Congenital muscular dystrophy: molecular and cellular aspects

Abstract

The congenital muscular dystrophies are a clinically and genetically heterogeneous group of neuromuscular disorders. Each form has a characteristic phenotype, but there is overlap between some entities and their classification is based on a combination of clinical features and the primary or secondary protein defect. Recent studies have identified the genetic basis of a number of congenital muscular dystrophies (11 genes in total) and have recognised a novel pathological mechanism that highlights the importance of the correct posttranslational processing of proteins, in particular alpha-dystroglycan. Diagnosis of these conditions has been aided by the availability of specific antibodies for each protein and a better understanding of the protein changes that accompany each condition. In this review we present the major molecular, clinical and diagnostic aspects of each group of congenital muscular dystrophy with an emphasis in the more recent developments.

Congenital muscular dystrophy. Part II: a review of pathogenesis and therapeutic perspectives

“…The clinical course is broadly variable and can comprise the involvement of the brain and eyes [1][2][3][4][5][6][7] .…”

“…A computerized version of the classification is accessible at http://www.musclegenetable.org and http://194.167.35.195/. Most of the different genes involved with the pathogenesis of the CMD subtypes are related to the function of the dystrophin-glycoproteins associated complex (DGC) in the sarcolemma and extracellular matrix and their mutations lead either to defects in the glycosylation of alpha-dystroglycan (alpha-dystroglycanopathies) or to abnormalities of extracellular matrix proteins (MDC1A and collagen VI related disorders) [1][2][3][4][5][6][7] . A fourth subtype, rigid spine CMD, is related to a defect of an endoplasmic reticulum protein, selenoprotein N 9 , and recently a new subtype 10 was associated to a defect of a nuclear protein, lamin A/C.…”

“…Molecular changes in genes that codified glycosyltransferases affecting this step of the DAG chain of links are responsible for the pathogenesis of five CMDs named alpha-dystroglycanopathies or CMDs by defects of the omannosyl-glycosylation of alpha-DG [1][2][3][4][5][6][7]15,30,33,[36][37][38][39][40][41][42][43][44][45][46][47][48][49][50] : Fukuyama CMD (FCMD), "muscle-eye-brain" (MeB) disease, WalkerWarburg syndrome (WWs), MDC1C and MCD1D.…”

Mechanisms of Disease: congenital muscular dystrophies—glycosylation takes center stage

“…[1][2][3][4][5][6][7][8] Approximately one-third of all CMDs are caused by mutations in the LAMA2 gene, which encodes the α2 chain of laminin. Mutations in COL6A1, COL6A2 and COL6A3, which encode the three chains of collagen type VI, give rise to Ullrich congenital muscular dystrophy and Bethlem myopathy.…”

“…These genes include ITGA7-the gene that encodes integrin α7 (the predominant integrin α chain in skeletal muscle)-and six genes (fukutin [FCMD], fukutin-related protein [FKRP], protein O-linked mannose β1,2-N-acetylglucosaminyltransferase [POMGnT1], protein-O-mannosyltransferases 1 and 2 [POMT1/2], and like-glycosyltransferase [LARGE]), the products of which affect the glycosylation of α-dystroglycan. [1][2][3][4][5][6][7][8] α-Dystroglycan is an important membrane protein that, like integrins, binds to the extracellular matrix. Diseases resulting from mutations that affect α-dystroglycan glycosylation have been grouped together under the heading dystroglycanopathies.…”