
|
Publisher License: |
Creative Commons: Attribution 4.0 |
Projects: |
|
URI: |
https://openaccess.sgul.ac.uk/id/eprint/111289 |
Publisher's version: |
https://doi.org/10.3389/fnins.2019.00974 |
Statistics
Item downloaded times since 15 Oct 2019.
Actions (login required)
![Edit Item](/style/images/action_view.png) |
Edit Item |