Universität zu Köln

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:	Creators Email ORCID ORCID Put Code Wang, Haicui UNSPECIFIED UNSPECIFIED UNSPECIFIED Bayram, Ayse Kacar UNSPECIFIED UNSPECIFIED UNSPECIFIED Sprute, Rosaenn UNSPECIFIED UNSPECIFIED UNSPECIFIED Ozdemir, Ozkan UNSPECIFIED UNSPECIFIED UNSPECIFIED Cooper, Emily UNSPECIFIED UNSPECIFIED UNSPECIFIED Pergande, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Efthymiou, Stephanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Nedic, Ivana UNSPECIFIED UNSPECIFIED UNSPECIFIED Mazaheri, Neda UNSPECIFIED UNSPECIFIED UNSPECIFIED Stumpfe, Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED Malamiri, Reza Azizi UNSPECIFIED UNSPECIFIED UNSPECIFIED Shariati, Gholamreza UNSPECIFIED UNSPECIFIED UNSPECIFIED Zeighami, Jawaher UNSPECIFIED UNSPECIFIED UNSPECIFIED Bayram, Nurettin UNSPECIFIED UNSPECIFIED UNSPECIFIED Naghibzadeh, Seyed Kianoosh UNSPECIFIED UNSPECIFIED UNSPECIFIED Tajik, Mohamad UNSPECIFIED UNSPECIFIED UNSPECIFIED Yasar, Mehmet UNSPECIFIED UNSPECIFIED UNSPECIFIED Guven, Ahmet Sami UNSPECIFIED UNSPECIFIED UNSPECIFIED Bibi, Farah UNSPECIFIED UNSPECIFIED UNSPECIFIED Sultan, Tipu UNSPECIFIED UNSPECIFIED UNSPECIFIED Salpietro, Vincenzo UNSPECIFIED UNSPECIFIED UNSPECIFIED Houlden, Henry UNSPECIFIED UNSPECIFIED UNSPECIFIED Per, Huseyin UNSPECIFIED UNSPECIFIED UNSPECIFIED Galehdari, Hamid UNSPECIFIED UNSPECIFIED UNSPECIFIED Shalbafan, Bita UNSPECIFIED UNSPECIFIED UNSPECIFIED Jamshidi, Yalda UNSPECIFIED orcid.org/0000-0003-0151-6482 UNSPECIFIED Cirak, Sebahattin UNSPECIFIED UNSPECIFIED UNSPECIFIED
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:	Keywords Language MYOTUBULARIN-RELATED PROTEIN-2; CONGENITAL MUSCULAR-DYSTROPHY; GENE; NEUROPATHY; ASSOCIATION; MYOPATHY; DYNAMIN; CELLS; MOTOR Multiple languages Neurosciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/13092