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Congenital muscular dystrophy laminin

Hirokazu Yagi, Chu-Wei Kuo, Takayuki Obayashi, Satoshi Ninagawa, Kay-Hooi Khoo, Koichi Kato
Dystroglycanopathy is a major class of congenital muscular dystrophy caused by a deficiency of functional glycans on α-dystroglycan (αDG) with laminin-binding activity. Recent advances have led to identification of several causative gene products of dystroglycanopathy and characterization of their in vitro enzymatic activities. However, the in vivo functional roles remain equivocal for enzymes such as ISPD, FKTN, FKRP, and TMEM5 that are supposed to be involved in post-phosphoryl modifications linking the GalNAc-β3-GlcNAc-β34-Man-6-phosphate core and the outer laminin-binding glycans...
September 6, 2016: Molecular & Cellular Proteomics: MCP
Kaumudi Konkay, Meena Angamuthu Kannan, Lokesh Lingappa, Megha S Uppin, Sundaram Challa
BACKGROUND AND PURPOSE: Muscle biopsy features of congenital muscular dystrophies (CMD) vary from usual dystrophic picture to normal or nonspecific myopathic picture or prominent fibrosis or striking inflammatory infiltrate, which may lead to diagnostic errors. A series of patients of CMD with significant inflammatory infiltrates on muscle biopsy were correlated with laminin α2 deficiency on immunohistochemistry (IHC). MATERIAL AND METHODS: Cryostat sections of muscle biopsies from the patients diagnosed as CMD on clinical and muscle biopsy features from 1996 to 2014 were reviewed with hematoxylin and eosin(H&E), enzyme and immunohistochemistry (IHC) with laminin α2...
July 2016: Annals of Indian Academy of Neurology
Paul J Thomas, Rui Xu, Paul T Martin
Overexpression of B4GALNT2 (previously GALGT2) inhibits the development of muscle pathology in mouse models of Duchenne muscular dystrophy, congenital muscular dystrophy 1A, and limb girdle muscular dystrophy 2D. In these models, muscle GALGT2 overexpression induces the glycosylation of α dystroglycan with the cytotoxic T cell glycan and increases the overexpression of dystrophin and laminin α2 surrogates known to inhibit disease. Here, we show that GALGT2 gene therapy significantly reduces muscle pathology in FKRP P448Lneo(-) mice, a model for limb girdle muscular dystrophy 2I...
September 2016: American Journal of Pathology
Naoyuki Kuwabara, Hiroshi Manya, Takeyuki Yamada, Hiroaki Tateno, Motoi Kanagawa, Kazuhiro Kobayashi, Keiko Akasaka-Manya, Yuriko Hirose, Mamoru Mizuno, Mitsunori Ikeguchi, Tatsushi Toda, Jun Hirabayashi, Toshiya Senda, Tamao Endo, Ryuichi Kato
The dystrophin glycoprotein complex, which connects the cell membrane to the basement membrane, is essential for a variety of biological events, including maintenance of muscle integrity. An O-mannose-type GalNAc-β1,3-GlcNAc-β1,4-(phosphate-6)-Man structure of α-dystroglycan (α-DG), a subunit of the complex that is anchored to the cell membrane, interacts directly with laminin in the basement membrane. Reduced glycosylation of α-DG is linked to some types of inherited muscular dystrophy; consistent with this relationship, many disease-related mutations have been detected in genes involved in O-mannosyl glycan synthesis...
August 16, 2016: Proceedings of the National Academy of Sciences of the United States of America
Lucile Ryckebüsch, Lydia Hernandez, Carole Wang, Jenny Phan, Deborah Yelon
Skeletal muscle morphogenesis depends upon interactions between developing muscle fibers and the extracellular matrix (ECM) that anchors fibers to the myotendinous junction (MTJ). The pathways that organize the ECM and regulate its engagement by cell-matrix adhesion complexes (CMACs) are therefore essential for muscle integrity. Here, we demonstrate the impact of transmembrane protein 2 (tmem2) on cell-matrix interactions during muscle morphogenesis in zebrafish. Maternal-zygotic tmem2 mutants (MZtmem2) exhibit muscle fiber detachment, in association with impaired laminin organization and ineffective fibronectin degradation at the MTJ...
August 15, 2016: Development
Xiaona Fu, Haipo Yang, Cuijie Wei, Hui Jiao, Shuo Wang, Yanling Yang, Chunxi Han, Xiru Wu, Hui Xiong
Mutations in the fukutin-related protein (FKRP) gene have been associated with dystroglycanopathies, which are common in Europe but rare in Asia. Our study aimed to retrospectively analyze and characterize the clinical, myopathological and genetic features of 12 Chinese patients with FKRP mutations. Three patients were diagnosed with congenital muscular dystrophy type 1C (MDC1C) and nine patients were diagnosed with limb girdle muscular dystrophy type 2I (LGMD2I). Three muscle biopsy specimens had dystrophic changes and reduced glycosylated α-dystroglycan staining, and two showed reduced expression of laminin α2...
July 21, 2016: Journal of Human Genetics
Mariko Taniguchi-Ikeda, Ichiro Morioka, Kazumoto Iijima, Tatsushi Toda
α-Dystroglycanopathy, an autosomal recessive disease, is associated with the development of a variety of diseases, including muscular dystrophy. In humans, α-dystroglycanopathy includes various types of congenital muscular dystrophy such as Fukuyama type congenital muscular dystrophy (FCMD), muscle eye brain disease (MEB), and the Walker Warburg syndrome (WWS), and types of limb girdle muscular dystrophy 2I (LGMD2I). α-Dystroglycanopathy share a common etiology, since it is invariably caused by gene mutations that are associated with the O-mannose glycosylation pathway of α-dystroglycan (α-DG)...
October 2016: Molecular Aspects of Medicine
Gina L O'Grady, Monkol Lek, Shireen R Lamande, Leigh Waddell, Emily C Oates, Jaya Punetha, Roula Ghaoui, Sarah A Sandaradura, Heather Best, Simranpreet Kaur, Mark Davis, Nigel G Laing, Francesco Muntoni, Eric Hoffman, Daniel G MacArthur, Nigel F Clarke, Sandra Cooper, Kathryn North
OBJECTIVE: To evaluate the diagnostic outcomes in a large cohort of congenital muscular dystrophy (CMD) patients using traditional and next generation sequencing (NGS) technologies. METHODS: A total of 123 CMD patients were investigated using the traditional approaches of histology, immunohistochemical analysis of muscle biopsy, and candidate gene sequencing. Undiagnosed patients available for further testing were investigated using NGS. RESULTS: Muscle biopsy and immunohistochemical analysis found deficiencies of laminin α2, α-dystroglycan, or collagen VI in 50% of patients...
July 2016: Annals of Neurology
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
Zandra Körner, Madeleine Durbeej
Congenital muscular dystrophy with laminin α2 chain-deficiency, also known as MDC1A, is a severe neuromuscular disorder for which there is no cure. Patients with complete laminin α2 chain-deficiency typically have an early onset disease with a more severe muscle phenotype while patients with residual laminin α2 chain expression usually have a milder disease course. Similar genotype-phenotype correlations can be seen in the dy3K/dy3K and dy2J/dy2J mouse models of MDC1A, respectively, with dy3K/dy3K mice presenting the more severe phenotype...
2016: PloS One
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
Rui Xu, Neha Singhal, Yelda Serinagaoglu, Kumaran Chandrasekharan, Mandar Joshi, John A Bauer, Paulus M L Janssen, Paul T Martin
Transgenic overexpression of Galgt2 (official name B4Galnt2) in skeletal muscle stimulates the glycosylation of α dystroglycan (αDG) and the up-regulation of laminin α2 and dystrophin surrogates known to inhibit muscle pathology in mouse models of congenital muscular dystrophy 1A and Duchenne muscular dystrophy. Skeletal muscle Galgt2 gene expression is also normally increased in the mdx mouse model of Duchenne muscular dystrophy compared with the wild-type mice. To assess whether this increased endogenous Galgt2 expression could affect disease, we quantified muscular dystrophy measures in mdx mice deleted for Galgt2 (Galgt2(-/-)mdx)...
October 2015: American Journal of Pathology
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
Daniel P Schwartz, Jahannaz Dastgir, Anam Salman, Barbara Lear, Carsten G Bönnemann, Tanya J Lehky
INTRODUCTION: Electrical impedance myography (EIM) is an emerging non-invasive, highly reproducible electrophysiological technique that objectively characterizes muscle structure and composition by measuring bioimpedance. We assessed the ability of EIM ability to discriminate 2 forms of congenital muscular dystrophy (CMD), laminin α2 (LAMA2)-deficient CMD and collagen VI-deficient (COL6) CMD, from a group of healthy children. We also investigated correlations between subcutaneous fat thickness and EIM parameters...
March 2016: Muscle & Nerve
Toot Moran, Yair Gat, Deborah Fass
UNLABELLED: The ~ 800 kDa laminin heterotrimer forms a distinctive cross-shaped structure that further self-assembles into networks within the extracellular matrix. The domains at the laminin chain termini, which engage in network formation and cell-surface interaction, are well understood both structurally and functionally. By contrast, the structures and roles of additional domains embedded within the limbs of the laminin cross have remained obscure. Here, we report the X-ray crystal structure, determined to 1...
July 2015: FEBS Journal
Takako Yoshida-Moriguchi, Kevin P Campbell
Associations between cells and the basement membrane are critical for a variety of biological events including cell proliferation, cell migration, cell differentiation and the maintenance of tissue integrity. Dystroglycan is a highly glycosylated basement membrane receptor, and is involved in physiological processes that maintain integrity of the skeletal muscle, as well as development and function of the central nervous system. Aberrant O-glycosylation of the α subunit of this protein, and a concomitant loss of dystroglycan's ability to function as a receptor for extracellular matrix (ECM) ligands that bear laminin globular (LG) domains, occurs in several congenital/limb-girdle muscular dystrophies (also referred to as dystroglycanopathies)...
July 2015: Glycobiology
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
Jaehong Suh, Juliet A Moncaster, Lirong Wang, Imran Hafeez, Joachim Herz, Rudolph E Tanzi, Lee E Goldstein, Suzanne Y Guénette
FE65 and FE65L1 are cytoplasmic adaptor proteins that bind a variety of proteins, including the amyloid precursor protein, and that mediate the assembly of multimolecular complexes. We previously reported that FE65/FE65L1 double knockout (DKO) mice display disorganized laminin in meningeal fibroblasts and a cobblestone lissencephaly-like phenotype in the developing cortex. Here, we examined whether loss of FE65 and FE65L1 causes ocular and muscular deficits, 2 phenotypes that frequently accompany cobblestone lissencephaly...
June 2015: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
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