Glycosylation defects: a new mechanism formuscular dystrophy?Prabhjit K. Grewal{and Jane E. Hewitt*Institute of Genetics, Queen’s Medical Centre, University of Nottingham, Nottingham, UKReceived July 2, 2003; Accepted July 18, 2003Recently, post-tran slational modification of proteins has been defined as a new area of focus for musculardystrophy research by the identification of a group of disease genes that encode known or putativeglycosylation enzymes. Walker–Warburg Syndrome (WWS) and muscle–eye–brain disease (MEB) are causedby mutations in two genes involved in O-mannosylation, POMT1 and POMGnT1, respectively. Fukuyamamuscular dyst rophy (FCMD) is due to mutations in fukutin, a putative phospholigand transferase. Congenitalmuscular dystrophy type 1C and limb girdle muscular dystrophy type 2I are allelic, both being due to mutationsin 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 alsoassociated with neuronal migration abnormalities (often type II lissencephaly) and ocular or retinal defects.A deficiency in post-translational modification of a-dystroglycan is a common feature of all the se musculardystrophies and is thought to involve O-glycosylation pathways. This abnormally modified a-dystroglycanis deficient in binding to extracellular matrix ligands, including laminin and agrin. Selective deletion of dystro-glycan in the central nervous system (CNS) produces br ain abnormalities with striking similarities to WWS,MEB, FCMD and the myd mouse. Thus, impaired dystroglycan function is strongly implicated in thesediseases. However, it is unlikely that these five glycosylation enzymes only have a role in glycosylation ofa-dystroglycan and it is important that other protein targets are identified.INTRODUCTIONThe isolation of dystrophin and subsequent advances inidentification of the interacting proteins that form thedystrophin-associated glycoprotein complex (DGC) led to anexplosion in characterization of the muscular dystrophies (1–5).Recently, the focus has shifted to post-translational modifica-tions of proteins as genes encoding proteins involved inglycosylation have defined a new area of attention in musculardystrophy research. As well as giving further insights intomechanisms underlying muscular dystrophy, study of thesediseases may increase our understanding of the functions ofprotein glycosylation. Althoug h the function of most glycosy-lation is poorly understood, many vertebrate proteins are post-translationally modified by carbohydrates and it has beenestimated that 1% of human genes encode enzymes involved inoligosaccharide synthesis and function (6).These types of muscular dystrophy appear to be distinct fromthe congenital disorders of glycosylation (CDGs), a group ofdiseases caused by defects in the well-characterized and highlyconserved N-glycosylation pathways (7). Many CDGs aremultisystemic due to defects in the modification of a widerange of proteins. In contrast, the glycosylation-deficientmuscular dystrophies appear to involve the less well-definedO-glycosylation pathways and defective post-translation mod-ification seems to be confined to a small number of proteins (ofwhich only one has so far been identified; dystroglycan). In thisreview, we focus on those genes whose mutation appears todisrupt the function of the DGC.GLYCOSYLATION GENES ASSOCIATED WITHINHERITED MUSCULAR DYSTROPHIESPOMT1POMT1 is the human homologue of the Drosophila rotatedabdomen (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: þ44 1158493229; Fax: þ44 1159709906; Email: [email protected]{Present address:Department of Cellular and Molecular Medicine, Howard Hughes Medical Institute, University of California San Diego, California 92093, USA.Human Molecular Genetics, 2003, Vol. 12, Review Issue 2 R259–R264DOI: 10.1093/hmg/ddg272Human Molecular Genetics, Vol. 12, Review Issue 2 # Oxford University Press 2003; all rights reservedand encodes a predi cted transmembrane protein with highhomology to the yeast mannosyltransferases, suggesting afunction in the first step in O-mannosylation of proteins.O-mannosylation is rare in mammals and has only beenidentified in a limit ed number of glycoproteins in brain, nerveand skeletal muscle (9). Homozygous rt Drosophila haveabnormal embryonic muscle development (10), and Jurado etal. were the first to suggest that glycosylation might beimportant in the formation or maintenance of musc le (8).Mutations in POMT1 cause Walker–Warburg Syndrome(WWS, MIM:236670), a very severe, recessive form ofcongenital muscular dystrophy (CMD) (11). Walker–WarburgSyndrome patients also have ocular and retinal abnormalitiesand brain defects including type II lissencephaly (12,13).WWS is genetically heterogeneous as only about 20% ofpatients have point mutations in POMT1 (14). Anothercandidate gene is POMT2, which encodes a closely relatedprotein (15). However, POMT2 is expressed at very low levelsin skeletal muscle (15). Two WWS patients have recently beendescribed with mutations in fukutin (see below), highlightingthe clinical overlap of some of these diseases.Although it is likely that both POMT1 and POMT2 encodemannosyltransferases, this catalytic activity has not yet beenproven. Epitope-tagged POM T2 localizes to the endoplasmicreticulum membrane (15). Although in vitro assays failed todemonstrate an O-mannosyl transfer reaction for either POMT1or POMT2, this is likely to be due to technical difficulties (15).POMGnT1POMGnT1 encodes the protein O-linked mannose b1,2-N-acetylglucosaminyltransferase 1 (16,17). Mutations inPOMGnT1 have been described in muscle–eye–brain disease(MEB, MIM:253280), an autosomal recessive disorder char-acterized by congenital muscular dystrophy, brain malforma-tions and ocular abnormalities (16,18). POMGnT1 catalyzesthe transfer of N-acetylglucosamine from UDP-GlcNAc to O-mannosyl glycoproteins (16,17,19). Mutations in MEB pro-duce proteins that are nonfunctional when assayed in vitro (16).This is the strongest evidence in support of O-mannosylationdefects in these muscular dystrophies and the similaritybetween the phenotypes of WWS and MEB is consistent withPOMT1 acting as an O-mannosyl