Wang, Haicui, Bayram, Ayse Kacar, Sprute, Rosaenn, Ozdemir, Ozkan, Cooper, Emily, Pergande, Matthias, Efthymiou, Stephanie, Nedic, Ivana, Mazaheri, Neda, Stumpfe, Katharina, Malamiri, Reza Azizi, Shariati, Gholamreza, Zeighami, Jawaher, Bayram, Nurettin, Naghibzadeh, Seyed Kianoosh, Tajik, Mohamad, Yasar, Mehmet, Guven, Ahmet Sami, Bibi, Farah, Sultan, Tipu, Salpietro, Vincenzo, Houlden, Henry, Per, Huseyin, Galehdari, Hamid, Shalbafan, Bita, Jamshidi, Yalda ORCID: 0000-0003-0151-6482 and Cirak, Sebahattin (2019). Genotype-Phenotype Correlations in Charcot-Marie-Tooth Disease Due to MTMR2 Mutations and Implications in Membrane Trafficking. Front. Neurosci., 13. LAUSANNE: FRONTIERS MEDIA SA. ISSN 1662-453X

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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: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Wang, HaicuiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bayram, Ayse KacarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sprute, RosaennUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ozdemir, OzkanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cooper, EmilyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pergande, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Efthymiou, StephanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nedic, IvanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mazaheri, NedaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stumpfe, KatharinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Malamiri, Reza AziziUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shariati, GholamrezaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zeighami, JawaherUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bayram, NurettinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Naghibzadeh, Seyed KianooshUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tajik, MohamadUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yasar, MehmetUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guven, Ahmet SamiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bibi, FarahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sultan, TipuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Salpietro, VincenzoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Houlden, HenryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Per, HuseyinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Galehdari, HamidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shalbafan, BitaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jamshidi, YaldaUNSPECIFIEDorcid.org/0000-0003-0151-6482UNSPECIFIED
Cirak, SebahattinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-130920
DOI: 10.3389/fnins.2019.00974
Journal or Publication Title: Front. Neurosci.
Volume: 13
Date: 2019
Publisher: FRONTIERS MEDIA SA
Place of Publication: LAUSANNE
ISSN: 1662-453X
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MYOTUBULARIN-RELATED PROTEIN-2; CONGENITAL MUSCULAR-DYSTROPHY; GENE; NEUROPATHY; ASSOCIATION; MYOPATHY; DYNAMIN; CELLS; MOTORMultiple languages
NeurosciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/13092

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