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https://www.readbyqxmd.com/read/27548528/pik3c2b-inhibition-improves-function-and-prolongs-survival-in-myotubular-myopathy-animal-models
#1
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
#2
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
#3
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
#4
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...
May 4, 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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
https://www.readbyqxmd.com/read/26273216/dnm2-mutations-in-a-cohort-of-sporadic-patients-with-centronuclear-myopathy
#12
Osorio Abath Neto, Cristiane de Araújo Martins, Mary Carvalho, Gerson Chadi, Katia Werneck Seitz, Acary Souza Bulle Oliveira, Umbertina Conti Reed, Jocelyn Laporte, Edmar Zanoteli
Centronuclear myopathy (CNM) is a rare congenital muscle disease characterized by fibers with prominent centralized nuclei in muscle biopsies. The disease is clinically heterogeneous, ranging from severe neonatal hypotonic phenotypes to adult-onset mild muscle weakness, and can have multiple modes of inheritance in association with various genes, including MTM1, DNM2, BIN1 and RYR1. Here we analyzed 18 sporadic patients with clinical and histological diagnosis of CNM and sequenced the DNM2 gene, which codes for the dynamin 2 protein...
May 2015: Genetics and Molecular Biology
https://www.readbyqxmd.com/read/26086764/validity-of-a-neurological-scoring-system-for-canine-x-linked-myotubular-myopathy
#13
Jessica M Snyder, Allison Meisner, David Mack, Melissa Goddard, Ian T Coulter, Robert Grange, Martin K Childers
A simple clinical neurological test was developed to evaluate response to gene therapy in a preclinical canine model of X-linked myotubular myopathy (XLMTM). This devastating congenital myopathy is caused by mutation in the myotubularin (MTM1) gene. Clinical signs include muscle weakness, early respiratory failure, and ventilator dependence. A spontaneously occurring canine model has a similar clinical picture and histological abnormalities on muscle biopsy compared with patients. We developed a neuromuscular assessment score, graded on a scale from 10 (normal) to 1 (unable to maintain sternal recumbency)...
June 2015: Human Gene Therapy. Clinical Development
https://www.readbyqxmd.com/read/25970698/validity-of-a-neurological-scoring-system-for-canine-x-linked-myotubular-myopathy
#14
Jessica M Snyder, Allison Meisner, David Mack, Melissa Goddard, Ian T Coulter, Robert Grange, Martin Childers
A simple clinical neurological test was developed to evaluate response to gene therapy in a preclinical canine model of X-linked Myotubular Myopathy (XLMTM). This devastating congenital myopathy is caused by mutation in the myotubularin (MTM1) gene. Clinical signs include muscle weakness, early respiratory failure and ventilator dependence. A spontaneously occurring canine model has a similar clinical picture and histological abnormalities on muscle biopsy compared to patients. We developed a neuromuscular assessment score, graded on a scale from 10 (normal) to 1 (unable to maintain sternal recumbency)...
May 13, 2015: Human Gene Therapy. Clinical Development
https://www.readbyqxmd.com/read/25957634/centronuclear-myopathies-genotype-phenotype-correlation-and-frequency-of-defined-genetic-forms-in-an-italian-cohort
#15
Fabiana Fattori, Lorenzo Maggi, Claudio Bruno, Denise Cassandrini, Valentina Codemo, Michela Catteruccia, Giorgio Tasca, Angela Berardinelli, Francesca Magri, Marika Pane, Anna Rubegni, Lucio Santoro, Lucia Ruggiero, Patrizio Fiorini, Antonella Pini, Tiziana Mongini, Sonia Messina, Giacomo Brisca, Irene Colombo, Guja Astrea, Chiara Fiorillo, Cinzia Bragato, Isabella Moroni, Elena Pegoraro, Maria Rosaria D'Apice, Enrico Alfei, Marina Mora, Lucia Morandi, Alice Donati, Anni Evilä, Anna Vihola, Bjarne Udd, Pia Bernansconi, Eugenio Mercuri, Filippo Maria Santorelli, Enrico Bertini, Adele D'Amico
Centronuclear myopathies (CNMs) are a group of clinically and genetically heterogeneous muscle disorders. To date, mutation in 7 different genes has been reported to cause CNMs but 30 % of cases still remain genetically undefined. Genetic investigations are often expensive and time consuming. Clinical and morphological clues are needed to facilitate genetic tests and to choose the best approach for genetic screening. We aimed to describe genotype-phenotype correlation in an Italian cohort of patients affected by CNMs, to define the relative frequencies of its defined genetic forms and to draw a diagnostic algorithm to address genetic investigations...
July 2015: Journal of Neurology
https://www.readbyqxmd.com/read/25664165/x-linked-myotubular-myopathy-in-rottweiler-dogs-is-caused-by-a-missense-mutation-in-exon-11-of-the-mtm1-gene
#16
G Diane Shelton, Branden E Rider, Georgina Child, Sophia Tzannes, Ling T Guo, Behzad Moghadaszadeh, Emily C Troiano, Bianca Haase, Claire M Wade, Alan H Beggs
BACKGROUND: Congenital and inherited myopathies in dogs are faithful models of human muscle diseases and are being recognized with increasing frequency. In fact, canine models of dystrophin deficient muscular dystrophy and X-linked myotubular myopathy are of tremendous value in the translation of new and promising therapies for the treatment of these diseases. We have recently identified a family of Australian Rottweilers in which male puppies were clinically affected with severe muscle weakness and atrophy that resulted in early euthanasia or death...
2015: Skeletal Muscle
https://www.readbyqxmd.com/read/25637770/the-mtm1p-carrier-and-pyridoxal-5-phosphate-cofactor-trafficking-in-yeast-mitochondria
#17
Mei M Whittaker, Aravind Penmatsa, James W Whittaker
Biochemical communication between the cytoplasmic and mitochondrial subsystems of the cell depends on solute carriers in the mitochondrial inner membrane that transport metabolites between the two compartments. We have expressed and purified a yeast mitochondrial carrier protein (Mtm1p, YGR257cp), originally identified as a manganese ion carrier, for biochemical characterization aimed at resolving its function. High affinity, stoichiometric pyridoxal 5'-phosphate (PLP) cofactor binding was characterized by fluorescence titration and calorimetry, and the biochemical effects of mtm1 gene deletion on yeast mitochondria were investigated...
February 15, 2015: Archives of Biochemistry and Biophysics
https://www.readbyqxmd.com/read/25633151/a-novel-dynamin-2-gene-mutation-associated-with-a-late-onset-centronuclear-myopathy-with-necklace-fibres
#18
Olivera Casar-Borota, Johan Jacobsson, Rolf Libelius, Carola Hedberg Oldfors, Edoardo Malfatti, Norma Beatriz Romero, Anders Oldfors
Nuclear centralisation and internalisation, sarcoplasmic radiating strands and type 1 muscle fibre predominance and hypotrophy characterise dynamin-2 (DNM2) associated centronuclear myopathy, whereas necklace fibres are typically seen in late onset myotubularin-1 (MTM1)-related myopathy. We report a woman with unilateral symptoms probably related to brachial plexus neuritis. Electromyography revealed localised neuropathic and generalised myopathic abnormalities. The typical features of DNM2 centronuclear myopathy with additional necklace fibres were found in the muscle biopsy...
April 2015: Neuromuscular Disorders: NMD
https://www.readbyqxmd.com/read/25566070/pathogenic-mechanisms-in-centronuclear-myopathies
#19
REVIEW
Heinz Jungbluth, Mathias Gautel
Centronuclear myopathies (CNMs) are a genetically heterogeneous group of inherited neuromuscular disorders characterized by clinical features of a congenital myopathy and abundant central nuclei as the most prominent histopathological feature. The most common forms of congenital myopathies with central nuclei have been attributed to X-linked recessive mutations in the MTM1 gene encoding myotubularin ("X-linked myotubular myopathy"), autosomal-dominant mutations in the DNM2 gene encoding dynamin-2 and the BIN1 gene encoding amphiphysin-2 (also named bridging integrator-1, BIN1, or SH3P9), and autosomal-recessive mutations in BIN1, the RYR1 gene encoding the skeletal muscle ryanodine receptor, and the TTN gene encoding titin...
2014: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/25502460/chromosomal-instability-and-phosphoinositide-pathway-gene-signatures-in-glioblastoma-multiforme
#20
Mark G Waugh
Structural rearrangements of chromosome 10 are frequently observed in glioblastoma multiforme and over 80 % of tumour samples archived in the catalogue of somatic mutations in cancer database had gene copy number loss for PI4K2A which encodes phosphatidylinositol 4-kinase type IIalpha. PI4K2A loss of heterozygosity mirrored that of PTEN, another enzyme that regulates phosphoinositide levels and also PIK3AP1, MINPP1, INPP5A and INPP5F. These results indicated a reduction in copy number for a set of phosphoinositide signalling genes that co-localise to chromosome 10q...
January 2016: Molecular Neurobiology
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