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Matthieu A Raess, Sylvie Friant, Belinda S Cowling, Jocelyn Laporte
Myotubularins define a large family of proteins conserved through evolution. Several members are mutated in different neuromuscular diseases including centronuclear myopathies and Charcot-Marie-Tooth (CMT) neuropathies, or are linked to a predisposition to obesity and cancer. While some members have phosphatase activity against the 3-phosphate of phosphoinositides, regulating the phosphorylation status of PtdIns3P and PtdIns(3,5)P2 implicated in membrane trafficking and autophagy, and producing PtdIns5P, others lack key residues in the catalytic site and are classified as dead-phosphatases...
September 15, 2016: Advances in Biological Regulation
Wei X Teo, Markus C Kerr, Rohan D Teasdale
The intracellular pathogen Salmonella enterica servovar Typhimurium (S.typhimurium) modulates the host cell's phosphoinositide (PI) metabolism to establish its intracellular replicative niche, the Salmonella-containing vacuole (SCV). Upon invasion, phosphoinositide 3-phosphate (PI(3)P) and other early endosomal markers are rapidly recruited to and remain associated with the SCV throughout its early maturation. While the phosphoinositide 3-phosphatase myotubularin 4 (MTMR4) has an established role in regulating autophagy and cellular PI(3)P-content, two processes associated with the intracellular survival of S...
2016: Frontiers in Cellular and Infection Microbiology
Vladimir Tesar, Zdenka Hruskova
BACKGROUND: Lupus nephritis (LN) is still associated with significant mortality and substantial risk of progression to end-stage renal failure. Its outcome is related to the class and severity of LN and response to treatment, and it is poorer in patients with renal relapses. Ethnicity has a relatively well-defined impact on the outcome of the patients and their response to treatment and must always be taken into consideration in treatment decisions. SUMMARY: In this article, we provide a review of the impact of ethnicity on the prevalence of systemic lupus erythematosus (SLE), the proportion of patients with SLE developing LN, outcomes of SLE and LN and response of LN to treatment...
September 2015: Kidney Diseases
Desmond Y H Yap, Tak Mao Chan
BACKGROUND: Lupus nephritis (LN) is a common and severe organ involvement manifesting itself in systemic lupus erythematosus (SLE). There is a considerable difference in prevalence, severity, treatment response and outcomes between Asian LN patients and LN patients from other racial backgrounds. SUMMARY: Asian SLE patients have a higher prevalence of LN than Caucasian SLE patients and often present with a more severe disease. Increasing data from genetic studies, accompanied by progress in high-throughput genotyping, have advanced our knowledge about genetic predispositions that might partly contribute to the clinical variations observed...
September 2015: Kidney Diseases
Elizabeth A Fogarty, Megan H Brewer, Jose F Rodriguez-Molina, William D Law, Ki H Ma, Noah M Steinberg, John Svaren, Anthony Antonellis
Schwann cells are the myelinating glia of the peripheral nervous system and dysfunction of these cells causes motor and sensory peripheral neuropathy. The transcription factor SOX10 is critical for Schwann cell development and maintenance, and many SOX10 target genes encode proteins required for Schwann cell function. Loss-of-function mutations in the gene encoding myotubularin related protein 2 (MTMR2) cause Charcot-Marie-Tooth disease type 4B1 (CMT4B1), a severe demyelinating peripheral neuropathy characterized by myelin outfoldings along peripheral nerves...
July 27, 2016: Human Molecular Genetics
Philip Weidner, Michaela Söhn, Tobias Gutting, Teresa Friedrich, Timo Gaiser, Julia Magdeburg, Peter Kienle, Hermelindis Ruh, Carsten Hopf, Hans-Michael Behrens, Christoph Röcken, Tamar Hanoch, Rony Seger, Matthias P A Ebert, Elke Burgermeister
Phosphoinositide (PIP) phosphatases such as myotubularins (MTMs) inhibit growth factor receptor signaling. However, the function of myotubularin-related protein 7 (MTMR7) in cancer is unknown. We show that MTMR7 protein was down-regulated with increasing tumor grade (G), size (T) and stage (UICC) in patients with colorectal cancer (CRC) (n=1786). The presence of MTMR7 in the stroma correlated with poor prognosis, whereas MTMR7 expression in the tumor was not predictive for patients' survival. Insulin reduced MTMR7 protein levels in human CRC cell lines, and CRC patients with type 2 diabetes mellitus (T2DM) or loss of imprinting (LOI) of insulin-like growth factor 2 (IGF2) had an increased risk for MTMR7 loss...
July 7, 2016: Oncotarget
Annika Hohendahl, Aurélien Roux, Valentina Galli
Centronuclear myopathies (CNMs) are genetic diseases whose symptoms are muscle weakness and atrophy (wasting) and centralised nuclei. Recent human genetic studies have isolated several groups of mutations. Among them, many are found in two interacting proteins essential to clathrin-mediated endocytosis, dynamin and the BIN-Amphiphysin-Rvs (BAR) protein BIN1/amphiphysin 2. In this review, by using structural and functional data from the study of endocytosis mainly, we discuss how the CNM mutations could affect the structure and the function of these ubiquitous proteins and cause the muscle-specific phenotype...
October 2016: Journal of Structural Biology
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
František Liška, Blanka Chylíková, Michaela Janků, Ondřej Šeda, Zdeňka Vernerová, Michal Pravenec, Vladimír Křen
In the inbred SHR/OlaIpcv rat colony, we identified males with small testicles and inability to reproduce. By selectively breeding their parents, we revealed the infertility to segregate as an autosomal recessive Mendelian character. No other phenotype was observed in males, and females were completely normal. By linkage using a backcross with Brown Norway strain, we mapped the locus to a 1.2Mbp segment on chromosome 7, harboring 35 genes. Sequencing of candidate genes revealed a G to A substitution in a canonical 'AG' splice site of intron 37 in Sbf1 (SET binding factor 1, alias myotubularin-related protein 5)...
September 2016: Reproduction: the Official Journal of the Society for the Study of Fertility
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
Mingxing Feng, Zhenyu He, Yuanyuan Wang, Xiufang Yan, Jiwen Zhang, Zhaonong Hu, Wenjun Wu
Periplocosides, which are insecticidal compounds isolated from the root bark of Periploca sepium Bunge, can affect the digestive system of insects. However, the mechanism though which periplocosides induces a series of symptoms remains unknown. In this study, affinity chromatography was conducted by coupling periplocoside E-semi-succinic acid ester with epoxy amino hexyl (EAH) sepharose 4B. Sodium dodecyl sulfonate-polyacrylamide gelelectrophoresis (SDS-PAGE) was performed to analyze the fraction eluted by periplocoside E...
2016: Toxins
Marta Romani, Cybel Mehawej, Tommaso Mazza, Andre Mégarbané, Enza Maria Valente
Charcot-Marie-Tooth neuropathy type 4 (CMT4) comprises a large group of genetically heterogeneous progressive sensory motor neuropathies characterized by autosomal recessive inheritance. Among these, CMT4B includes 3 forms related to genes of the myotubularin family, namely CMT4B1 (MTMR2), CMT4B2 (MTMR13/SBF2), and CMT4B3 (MTMR5/SBF1).
April 2016: Neurology. Genetics
Seoung Min Bong, Kka-bi Son, Seung-Won Yang, Jae-Won Park, Jea-Won Cho, Kyung-Tae Kim, Hackyoung Kim, Seung Jun Kim, Young Jun Kim, Byung Il Lee
Myotubularin-related protein 1 (MTMR1) is a phosphatase that belongs to the tyrosine/dual-specificity phosphatase superfamily. MTMR1 has been shown to use phosphatidylinositol 3-monophosphate (PI(3)P) and/or phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) as substrates. Here, we determined the crystal structure of human MTMR1. The refined model consists of the Pleckstrin homology (PH)-GRAM and phosphatase (PTP) domains. The overall structure was highly similar to the previously reported MTMR2 structure. Interestingly, two phosphate molecules were coordinated by strictly conserved residues located in the C(X)5R motif of the active site...
2016: PloS One
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
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
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
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
Martin K Childers, Alan H Beggs, Ana Buj-Bello
No abstract text is available yet for this article.
October 2015: Annals of Translational Medicine
Shahnaz Ali, Kanjaksha Ghosh, Shrimati Shetty
Bengal macrothrombocytopenia (BMTCP) is a giant platelet disorder with mild to moderate thrombocytopenia, clinically characterized by mild bleeding symptoms to totally asymptomatic condition. The pathophysiological mechanism of this condition is not fully understood yet. In the present study, 5 subjects (P1-P5) with BMTCP whose platelet counts ranged between 36140X10(9)/l and mean platelet volume (MPV)13.5-16.1fl were analyzed for differential gene expression of platelets by suppressive subtractive hybridization (SSH) technique...
December 2015: Blood Cells, Molecules & Diseases
Diána Papp, Tibor Kovács, Viktor Billes, Máté Varga, Anna Tarnóci, László Hackler, László G Puskás, Hanna Liliom, Krisztián Tárnok, Katalin Schlett, Adrienn Borsy, Zsolt Pádár, Attila L Kovács, Krisztina Hegedűs, Gábor Juhász, Marcell Komlós, Attila Erdős, Balázs Gulyás, Tibor Vellai
Autophagy is a major molecular mechanism that eliminates cellular damage in eukaryotic organisms. Basal levels of autophagy are required for maintaining cellular homeostasis and functioning. Defects in the autophagic process are implicated in the development of various age-dependent pathologies including cancer and neurodegenerative diseases, as well as in accelerated aging. Genetic activation of autophagy has been shown to retard the accumulation of damaged cytoplasmic constituents, delay the incidence of age-dependent diseases, and extend life span in genetic models...
2016: Autophagy
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