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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
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
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
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
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
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
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
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
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
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
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
Hyo Jeong Kim, Young-Chul Choi, Hyung Jun Park, Young-Mock Lee, Heung Dong Kim, Joon Soo Lee, Hoon-Chul Kang
Congenital muscular dystrophy type 1A (MDC1A) is an autosomal recessive disorder characterized by hypotonia, elevated serum creatine kinase level, delayed motor milestones, white matter changes observed by brain magnetic resonance imaging, and normal intelligence. A mutation in the laminin α2 (LAMA2) gene, located at 6q22-23, is a genetic cause of MDC1A. Patients have merosin (laminin α2)-deficient skeletal muscles. However, the degree of merosin expression ranges from total absence to partial reduction. Patients with residual merosin expression have more variable and milder phenotypes than those with absolute merosin deficiency...
March 2014: Korean Journal of Pediatrics
Fumiaki Saito, Motoi Kanagawa, Miki Ikeda, Hiroki Hagiwara, Toshihiro Masaki, Hidehiko Ohkuma, Yuki Katanosaka, Teruo Shimizu, Masahiro Sonoo, Tatsushi Toda, Kiichiro Matsumura
Several types of muscular dystrophy are caused by defective linkage between α-dystroglycan (α-DG) and laminin. Among these, dystroglycanopathy, including Fukuyama-type congenital muscular dystrophy (FCMD), results from abnormal glycosylation of α-DG. Recent studies have shown that like-acetylglucosaminyltransferase (LARGE) strongly enhances the laminin-binding activity of α-DG. Therefore, restoration of the α-DG-laminin linkage by LARGE is considered one of the most promising possible therapies for muscular dystrophy...
September 1, 2014: Human Molecular Genetics
Soonsang Yoon, Guido Stadler, Mary Lou Beermann, Eric V Schmidt, James A Windelborn, Peter Schneiderat, Woodring E Wright, Jeffrey Boone Miller
BACKGROUND: Congenital muscular dystrophy Type 1A (MDC1A) is a severe, recessive disease of childhood onset that is caused by mutations in the LAMA2 gene encoding laminin-α2. Studies with both mouse models and primary cultures of human MDC1A myogenic cells suggest that aberrant activation of cell death is a significant contributor to pathogenesis in laminin-α2-deficiency. METHODS: To overcome the limited population doublings of primary cultures, we generated immortalized, clonal lines of human MDC1A myogenic cells via overexpression of both CDK4 and the telomerase catalytic component (human telomerase reverse transcriptase (hTERT))...
2013: Skeletal Muscle
Maria de los Angeles Beytía, Gabriele Dekomien, Sabine Hoffjan, Verena Haug, Constantin Anastasopoulos, Janbernd Kirschner
Primary deficiency of laminin alpha-2 due to mutations in the LAMA2 gene accounts for 30% of all patients with congenital muscular dystrophy. Here, we present seven patients with partial or total laminin alpha-2 deficiency (MDC1A) with a wide clinical spectrum, ranging from ambulant patients to patients who were never able to stand or sit. We identified two pathogenic mutations in the LAMA2 gene in all patients except for one patient in whom only one mutation was found. Six of the mutations were previously undescribed...
August 2014: Molecular and Cellular Probes
Zhanwen He, Xiangyang Luo, Liyang Liang, Pinggan Li, Dongfang Li, Meng Zhe
The aim of this study was to characterize the clinical and genetic features of a 4-year-old female with merosin-deficient congenital muscular dystrophy type 1A (MDC1A). MDC1A is the most common form of congenital muscular dystrophy. MDC1A is caused by mutation of the laminin α-2 gene (LAMA2), localized to chromosome 6q22-23. Clinical presentation, as well as the results of neuro-imaging, electrophysiology and molecular genetic tests were used to evaluate a patient with MDC1A. The patient exhibited severe hypotonia and marked proximal weakness at 6 months of age, as well as delayed developmental milestones...
November 2013: Experimental and Therapeutic Medicine
Pam M Van Ry, Priscilla Minogue, Bradley L Hodges, Dean J Burkin
Merosin-deficient congenital muscular dystrophy type 1A (MDC1A) is a severe and fatal muscle-wasting disease with no cure. MDC1A patients and the dy(W-/-) mouse model exhibit severe muscle weakness, demyelinating neuropathy, failed muscle regeneration and premature death. We have recently shown that laminin-111, a form of laminin found in embryonic skeletal muscle, can substitute for the loss of laminin-211/221 and prevent muscle disease progression in the dy(W-/-) mouse model. What is unclear from these studies is whether laminin-111 can restore failed regeneration to laminin-α2-deficient muscle...
January 15, 2014: Human Molecular Genetics
Yoshitsugu Aoki, Tetsuya Nagata, Toshifumi Yokota, Akinori Nakamura, Matthew J A Wood, Terence Partridge, Shin'ichi Takeda
Phosphorodiamidate morpholino oligomer (PMO)-mediated exon skipping is among the more promising approaches to the treatment of several neuromuscular disorders including Duchenne muscular dystrophy. The main weakness of this approach arises from the low efficiency and sporadic nature of the delivery of charge-neutral PMO into muscle fibers, the mechanism of which is unknown. In this study, to test our hypothesis that muscle fibers take up PMO more efficiently during myotube formation, we induced synchronous muscle regeneration by injection of cardiotoxin into the tibialis anterior muscle of Dmd exon 52-deficient mdx52 and wild-type mice...
December 15, 2013: Human Molecular Genetics
Jenny Yamauchi, Ajay Kumar, Lina Duarte, Thomas Mehuron, Mahasweta Girgenrath
Merosin-deficient congenital muscular dystrophy type 1A (MDC1A) is an autosomal recessive disorder caused by mutations in the laminin-α2 gene (OMIM: 607855). Currently, no treatment other than palliative care exists for this disease. In our previous work, genetic interventions in the Lama2(Dy-w) mouse model for MDC1A demonstrated that limited regeneration and uncontrolled apoptosis are important drivers of this disease. However, targeting one of these disease drivers without addressing the other results in only partial rescue of the phenotype...
November 1, 2013: Human Molecular Genetics
Qing Yu, Arpana Sali, Jack Van der Meulen, Brittany K Creeden, Heather Gordish-Dressman, Anne Rutkowski, Sree Rayavarapu, Kitipong Uaesoontrachoon, Tony Huynh, Kanneboyina Nagaraju, Christopher F Spurney
INTRODUCTION: Congenital muscular dystrophy is a distinct group of diseases presenting with weakness in infancy or childhood and no current therapy. One form, MDC1A, is the result of laminin alpha-2 deficiency and results in significant weakness, respiratory insufficiency and early death. Modification of apoptosis is one potential pathway for therapy in these patients. METHODS: dy(2J) mice were treated with vehicle, 0.1 mg/kg or 1 mg/kg of omigapil daily via oral gavage over 17...
2013: PloS One
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