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https://www.readbyqxmd.com/read/28367954/bioenergetic-impairment-in-congenital-muscular-dystrophy-type-1a-and-leigh-syndrome-muscle-cells
#1
Cibely C Fontes-Oliveira, Maarten Steinz, Peter Schneiderat, Hindrik Mulder, Madeleine Durbeej
Skeletal muscle has high energy requirement and alterations in metabolism are associated with pathological conditions causing muscle wasting and impaired regeneration. Congenital muscular dystrophy type 1A (MDC1A) is a severe muscle disorder caused by mutations in the LAMA2 gene. Leigh syndrome (LS) is a neurometabolic disease caused by mutations in genes related to mitochondrial function. Skeletal muscle is severely affected in both diseases and a common feature is muscle weakness that leads to hypotonia and respiratory problems...
April 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28334989/impaired-fetal-muscle-development-and-jak-stat-activation-mark-disease-onset-and-progression-in-a-mouse-model-for-merosin-deficient-congenital-muscular-dystrophy
#2
Andreia M Nunes, Ryan D Wuebbles, Apurva Sarathy, Tatiana M Fontelonga, Marianne Deries, Dean J Burkin, Sólveig Thorsteinsdóttir
Merosin-deficient congenital muscular dystrophy type 1A (MDC1A) is a dramatic neuromuscular disease in which crippling muscle weakness is evident from birth. Here, we use the dyW mouse model for human MDC1A to trace the onset of the disease during development in utero. We find that myotomal and primary myogenesis proceed normally in homozygous dyW-/- embryos. Fetal dyW-/- muscles display the same number of myofibers as wildtype (WT) muscles, but by E18.5 dyW-/- muscles are significantly smaller and muscle size is not recovered post-natally...
June 1, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28281577/potent-pro-inflammatory-and-pro-fibrotic-molecules-osteopontin-and-galectin-3-are-not-major-disease-modulators-of-laminin-%C3%AE-2-chain-deficient-muscular-dystrophy
#3
Kinga I Gawlik, Johan Holmberg, Martina Svensson, Mikaela Einerborg, Bernardo M S Oliveira, Tomas Deierborg, Madeleine Durbeej
A large number of human diseases are caused by chronic tissue injury with fibrosis potentially leading to organ failure. There is a need for more effective anti-fibrotic therapies. Congenital muscular dystrophy type 1A (MDC1A) is a devastating form of muscular dystrophy caused by laminin α2 chain-deficiency. It is characterized with early inflammation and build-up of fibrotic lesions, both in patients and MDC1A mouse models (e.g. dy(3K)/dy(3K)). Despite the enormous impact of inflammation on tissue remodelling in disease, the inflammatory response in MDC1A has been poorly described...
March 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28241031/a-novel-early-onset-phenotype-in-a-zebrafish-model-of-merosin-deficient-congenital-muscular-dystrophy
#4
Sarah J Smith, Jeffrey C Wang, Vandana A Gupta, James J Dowling
Merosin deficient congenital muscular dystrophy (MDC1A) is a severe neuromuscular disorder with onset in infancy that is associated with severe morbidities (particularly wheelchair dependence) and early mortality. It is caused by recessive mutations in the LAMA2 gene that encodes a subunit of the extracellular matrix protein laminin 211. At present, there are no treatments for this disabling disease. The zebrafish has emerged as a powerful model system for the identification of novel therapies. However, drug discovery in the zebrafish is largely dependent on the identification of phenotypes suitable for chemical screening...
2017: PloS One
https://www.readbyqxmd.com/read/28218619/muscular-dystrophy-meets-protein-biochemistry-the-mother-of-invention
#5
Steven D Funk, Jeffrey H Miner
Muscular dystrophies result from a defect in the linkage between the muscle fiber cytoskeleton and the basement membrane (BM). Congenital muscular dystrophy type MDC1A is caused by mutations in laminin α2 that either reduce its expression or impair its ability to polymerize within the muscle fiber BM. Defects in this BM lead to muscle fiber damage from the force of contraction. In this issue of the JCI, McKee and colleagues use a laminin polymerization-competent, designer chimeric BM protein in vivo to restore function of a polymerization-defective laminin, leading to normalized muscle structure and strength in a mouse model of MDC1A...
March 1, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27932089/clinical-and-neuroimaging-findings-in-two-brothers-with-limb-girdle-muscular-dystrophy-due-to-lama2-mutations
#6
Elizabeth Harris, Meriel McEntagart, Ana Topf, Hanns Lochmüller, Kate Bushby, Caroline Sewry, Volker Straub
Recessive mutations in LAMA2 commonly cause congenital muscular dystrophy (MDC1A) and, rarely, limb girdle muscular dystrophy (LGMD). We report 2 brothers who presented in adulthood with LGMD due to novel mutations in LAMA2 identified by whole exome sequencing (WES). Muscle biopsy more than 30 years ago demonstrated dystrophic changes but was not available for immunoanalysis. Muscle MRI demonstrated involvement of peripheral muscle with internal sparing classically seen in collagen-VI related disorders. Extensive genetic testing, including COL6A1/2/3, was performed prior to WES...
November 3, 2016: Neuromuscular Disorders: NMD
https://www.readbyqxmd.com/read/27906075/nuclear-bodies-reorganize-during-myogenesis-in-vitro-and-are-differentially-disrupted-by-expression-of-fshd-associated-dux4
#7
Sachiko Homma, Mary Lou Beermann, Bryant Yu, Frederick M Boyce, Jeffrey Boone Miller
BACKGROUND: Nuclear bodies, such as nucleoli, PML bodies, and SC35 speckles, are dynamic sub-nuclear structures that regulate multiple genetic and epigenetic processes. Additional regulation is provided by RNA/DNA handling proteins, notably TDP-43 and FUS, which have been linked to ALS pathology. Previous work showed that mouse cell line myotubes have fewer but larger nucleoli than myoblasts, and we had found that nuclear aggregation of TDP-43 in human myotubes was induced by expression of DUX4-FL, a transcription factor that is aberrantly expressed and causes pathology in facioscapulohumeral dystrophy (FSHD)...
December 1, 2016: Skeletal Muscle
https://www.readbyqxmd.com/read/27798092/igf-1-gh-axis-enhances-losartan-treatment-in-lama2-related-muscular-dystrophy
#8
Anthony Accorsi, Ajay Kumar, Younghwa Rhee, Alex Miller, Mahasweta Girgenrath
As the complexities of dystrophic pathology have been elucidated over the last few years, it has become increasingly clear that primary monogenetic defects result in multiple secondary pathologies capable of autonomously driving disease progression. Consequently, single-mode therapies fail to comprehensively ameliorate all aspects of pathology. Lama2-related muscular dystrophy (MDC1A) is a devastating congenital muscular dystrophy caused by mutations in the LAMA2 gene that results in multi-faceted secondary pathologies that include inflammation, fibrosis, apoptosis, and necrosis leading to severe muscle weakness and minimal postnatal growth...
October 24, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/27784478/-correlation-between-thigh-muscle-magnetic-resonance-imaging-findings-and-clinical-features-of-congenital-muscular-dystrophies-a-preliminary-study
#9
L L Wang, J Du, X N Fu, Y B Fan, C J Wei, J Ding, D D Tan, J X Xiao, H Xiong
Objective: To analyze the clinical and magnetic resonance imaging (MRI) features of congenital muscular dystrophy (CMD) to improve the diagnostic level. Method: Clinical manifestations and thigh muscle MRI results of 8 cases of CMD diagnosed on genetic level from April 2013 to November 2015 were investigated. MRI was performed on the thigh muscles of all cases. Fatty infiltration of different muscles described in T1WI was graded to evaluate. Clinical symptoms and signs, as well as muscle MRI features were analyzed by statistical description...
October 2, 2016: Zhonghua Er Ke za Zhi. Chinese Journal of Pediatrics
https://www.readbyqxmd.com/read/26962340/merosin-negative-congenital-muscular-dystrophy-report-of-five-cases
#10
Faruk Incecik, Ozlem M Herguner, Serdar Ceylaner, Sakir Altunbasak
CONTEXT: Congenital muscular dystrophy type 1A (MDC1A) is caused by mutations in the laminin α-2 gene encoding laminin-a2. AIMS: The purpose of this study is to determine clinical and genetic results in five Turkish patients with MDC1A. SETTING AND DESIGNS: Five children with MDC1A were retrospectively analyzed. RESULTS: Three (60%) were boys, and 2 (40%) were girls. Parental consanguinity was found in all the families...
October 2015: Journal of Pediatric Neurosciences
https://www.readbyqxmd.com/read/26610911/laminin-%C3%AE-2-chain-deficient-congenital-muscular-dystrophy-pathophysiology-and-development-of-treatment
#11
REVIEW
Madeleine Durbeej
Laminin-211 is a major constituent of the skeletal muscle basement membrane. It stabilizes skeletal muscle and influences signal transduction events from the myomatrix to the muscle cell. Mutations in the gene encoding the α2 chain of laminin-211 lead to congenital muscular dystrophy type 1A (MDC1A), a life-threatening disease characterized by severe hypotonia, progressive muscle weakness, and joint contractures. Common complications include severely impaired motor ability, respiratory failure, and feeding difficulties...
2015: Current Topics in Membranes
https://www.readbyqxmd.com/read/26379183/magnetic-resonance-imaging-is-sensitive-to-pathological-amelioration-in-a-model-for-laminin-deficient-congenital-muscular-dystrophy-mdc1a
#12
Ravneet Vohra, Anthony Accorsi, Ajay Kumar, Glenn Walter, Mahasweta Girgenrath
PURPOSE: To elucidate the reliability of MRI as a non-invasive tool for assessing in vivo muscle health and pathological amelioration in response to Losartan (Angiotensin II Type 1 receptor blocker) in DyW mice (mouse model for Laminin-deficient Congenital Muscular Dystrophy Type 1A). METHODS: Multiparametric MR quantifications along with histological/biochemical analyses were utilized to measure muscle volume and composition in untreated and Losartan-treated 7-week old DyW mice...
2015: PloS One
https://www.readbyqxmd.com/read/26347253/mesoangioblast-delivery-of-miniagrin-ameliorates-murine-model-of-merosin-deficient-congenital-muscular-dystrophy-type-1a
#13
Teuta Domi, Emanuela Porrello, Daniele Velardo, Alessia Capotondo, Alessandra Biffi, Rossana Tonlorenzi, Stefano Amadio, Alessandro Ambrosi, Yuko Miyagoe-Suzuki, Shin'ichi Takeda, Markus A Ruegg, Stefano Carlo Previtali
BACKGROUND: Merosin-deficient congenital muscular dystrophy type-1A (MDC1A) is characterized by progressive muscular dystrophy and dysmyelinating neuropathy caused by mutations of the α2 chain of laminin-211, the predominant laminin isoform of muscles and nerves. MDC1A has no available treatment so far, although preclinical studies showed amelioration of the disease by the overexpression of miniagrin (MAG). MAG reconnects orphan laminin-211 receptors to other laminin isoforms available in the extracellular matrix of MDC1A mice...
2015: Skeletal Muscle
https://www.readbyqxmd.com/read/26249246/merosin-deficient-congenital-muscular-dystrophy-a-novel-homozygous-mutation-in-the-laminin-2-gene
#14
Clinton Turner, Rachael Mein, Cynthia Sharpe, Donald R Love
Merosin deficient congenital muscular dystrophy (MDC1A) is an autosomal recessive disorder characterized by mutations in the LAMA2 gene at chromosome 6q22-23. This gene spans 65 exons and encodes the α2 chain subunit of laminin-2. A variety of deletions, missense, nonsense and splice site mutations have been described in the LAMA2 gene, with resultant MDC1A. We describe a novel LAMA2 homozygous sequence variant in a Samoan patient with MDC1A and confirm its pathogenic effect with merosin immunohistochemistry on skeletal muscle biopsy...
December 2015: Journal of Clinical Neuroscience: Official Journal of the Neurosurgical Society of Australasia
https://www.readbyqxmd.com/read/25766329/life-or-death-by-nf%C3%AE%C2%BAb-losartan-promotes-survival-in-dy2j-dy2j-mouse-of-mdc1a
#15
M Elbaz, N Yanay, S Laban, M Rabie, S Mitrani-Rosenbaum, Y Nevo
Inflammation and fibrosis are well-defined mechanisms involved in the pathogenesis of the incurable Laminin α2-deficient congenital muscular dystrophy (MDC1A), while apoptosis mechanism is barely discussed. Our previous study showed treatment with Losartan, an angiotensin II type I receptor antagonist, improved muscle strength and reduced fibrosis through transforming growth factor beta (TGF-β) and mitogen-activated protein kinases (MAPK) signaling inhibition in the dy(2J)/dy(2J) mouse model of MDC1A. Here we show for the first time that Losartan treatment up-regulates and shifts the nuclear factor kappa B (NFκB) signaling pathway to favor survival versus apoptosis/damage in this animal model...
2015: Cell Death & Disease
https://www.readbyqxmd.com/read/25449259/analysing-regenerative-potential-in-zebrafish-models-of-congenital-muscular-dystrophy
#16
A J Wood, P D Currie
The congenital muscular dystrophies (CMDs) are a clinically and genetically heterogeneous group of muscle disorders. Clinically hypotonia is present from birth, with progressive muscle weakness and wasting through development. For the most part, CMDs can mechanistically be attributed to failure of basement membrane protein laminin-α2 sufficiently binding with correctly glycosylated α-dystroglycan. The majority of CMDs therefore arise as the result of either a deficiency of laminin-α2 (MDC1A) or hypoglycosylation of α-dystroglycan (dystroglycanopathy)...
November 2014: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/25124546/segmental-uniparental-isodisomy-of-chromosome-6-causing-transient-diabetes-mellitus-and-merosin-deficient-congenital-muscular-dystrophy
#17
Raissa Coelho Andrade, Julián Nevado, Maria Angélica de Faria Domingues de Lima, Tânia Saad, Lucia Moraes, Leila Chimelli, Pablo Lapunzina, Fernando Regla Vargas
Segmental uniparental isodisomy (iUPD) is a rare genetic event that may cause aberrant expression of imprinted genes, and reduction to homozygosity of a recessive mutation. Transient neonatal diabetes mellitus (TNDM) is typically caused by imprinting aberrations in chromosome 6q24 TNDM differentially-methylated region (DMR). Approximately, 15.12 Mb upstream in 6q22-q23 is located LAMA2, the gene responsible of merosin-deficient congenital muscular dystrophy type 1A (MDC1A). We investigated a patient diagnosed both with TNDM and MDC1A, born from a twin dichorionic discordant pregnancy...
November 2014: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/25075272/dysregulation-of-matricellular-proteins-is-an-early-signature-of-pathology-in-laminin-deficient-muscular-dystrophy
#18
Thomas Mehuron, Ajay Kumar, Lina Duarte, Jenny Yamauchi, Anthony Accorsi, Mahasweta Girgenrath
BACKGROUND: MDC1A is a congenital neuromuscular disorder with developmentally complex and progressive pathologies that results from a deficiency in the protein laminin α2. MDC1A is associated with a multitude of pathologies, including increased apoptosis, inflammation and fibrosis. In order to assess and treat a complicated disease such as MDC1A, we must understand the natural history of the disease so that we can identify early disease drivers and pinpoint critical time periods for implementing potential therapies...
2014: Skeletal Muscle
https://www.readbyqxmd.com/read/25071564/laminin-%C3%AE-2-chain-deficiency-is-associated-with-microrna-deregulation-in-skeletal-muscle-and-plasma
#19
Johan Holmberg, Azra Alajbegovic, Kinga Izabela Gawlik, Linda Elowsson, Madeleine Durbeej
microRNAs (miRNAs) are widespread regulators of gene expression, but little is known of their potential roles in congenital muscular dystrophy type 1A (MDC1A). MDC1A is a severe form of muscular dystrophy caused by mutations in the gene encoding laminin α2 chain. To gain insight into the pathophysiological roles of miRNAs associated with MDC1A pathology, laminin α2 chain-deficient mice were evaluated by quantitative PCR. We demonstrate that expression of muscle-specific miR-1, miR-133a, and miR-206 is deregulated in laminin α2 chain-deficient muscle...
2014: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/24994560/quantitative-proteomic-analysis-reveals-metabolic-alterations-calcium-dysregulation-and-increased-expression-of-extracellular-matrix-proteins-in-laminin-%C3%AE-2-chain-deficient-muscle
#20
Bruno Menezes de Oliveira, Cintia Y Matsumura, Cibely C Fontes-Oliveira, Kinga I Gawlik, Helena Acosta, Patrik Wernhoff, Madeleine Durbeej
Congenital muscular dystrophy with laminin α2 chain deficiency (MDC1A) is one of the most severe forms of muscular disease and is characterized by severe muscle weakness and delayed motor milestones. The genetic basis of MDC1A is well known, yet the secondary mechanisms ultimately leading to muscle degeneration and subsequent connective tissue infiltration are not fully understood. In order to obtain new insights into the molecular mechanisms underlying MDC1A, we performed a comparative proteomic analysis of affected muscles (diaphragm and gastrocnemius) from laminin α2 chain-deficient dy(3K)/dy(3K) mice, using multidimensional protein identification technology combined with tandem mass tags...
November 2014: Molecular & Cellular Proteomics: MCP
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