Human Molecular Genetics 2003 Vol 12 Review Issue 2 DOI 10 1093 hmg ddg272 R259 R264 Glycosylation defects a new mechanism for muscular dystrophy Prabhjit K Grewal and Jane E Hewitt Institute of Genetics Queen s Medical Centre University of Nottingham Nottingham UK Received July 2 2003 Accepted July 18 2003 Recently post translational modi cation of proteins has been de ned as a new area of focus for muscular dystrophy research by the identi cation of a group of disease genes that encode known or putative glycosylation enzymes Walker Warburg Syndrome WWS and muscle eye brain disease MEB are caused by mutations in two genes involved in O mannosylation POMT1 and POMGnT1 respectively Fukuyama muscular dystrophy FCMD is due to mutations in fukutin a putative phospholigand transferase Congenital muscular dystrophy type 1C and limb girdle muscular dystrophy type 2I are allelic both being due to mutations in the gene encoding fukutin related protein FKRP Finally the causative gene in the myodystrophy myd mouse is a putative bifunctional glycosyltransferase Large WWS MEB FCMD and the myd mouse are also associated with neuronal migration abnormalities often type II lissencephaly and ocular or retinal defects A de ciency in post translational modi cation of a dystroglycan is a common feature of all these muscular dystrophies and is thought to involve O glycosylation pathways This abnormally modi ed a dystroglycan is de cient in binding to extracellular matrix ligands including laminin and agrin Selective deletion of dystroglycan in the central nervous system CNS produces brain abnormalities with striking similarities to WWS MEB FCMD and the myd mouse Thus impaired dystroglycan function is strongly implicated in these diseases However it is unlikely that these ve glycosylation enzymes only have a role in glycosylation of a dystroglycan and it is important that other protein targets are identi ed INTRODUCTION The isolation of dystrophin and subsequent advances in identification of the interacting proteins that form the dystrophin associated glycoprotein complex DGC led to an explosion in characterization of the muscular dystrophies 1 5 Recently the focus has shifted to post translational modifications of proteins as genes encoding proteins involved in glycosylation have defined a new area of attention in muscular dystrophy research As well as giving further insights into mechanisms underlying muscular dystrophy study of these diseases may increase our understanding of the functions of protein glycosylation Although the function of most glycosylation is poorly understood many vertebrate proteins are posttranslationally modified by carbohydrates and it has been estimated that 1 of human genes encode enzymes involved in oligosaccharide synthesis and function 6 These types of muscular dystrophy appear to be distinct from the congenital disorders of glycosylation CDGs a group of diseases caused by defects in the well characterized and highly conserved N glycosylation pathways 7 Many CDGs are multisystemic due to defects in the modification of a wide range of proteins In contrast the glycosylation deficient muscular dystrophies appear to involve the less well defined O glycosylation pathways and defective post translation modification seems to be confined to a small number of proteins of which only one has so far been identified dystroglycan In this review we focus on those genes whose mutation appears to disrupt the function of the DGC GLYCOSYLATION GENES ASSOCIATED WITH INHERITED MUSCULAR DYSTROPHIES POMT1 POMT1 is the human homologue of the Drosophila rotated abdomen rt gene 8 The human gene is widely expressed To whom correspondence should be addressed at Institute of Genetics Queen s Medical Centre University of Nottingham Nottingham NG7 2UH UK Tel 44 1158493229 Fax 44 1159709906 Email jane hewitt nottingham ac uk Present address Department of Cellular and Molecular Medicine Howard Hughes Medical Institute University of California San Diego California 92093 USA Human Molecular Genetics Vol 12 Review Issue 2 Oxford University Press 2003 all rights reserved R260 Human Molecular Genetics 2003 Vol 12 Review Issue 2 and encodes a predicted transmembrane protein with high homology to the yeast mannosyltransferases suggesting a function in the first step in O mannosylation of proteins O mannosylation is rare in mammals and has only been identified in a limited number of glycoproteins in brain nerve and skeletal muscle 9 Homozygous rt Drosophila have abnormal embryonic muscle development 10 and Jurado et al were the first to suggest that glycosylation might be important in the formation or maintenance of muscle 8 Mutations in POMT1 cause Walker Warburg Syndrome WWS MIM 236670 a very severe recessive form of congenital muscular dystrophy CMD 11 Walker Warburg Syndrome patients also have ocular and retinal abnormalities and brain defects including type II lissencephaly 12 13 WWS is genetically heterogeneous as only about 20 of patients have point mutations in POMT1 14 Another candidate gene is POMT2 which encodes a closely related protein 15 However POMT2 is expressed at very low levels in skeletal muscle 15 Two WWS patients have recently been described with mutations in fukutin see below highlighting the clinical overlap of some of these diseases Although it is likely that both POMT1 and POMT2 encode mannosyltransferases this catalytic activity has not yet been proven Epitope tagged POMT2 localizes to the endoplasmic reticulum membrane 15 Although in vitro assays failed to demonstrate an O mannosyl transfer reaction for either POMT1 or POMT2 this is likely to be due to technical difficulties 15 POMGnT1 POMGnT1 encodes the protein O linked mannose b1 2 Nacetylglucosaminyltransferase 1 16 17 Mutations in POMGnT1 have been described in muscle eye brain disease MEB MIM 253280 an autosomal recessive disorder characterized by congenital muscular dystrophy brain malformations and ocular abnormalities 16 18 POMGnT1 catalyzes the transfer of N acetylglucosamine from UDP GlcNAc to Omannosyl glycoproteins 16 17 19 Mutations in MEB produce proteins that are nonfunctional when assayed in vitro 16 This is the strongest evidence in support of O mannosylation defects in these muscular dystrophies and the similarity between the phenotypes of WWS and MEB is consistent with POMT1 acting as an O mannosyl transferase Fukutin Fukutin mutations are associated with Fukuyama congenital muscular dystrophy FCMD MIM 253800 20