Genotype-Phenotype Correlations in Charcot-Marie-Tooth Disease Due to MTMR2 Mutations and Implications in Membrane Trafficking
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 trafficki...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2019-10-01
|
| Series: | Frontiers in Neuroscience |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fnins.2019.00974/full |
| _version_ | 1828415836289761280 |
|---|---|
| author | Haicui Wang Haicui Wang Ayşe Kaçar Bayram Rosanne Sprute Rosanne Sprute Ozkan Ozdemir Ozkan Ozdemir Emily Cooper Matthias Pergande Matthias Pergande Stephanie Efthymiou Ivana Nedic Neda Mazaheri Neda Mazaheri Katharina Stumpfe Reza Azizi Malamiri Gholamreza Shariati Gholamreza Shariati Jawaher Zeighami Nurettin Bayram Seyed Kianoosh Naghibzadeh Mohamad Tajik Mehmet Yaşar Ahmet Sami Güven Farah Bibi Tipu Sultan Vincenzo Salpietro Vincenzo Salpietro Vincenzo Salpietro Henry Houlden Hüseyin Per Hamid Galehdari Bita Shalbafan Yalda Jamshidi Sebahattin Cirak Sebahattin Cirak |
| author_facet | Haicui Wang Haicui Wang Ayşe Kaçar Bayram Rosanne Sprute Rosanne Sprute Ozkan Ozdemir Ozkan Ozdemir Emily Cooper Matthias Pergande Matthias Pergande Stephanie Efthymiou Ivana Nedic Neda Mazaheri Neda Mazaheri Katharina Stumpfe Reza Azizi Malamiri Gholamreza Shariati Gholamreza Shariati Jawaher Zeighami Nurettin Bayram Seyed Kianoosh Naghibzadeh Mohamad Tajik Mehmet Yaşar Ahmet Sami Güven Farah Bibi Tipu Sultan Vincenzo Salpietro Vincenzo Salpietro Vincenzo Salpietro Henry Houlden Hüseyin Per Hamid Galehdari Bita Shalbafan Yalda Jamshidi Sebahattin Cirak Sebahattin Cirak |
| author_sort | Haicui Wang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T13:52:22Z |
| format | Article |
| id | doaj.art-af45cf4def1647cbbe24bfce1e5d146f |
| institution | Directory Open Access Journal |
| issn | 1662-453X |
| language | English |
| last_indexed | 2024-12-10T13:52:22Z |
| publishDate | 2019-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neuroscience |
| spelling | doaj.art-af45cf4def1647cbbe24bfce1e5d146f2022-12-22T01:46:07ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2019-10-011310.3389/fnins.2019.00974474789Genotype-Phenotype Correlations in Charcot-Marie-Tooth Disease Due to MTMR2 Mutations and Implications in Membrane TraffickingHaicui Wang0Haicui Wang1Ayşe Kaçar Bayram2Rosanne Sprute3Rosanne Sprute4Ozkan Ozdemir5Ozkan Ozdemir6Emily Cooper7Matthias Pergande8Matthias Pergande9Stephanie Efthymiou10Ivana Nedic11Neda Mazaheri12Neda Mazaheri13Katharina Stumpfe14Reza Azizi Malamiri15Gholamreza Shariati16Gholamreza Shariati17Jawaher Zeighami18Nurettin Bayram19Seyed Kianoosh Naghibzadeh20Mohamad Tajik21Mehmet Yaşar22Ahmet Sami Güven23Farah Bibi24Tipu Sultan25Vincenzo Salpietro26Vincenzo Salpietro27Vincenzo Salpietro28Henry Houlden29Hüseyin Per30Hamid Galehdari31Bita Shalbafan32Yalda Jamshidi33Sebahattin Cirak34Sebahattin Cirak35Department of Pediatrics, University Hospital Cologne, Cologne, GermanyCenter for Molecular Medicine (CMMC), University of Cologne, Cologne, GermanyDepartment of Pediatric Neurology, University of Health Sciences, Kayseri City Hospital, Kayseri, TurkeyDepartment of Pediatrics, University Hospital Cologne, Cologne, GermanyCenter for Molecular Medicine (CMMC), University of Cologne, Cologne, GermanyDepartment of Pediatrics, University Hospital Cologne, Cologne, GermanyCenter for Molecular Medicine (CMMC), University of Cologne, Cologne, GermanyGenetics Research Centre, Molecular and Clinical Sciences Institute, St. George's, University of London, London, United KingdomDepartment of Pediatrics, University Hospital Cologne, Cologne, GermanyCenter for Molecular Medicine (CMMC), University of Cologne, Cologne, GermanyDepartment of Neuromuscular Disorders, Institute of Neurology, University College London, London, United KingdomGenetics Research Centre, Molecular and Clinical Sciences Institute, St. George's, University of London, London, United KingdomNarges Medical Genetics and Prenatal Diagnosis Laboratory, Ahvaz, IranDepartment of Genetics, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, IranDepartment of Pediatrics, University Hospital Cologne, Cologne, GermanyPaediatric Neurology, Department of Paediatric Neurology, Golestan Medical, Educational, and Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, IranNarges Medical Genetics and Prenatal Diagnosis Laboratory, Ahvaz, IranDepartment of Medical Genetics, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, IranNarges Medical Genetics and Prenatal Diagnosis Laboratory, Ahvaz, Iran0Department of Ophthalmology, University of Health Sciences, Kayseri City Hospital, Kayseri, Turkey1Department of Medicine, Azad University, Tehran, Iran2Department of Neurology, Firoozgar General Hospital, University of Medical Sciences, Tehran, Iran3Department of Ear Nose and Throat, University of Health Sciences, Kayseri City Hospital, Kayseri, Turkey4Department of Pediatric Neurology, Meram Medical Faculty, Necmettin Erbakan University, Konya, Turkey5Institute of Biochemistry and Biotechnology, PMAS Arid Agriculture University, Rawalpindi, Pakistan6Department of Pediatric Neurology, Institute of Child Health, The Children's Hospital Lahore, Lahore, PakistanDepartment of Neuromuscular Disorders, Institute of Neurology, University College London, London, United Kingdom7Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy8Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, ItalyDepartment of Neuromuscular Disorders, Institute of Neurology, University College London, London, United Kingdom9Department of Pediatric Neurology, Erciyes University Medical School, Kayseri, TurkeyDepartment of Genetics, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran0Iran Social Security Organization, Labafinejad Hospital, Tehran, IranGenetics Research Centre, Molecular and Clinical Sciences Institute, St. George's, University of London, London, United KingdomDepartment of Pediatrics, University Hospital Cologne, Cologne, GermanyCenter for Molecular Medicine (CMMC), University of Cologne, Cologne, GermanyCharcot-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.https://www.frontiersin.org/article/10.3389/fnins.2019.00974/fullCharcot-Marie-Tooth disease type 4B1myotubularin-related 2 genewhole-exome sequencingphosphoinositidesmembrane remodeling |
| spellingShingle | Haicui Wang Haicui Wang Ayşe Kaçar Bayram Rosanne Sprute Rosanne Sprute Ozkan Ozdemir Ozkan Ozdemir Emily Cooper Matthias Pergande Matthias Pergande Stephanie Efthymiou Ivana Nedic Neda Mazaheri Neda Mazaheri Katharina Stumpfe Reza Azizi Malamiri Gholamreza Shariati Gholamreza Shariati Jawaher Zeighami Nurettin Bayram Seyed Kianoosh Naghibzadeh Mohamad Tajik Mehmet Yaşar Ahmet Sami Güven Farah Bibi Tipu Sultan Vincenzo Salpietro Vincenzo Salpietro Vincenzo Salpietro Henry Houlden Hüseyin Per Hamid Galehdari Bita Shalbafan Yalda Jamshidi Sebahattin Cirak Sebahattin Cirak Genotype-Phenotype Correlations in Charcot-Marie-Tooth Disease Due to MTMR2 Mutations and Implications in Membrane Trafficking Frontiers in Neuroscience Charcot-Marie-Tooth disease type 4B1 myotubularin-related 2 gene whole-exome sequencing phosphoinositides membrane remodeling |
| title | Genotype-Phenotype Correlations in Charcot-Marie-Tooth Disease Due to MTMR2 Mutations and Implications in Membrane Trafficking |
| title_full | Genotype-Phenotype Correlations in Charcot-Marie-Tooth Disease Due to MTMR2 Mutations and Implications in Membrane Trafficking |
| title_fullStr | Genotype-Phenotype Correlations in Charcot-Marie-Tooth Disease Due to MTMR2 Mutations and Implications in Membrane Trafficking |
| title_full_unstemmed | Genotype-Phenotype Correlations in Charcot-Marie-Tooth Disease Due to MTMR2 Mutations and Implications in Membrane Trafficking |
| title_short | Genotype-Phenotype Correlations in Charcot-Marie-Tooth Disease Due to MTMR2 Mutations and Implications in Membrane Trafficking |
| title_sort | genotype phenotype correlations in charcot marie tooth disease due to mtmr2 mutations and implications in membrane trafficking |
| topic | Charcot-Marie-Tooth disease type 4B1 myotubularin-related 2 gene whole-exome sequencing phosphoinositides membrane remodeling |
| url | https://www.frontiersin.org/article/10.3389/fnins.2019.00974/full |
| work_keys_str_mv | AT haicuiwang genotypephenotypecorrelationsincharcotmarietoothdiseaseduetomtmr2mutationsandimplicationsinmembranetrafficking AT haicuiwang genotypephenotypecorrelationsincharcotmarietoothdiseaseduetomtmr2mutationsandimplicationsinmembranetrafficking AT aysekacarbayram genotypephenotypecorrelationsincharcotmarietoothdiseaseduetomtmr2mutationsandimplicationsinmembranetrafficking AT rosannesprute genotypephenotypecorrelationsincharcotmarietoothdiseaseduetomtmr2mutationsandimplicationsinmembranetrafficking AT rosannesprute genotypephenotypecorrelationsincharcotmarietoothdiseaseduetomtmr2mutationsandimplicationsinmembranetrafficking AT ozkanozdemir genotypephenotypecorrelationsincharcotmarietoothdiseaseduetomtmr2mutationsandimplicationsinmembranetrafficking AT ozkanozdemir genotypephenotypecorrelationsincharcotmarietoothdiseaseduetomtmr2mutationsandimplicationsinmembranetrafficking AT emilycooper genotypephenotypecorrelationsincharcotmarietoothdiseaseduetomtmr2mutationsandimplicationsinmembranetrafficking AT matthiaspergande genotypephenotypecorrelationsincharcotmarietoothdiseaseduetomtmr2mutationsandimplicationsinmembranetrafficking AT matthiaspergande genotypephenotypecorrelationsincharcotmarietoothdiseaseduetomtmr2mutationsandimplicationsinmembranetrafficking AT stephanieefthymiou genotypephenotypecorrelationsincharcotmarietoothdiseaseduetomtmr2mutationsandimplicationsinmembranetrafficking AT ivananedic genotypephenotypecorrelationsincharcotmarietoothdiseaseduetomtmr2mutationsandimplicationsinmembranetrafficking AT nedamazaheri genotypephenotypecorrelationsincharcotmarietoothdiseaseduetomtmr2mutationsandimplicationsinmembranetrafficking AT nedamazaheri genotypephenotypecorrelationsincharcotmarietoothdiseaseduetomtmr2mutationsandimplicationsinmembranetrafficking AT katharinastumpfe genotypephenotypecorrelationsincharcotmarietoothdiseaseduetomtmr2mutationsandimplicationsinmembranetrafficking AT rezaazizimalamiri genotypephenotypecorrelationsincharcotmarietoothdiseaseduetomtmr2mutationsandimplicationsinmembranetrafficking AT gholamrezashariati genotypephenotypecorrelationsincharcotmarietoothdiseaseduetomtmr2mutationsandimplicationsinmembranetrafficking AT gholamrezashariati genotypephenotypecorrelationsincharcotmarietoothdiseaseduetomtmr2mutationsandimplicationsinmembranetrafficking AT jawaherzeighami genotypephenotypecorrelationsincharcotmarietoothdiseaseduetomtmr2mutationsandimplicationsinmembranetrafficking AT nurettinbayram genotypephenotypecorrelationsincharcotmarietoothdiseaseduetomtmr2mutationsandimplicationsinmembranetrafficking AT seyedkianooshnaghibzadeh genotypephenotypecorrelationsincharcotmarietoothdiseaseduetomtmr2mutationsandimplicationsinmembranetrafficking AT mohamadtajik genotypephenotypecorrelationsincharcotmarietoothdiseaseduetomtmr2mutationsandimplicationsinmembranetrafficking AT mehmetyasar genotypephenotypecorrelationsincharcotmarietoothdiseaseduetomtmr2mutationsandimplicationsinmembranetrafficking AT ahmetsamiguven genotypephenotypecorrelationsincharcotmarietoothdiseaseduetomtmr2mutationsandimplicationsinmembranetrafficking AT farahbibi genotypephenotypecorrelationsincharcotmarietoothdiseaseduetomtmr2mutationsandimplicationsinmembranetrafficking AT tipusultan genotypephenotypecorrelationsincharcotmarietoothdiseaseduetomtmr2mutationsandimplicationsinmembranetrafficking AT vincenzosalpietro genotypephenotypecorrelationsincharcotmarietoothdiseaseduetomtmr2mutationsandimplicationsinmembranetrafficking AT vincenzosalpietro genotypephenotypecorrelationsincharcotmarietoothdiseaseduetomtmr2mutationsandimplicationsinmembranetrafficking AT vincenzosalpietro genotypephenotypecorrelationsincharcotmarietoothdiseaseduetomtmr2mutationsandimplicationsinmembranetrafficking AT henryhoulden genotypephenotypecorrelationsincharcotmarietoothdiseaseduetomtmr2mutationsandimplicationsinmembranetrafficking AT huseyinper genotypephenotypecorrelationsincharcotmarietoothdiseaseduetomtmr2mutationsandimplicationsinmembranetrafficking AT hamidgalehdari genotypephenotypecorrelationsincharcotmarietoothdiseaseduetomtmr2mutationsandimplicationsinmembranetrafficking AT bitashalbafan genotypephenotypecorrelationsincharcotmarietoothdiseaseduetomtmr2mutationsandimplicationsinmembranetrafficking AT yaldajamshidi genotypephenotypecorrelationsincharcotmarietoothdiseaseduetomtmr2mutationsandimplicationsinmembranetrafficking AT sebahattincirak genotypephenotypecorrelationsincharcotmarietoothdiseaseduetomtmr2mutationsandimplicationsinmembranetrafficking AT sebahattincirak genotypephenotypecorrelationsincharcotmarietoothdiseaseduetomtmr2mutationsandimplicationsinmembranetrafficking |