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https://www.readbyqxmd.com/read/28624463/insights-from-genotype-phenotype-correlations-by-novel-speg-mutations-causing-centronuclear-myopathy
#1
Haicui Wang, Claudia Castiglioni, Ayşe Kaçar Bayram, Fabiana Fattori, Serdar Pekuz, Diego Araneda, Hüseyin Per, Ricardo Erazo, Hakan Gümüş, Suzan Zorludemir, Kerstin Becker, Ximena Ortega, Jorge Alfredo Bevilacqua, Enrico Bertini, Sebahattin Cirak
Centronuclear myopathies (CNM) are a clinically and genetically heterogeneous group of congenital myopathies, defined histologically by increased number of fibres with centrally located nuclei, and type I fibre predominance in muscle biopsy. Myotubular myopathy, the X-linked form of CNM caused by mutations in the phosphoinositide phosphatase MTM1, is histologically characteristic since muscle fibres resemble myotubes. Here we present two unrelated patients with CNM and typical myotubular fibres in the muscle biopsy caused by mutations in striated muscle preferentially expressed protein kinase (SPEG)...
May 24, 2017: Neuromuscular Disorders: NMD
https://www.readbyqxmd.com/read/28622964/grand-paternal-inheritance-of-x-linked-myotubular-myopathy-due-to-mosaicism-and-identification-of-necklace-fibers-in-an-asymptomatic-male
#2
Carola Hedberg-Oldfors, Kittichate Visuttijai, Alexandra Topa, Mar Tulinius, Anders Oldfors
X-linked recessive myotubular myopathy (XLMTM) is a disorder associated with mutations in the myotubularin gene (MTM1) that usually affects boys, with transmission of the mutated allele from the mother. Here we describe a family with unexpected grand paternal transmission of a novel mutation in MTM1 (c.646_648dupGTT; p.Val216dup) identified in a severely affected infant boy with a centronuclear myopathy. We confirmed the carrier status of the mother, but surprisingly we found that her father was a carrier of the mutated MTM1 gene together with wild-type MTM1...
May 10, 2017: Neuromuscular Disorders: NMD
https://www.readbyqxmd.com/read/28589938/antisense-oligonucleotide-mediated-dnm2-knockdown-prevents-and-reverts-myotubular-myopathy-in-mice
#3
Hichem Tasfaout, Suzie Buono, Shuling Guo, Christine Kretz, Nadia Messaddeq, Sheri Booten, Sarah Greenlee, Brett P Monia, Belinda S Cowling, Jocelyn Laporte
Centronuclear myopathies (CNM) are non-dystrophic muscle diseases for which no effective therapy is currently available. The most severe form, X-linked CNM, is caused by myotubularin 1 (MTM1) loss-of-function mutations, while the main autosomal dominant form is due to dynamin2 (DNM2) mutations. We previously showed that genetic reduction of DNM2 expression in Mtm1 knockout (Mtm1KO) mice prevents development of muscle pathology. Here we show that systemic delivery of Dnm2 antisense oligonucleotides (ASOs) into Mtm1KO mice efficiently reduces DNM2 protein level in muscle and prevents the myopathy from developing...
June 7, 2017: Nature Communications
https://www.readbyqxmd.com/read/28370029/long-term-effects-of-systemic-gene-therapy-in-a-canine-model-of-myotubular-myopathy
#4
Matthew Elverman, Melissa A Goddard, David Mack, Jessica M Snyder, Michael W Lawlor, Hui Meng, Alan H Beggs, Ana Buj-Bello, Karine Poulard, Anthony P Marsh, Robert W Grange, Valerie E Kelly, Martin K Childers
INTRODUCTION: X-linked myotubular myopathy (XLMTM), a devastating pediatric disease caused by the absence of the protein myotubularin, results from mutations in the MTM1 gene. While there is no cure for XLMTM, we previously reported effects of MTM1 gene therapy using adeno-associated virus (AAV) vector on muscle weakness and pathology in MTM1-mutant dogs. Here, we followed 2 AAV-infused dogs over 4 years. METHODS: We evaluated gait, strength, respiration, neurological function, muscle pathology, AAV vector copy number (VCN), and transgene expression...
March 29, 2017: Muscle & Nerve
https://www.readbyqxmd.com/read/28357410/phenotypes-genotypes-and-prevalence-of-congenital-myopathies-older-than-5-years-in-denmark
#5
Nanna Witting, Ulla Werlauff, Morten Duno, John Vissing
OBJECTIVE: Congenital myopathy as a nosologic entity has long been recognized, but knowledge of overall and subtype prevalence and phenotype-genotype relationship is scarce, especially in the adult population. METHODS: A national cohort of 107 patients ≥5 years diagnosed with congenital myopathy were prospectively assessed clinically, histologically, and genetically. RESULTS: Twenty-five patients were excluded because of atypical features or alternative etiologies...
April 2017: Neurology. Genetics
https://www.readbyqxmd.com/read/28237839/systemic-aav8-mediated-gene-therapy-drives-whole-body-correction-of-myotubular-myopathy-in-dogs
#6
David L Mack, Karine Poulard, Melissa A Goddard, Virginie Latournerie, Jessica M Snyder, Robert W Grange, Matthew R Elverman, Jérôme Denard, Philippe Veron, Laurine Buscara, Christine Le Bec, Jean-Yves Hogrel, Annie G Brezovec, Hui Meng, Lin Yang, Fujun Liu, Michael O'Callaghan, Nikhil Gopal, Valerie E Kelly, Barbara K Smith, Jennifer L Strande, Fulvio Mavilio, Alan H Beggs, Federico Mingozzi, Michael W Lawlor, Ana Buj-Bello, Martin K Childers
X-linked myotubular myopathy (XLMTM) results from MTM1 gene mutations and myotubularin deficiency. Most XLMTM patients develop severe muscle weakness leading to respiratory failure and death, typically within 2 years of age. Our objective was to evaluate the efficacy and safety of systemic gene therapy in the p.N155K canine model of XLMTM by performing a dose escalation study. A recombinant adeno-associated virus serotype 8 (rAAV8) vector expressing canine myotubularin (cMTM1) under the muscle-specific desmin promoter (rAAV8-cMTM1) was administered by simple peripheral venous infusion in XLMTM dogs at 10 weeks of age, when signs of the disease are already present...
April 5, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28096301/phosphoinositol-3-phosphate-acts-as-a-timer-for-reactive-oxygen-species-production-in-the-phagosome
#7
Zhi Min Song, Leïla Bouchab, Elodie Hudik, Romain Le Bars, Oliver Nüsse, Sophie Dupré-Crochet
Production of reactive oxygen species (ROS) in the phagosome by the NADPH oxidase is critical for mammalian immune defense against microbial infections and phosphoinositides are important regulators in this process. Phosphoinositol 3-phosphate (PI(3)P) regulates ROS production at the phagosome via p40(phox) by an unknown mechanism. This study tested the hypothesis that PI(3)P controls ROS production by regulating the presence of p40(phox) and p67(phox) at the phagosomal membrane. Pharmacologic inhibition of PI(3)P synthesis at the phagosome decreased the ROS production both in differentiated PLB-985 cells and human neutrophils...
May 2017: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/28007904/cellular-biochemical-and-molecular-changes-in-muscles-from-patients-with-x-linked-myotubular-myopathy-due-to-mtm1-mutations
#8
Christoph Bachmann, Heinz Jungbluth, Francesco Muntoni, Adnan Y Manzur, Francesco Zorzato, Susan Treves
Centronuclear myopathies are early-onset muscle diseases caused by mutations in several genes including MTM1, DNM2, BIN1, RYR1 and TTN. The most severe and often fatal X-linked form of myotubular myopathy (XLMTM) is caused by mutations in the gene encoding the ubiquitous lipid phosphatase myotubularin, an enzyme specifically dephosphorylating phosphatidylinositol-3-phosphate and phosphatidylinositol-3,5-bisphosphate. Because XLMTM patients have a predominantly muscle-specific phenotype a number of pathogenic mechanisms have been proposed, including a direct effect of the accumulated lipid on the skeletal muscle calcium channel ryanodine receptor 1, a negative effect on the structure of intracellular organelles and defective autophagy...
January 15, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/27911767/phosphatidylinositol-3-kinase-inhibition-restores-ca2-release-defects-and-prolongs-survival-in-myotubularin-deficient-mice
#9
Candice Kutchukian, Mirella Lo Scrudato, Yves Tourneur, Karine Poulard, Alban Vignaud, Christine Berthier, Bruno Allard, Michael W Lawlor, Ana Buj-Bello, Vincent Jacquemond
Mutations in the gene encoding the phosphoinositide 3-phosphatase myotubularin (MTM1) are responsible for a pediatric disease of skeletal muscle named myotubular myopathy (XLMTM). Muscle fibers from MTM1-deficient mice present defects in excitation-contraction (EC) coupling likely responsible for the disease-associated fatal muscle weakness. However, the mechanism leading to EC coupling failure remains unclear. During normal skeletal muscle EC coupling, transverse (t) tubule depolarization triggers sarcoplasmic reticulum (SR) Ca(2+) release through ryanodine receptor channels gated by conformational coupling with the t-tubule voltage-sensing dihydropyridine receptors...
December 13, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27548528/pik3c2b-inhibition-improves-function-and-prolongs-survival-in-myotubular-myopathy-animal-models
#10
Nesrin Sabha, Jonathan R Volpatti, Hernan Gonorazky, Aaron Reifler, Ann E Davidson, Xingli Li, Nadine M Eltayeb, Claudia Dall'Armi, Gilbert Di Paolo, Susan V Brooks, Ana Buj-Bello, Eva L Feldman, James J Dowling
Myotubular myopathy (MTM) is a devastating pediatric neuromuscular disorder of phosphoinositide (PIP) metabolism resulting from mutations of the PIP phosphatase MTM1 for which there are no treatments. We have previously shown phosphatidylinositol-3-phosphate (PI3P) accumulation in animal models of MTM. Here, we tested the hypothesis that lowering PI3P levels may prevent or reverse the MTM disease process. To test this, we targeted class II and III PI3 kinases (PI3Ks) in an MTM1-deficient mouse model. Muscle-specific ablation of Pik3c2b, but not Pik3c3, resulted in complete prevention of the MTM phenotype, and postsymptomatic targeting promoted a striking rescue of disease...
September 1, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27353517/next-generation-sequencing-based-molecular-diagnosis-of-neonatal-hypotonia-in-chinese-population
#11
Yan Wang, Wei Peng, Hong-Yan Guo, Hui Li, Jie Tian, Yu-Jing Shi, Xiao Yang, Yao Yang, Wan-Qiao Zhang, Xin Liu, Guan-Nan Liu, Tao Deng, Yi-Min Sun, Wan-Li Xing, Jing Cheng, Zhi-Chun Feng
Neonatal hypotonia is extremely challenging to diagnose because numerous disorders present similar clinical manifestations. Two panels for diagnosing neonatal hypotonia were developed, which enriches 35 genes corresponding to 61 neonatal hypotonia-related disorders. A cohort of 214 neonates with hypotonia was recruited from 2012 to 2014 in China for this study. Of these subjects, twenty-eight neonates with hypotonia were eliminated according to exclusion criteria and 97 were confirmed using traditional detection methods...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27340857/subcellular-localizations-of-arabidopsis-myotubularins-mtm1-and-mtm2-suggest-possible-functions-in-vesicular-trafficking-between-er-and-cis-golgi
#12
Akanksha Nagpal, Ivan Ndamukong, Ammar Hassan, Zoya Avramova, František Baluška
The two Arabidopsis genes AtMTM1 and AtMTM2 encode highly similar phosphoinositide 3-phosphatases from the myotubularin family. Despite the high-level conservation of structure and biochemical activities, their physiological roles have significantly diverged. The nature of a membrane and the concentrations of their membrane-anchored substrates (PtdIns3P or PtdIns3,5P2) and/or products (PtdIns5P and PtdIns) are considered critical for determining the functional specificity of myotubularins. We have performed comprehensive analyses of the subcellular localization of AtMTM1 and AtMTM2 using a variety of specific constructs transiently expressed in Nicotiana benthamiana leaf epidermal cells under the control of 35S promoter...
August 1, 2016: Journal of Plant Physiology
https://www.readbyqxmd.com/read/27155155/expression-of-myotubularins-in-blood-platelets-characterization-and-potential-diagnostic-of-x-linked-myotubular-myopathy
#13
Rana Mansour, Sonia Severin, Jean-Marie Xuereb, Marie-Pierre Gratacap, Jocelyn Laporte, Ana Buj-Bello, Hélène Tronchère, Bernard Payrastre
Phosphoinositides play a key role in the spatiotemporal control of central intracellular processes and several specific kinases and phosphatases regulating the level of these lipids are implicated in human diseases. Myotubularins are a family of 3-phosphatases acting specifically on phosphatidylinositol 3-monophosphate and phosphatidylinositol 3,5 bisphosphate. Members of this family are mutated in genetic diseases including myotubularin 1 (MTM1) and myotubularin-related protein 2 (MTMR2) which mutations are responsible of X-linked centronuclear myopathy and Charcot-Marie-Tooth neuropathy, respectively...
July 29, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27017278/novel-findings-associated-with-mtm1-suggest-a-higher-number-of-female-symptomatic-carriers
#14
COMPARATIVE STUDY
Marco Savarese, Olimpia Musumeci, Teresa Giugliano, Anna Rubegni, Chiara Fiorillo, Fabiana Fattori, Annalaura Torella, Roberta Battini, Carmelo Rodolico, Aniello Pugliese, Giulio Piluso, Lorenzo Maggi, Adele D'Amico, Claudio Bruno, Enrico Bertini, Filippo Maria Santorelli, Marina Mora, Antonio Toscano, Carlo Minetti, Vincenzo Nigro
Mutations in the MTM1 gene cause X-linked myotubular myopathy (XLMTM), characterized by neonatal hypotonia and respiratory failure, and are responsible for a premature mortality in affected males. Female carriers are usually asymptomatic but they may present with muscular weakness because of a hypothesized skewed pattern of X-chromosome inactivation. By combining next generation sequencing (NGS) and CGH array approaches, we have investigated the role of MTM1 variants in a large cohort of undiagnosed patients with a wide spectrum of myopathies...
April 2016: Neuromuscular Disorders: NMD
https://www.readbyqxmd.com/read/27012108/-a-case-of-x-linked-myotubular-myopathy-with-chylothorax
#15
Taku Oishi, Tetsuya Sato, Kenshi Matsushita, Tomoki Takechi, Nobuyuki Murakami, Mikiya Fujieda
We report a case of X-linked myotubular myopathy with chylothorax. A male infant weighing 2,114 g was born to a mother whose pregnancy was complicated with polyhydramnios from gestational week 32. At gestational week 37, emergent caesarian section was performed due to membrane rupture followed by fetal bradycardia. Ventilatory support was necessary because the neonate showed severe birth asphyxia accompanied by hypotonia and dyspnea. He also showed a respiratory complication of chylothorax at 10 days old; therefore, thoracic drainage was performed...
January 2016: No to Hattatsu. Brain and Development
https://www.readbyqxmd.com/read/26995067/a-study-of-a-cohort-of-x-linked-myotubular-myopathy-at-the-clinical-histologic-and-genetic-levels
#16
Osorio Abath Neto, Marina Rodrigues E Silva, Cristiane de Araújo Martins, Acary de Souza Bulle Oliveira, Umbertina Conti Reed, Valérie Biancalana, João Bosco Pesquero, Jocelyn Laporte, Edmar Zanoteli
BACKGROUND: Myotubular myopathy is a rare X-linked congenital myopathy characterized by marked neonatal hypotonia and respiratory insufficiency, facial and ocular involvement, and muscle biopsy with prominent central nuclei in the majority of muscle fibers. It is caused by mutations in MTM1, which codes for the phosphoinositides phosphatase myotubularin. In this work, we established and detailed a new cohort of six patients at the clinical, histologic, and genetic levels. PATIENTS AND METHODS: Patients were recruited after screening 3065 muscle biopsy reports from two large biopsy banks in Sao Paulo, Brazil from the years 2008 to 2013, and from referrals to a neuromuscular outpatient clinic between 2011 and 2013...
May 2016: Pediatric Neurology
https://www.readbyqxmd.com/read/26823526/skeletal-muscle-pathology-in-x-linked-myotubular-myopathy-review-with-cross-species-comparisons
#17
REVIEW
Michael W Lawlor, Alan H Beggs, Ana Buj-Bello, Martin K Childers, James J Dowling, Emma S James, Hui Meng, Steven A Moore, Suyash Prasad, Benedikt Schoser, Caroline A Sewry
X-linked myotubular myopathy (XLMTM) is a devastating, rare, congenital myopathy caused by mutations in the MTM1 gene, resulting in a lack of or dysfunction of the enzyme myotubularin. This leads to severe perinatal weakness and distinctive muscle pathology. It was originally thought that XLMTM was related to developmental arrest in myotube maturation; however, the generation and characterization of several animal models have significantly improved our understanding of clinical and pathological aspects of this disorder...
February 2016: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/26760201/a-phosphoinositide-conversion-mechanism-for-exit-from-endosomes
#18
Katharina Ketel, Michael Krauss, Anne-Sophie Nicot, Dmytro Puchkov, Marnix Wieffer, Rainer Müller, Devaraj Subramanian, Carsten Schultz, Jocelyn Laporte, Volker Haucke
Phosphoinositides are a minor class of short-lived membrane phospholipids that serve crucial functions in cell physiology ranging from cell signalling and motility to their role as signposts of compartmental membrane identity. Phosphoinositide 4-phosphates such as phosphatidylinositol 4-phosphate (PI(4)P) and phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) are concentrated at the plasma membrane, on secretory organelles, and on lysosomes, whereas phosphoinositide 3-phosphates, most notably phosphatidylinositol 3-phosphate (PI(3)P), are a hallmark of the endosomal system...
January 21, 2016: Nature
https://www.readbyqxmd.com/read/26605308/muscle-pathology-limb-strength-walking-gait-respiratory-function-and-neurological-impairment-establish-disease-progression-in-the-p-n155k-canine-model-of-x-linked-myotubular-myopathy
#19
Melissa A Goddard, David L Mack, Stefan M Czerniecki, Valerie E Kelly, Jessica M Snyder, Robert W Grange, Michael W Lawlor, Barbara K Smith, Alan H Beggs, Martin K Childers
BACKGROUND: Loss-of-function mutations in the myotubularin (MTM1) gene cause X-linked myotubular myopathy (XLMTM), a fatal, inherited pediatric disease that affects the entire skeletal musculature. Labrador retriever dogs carrying an MTM1 missense mutation exhibit strongly reduced synthesis of myotubularin, the founder member of a lipid phosphatase required for normal skeletal muscle function. The resulting canine phenotype resembles that of human patients with comparably severe mutations, and survival does not normally exceed 4 months...
October 2015: Annals of Translational Medicine
https://www.readbyqxmd.com/read/26338224/mutation-spectrum-of-the-mtm1-gene-in-xlmtm-patients-10-years-of-experience-in-prenatal-and-postnatal-diagnosis
#20
G Longo, S Russo, G Novelli, F Sangiuolo, M R D'Apice
X-linked myotubular myopathy (XLMTM) is a congenital neuromuscular disorder defined by severe hypotonia, respiratory failure and histopathologic changes in muscle biopsy. The objective of this report is to inform about our experience of genetic analysis on a group of 25 unrelated XLMTM patients, clinically diagnosed by several Italian and European Medical Institutes from 2006 to 2015. The molecular strategy used for genotyping involved Sanger sequencing of coding and intron/exon regions and the Multiplex Ligation Probe Amplification method...
January 2016: Clinical Genetics
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