Human Molecular Genetics

Human Molecular Genetics Advance Access originally published online on August 12, 2003

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Human Molecular Genetics, 2003, Vol. 12, Review Issue 2 R259-R264
DOI: 10.1093/hmg/ddg272
© 2003 Oxford University Press

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

	ABSTRACT

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Recently, post-translational modification of proteins has been defined as a new area of focus for muscular dystrophy research by the identification 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 deficiency in post-translational modification of -dystroglycan is a common feature of all these muscular dystrophies and is thought to involve O-glycosylation pathways. This abnormally modified -dystroglycan is deficient 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 five glycosylation enzymes only have a role in glycosylation of -dystroglycan and it is important that other protein targets are identified.

	INTRODUCTION

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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 post-translationally 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

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POMT1
POMT1 is the human homologue of the Drosophila rotated abdomen (rt) gene (8). The human gene is widely expressed 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 ß1,2-N-acetylglucosaminyltransferase 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 O-mannosyl 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) (20,21). In addition to severe muscle weakness, there is also always severe mental retardation, with seizures occurring in about half the cases (21). The disease is most prevalent in Japan, where patients carry at least one copy of an ancestral founder mutation (integration of a 3 kb retrotransposon element into the 3' UTR) that results in a reduction in fukutin mRNA levels (21). Individuals who are homozygous for the founder mutation are less severely affected than compound heterozygotes with a point mutation on the other allele, presumably because they have a higher residual activity of fukutin (21). Recently, two non-Japanese individuals homozygous for truncating mutations have been reported with a WWS-type phenotype rather than FCMD (14,22). Clinically, it can be difficult to differentiate between severe FCMD and mild WWS cases (23) and this genetic overlap implicates a function for fukutin in the same pathway as POMT1.

Null mouse mutants of fukutin are embryonic lethal. However, fukutin-deficient chimeric mice generated using embryonic stem (ES) cells targeted for both fukutin alleles have a phenotype that resembles WWS (24). The mice have a severe muscular dystrophy and neuronal migration defects, including disorganized laminar structures and fusion of medial surfaces of the cerebral cortex. Striking ocular abnormalities include abnormal lens development and loss of laminar structure in the retina.

The primary sequence of fukutin shows similarity to microbial proteins involved in polysaccharide/phosphorylcholine modification and mannosyl phosphorylation (25). The protein contains an N-terminal hydrophic signal sequence but lacks a transmembrane domain and was initially suggested to be an extracellular protein (20). However, epitope-tagged protein has recently been reported to localize to the medial Golgi (20,26). No biochemical activity has yet been reported.

Fukutin-related protein (FKRP)
The gene for FKRP was cloned on the basis of homology to the putative catalytic domain of fukutin (27). Mutations in this gene were identified in a subgroup of CMD patients (MDC1C, MIM:606612), with severe muscle weakness and inability to stand unsupported, but no evidence of brain involvement (27). Mutations in FKRP also account for the milder limb girdle muscular dystrophy type 2I (LGMD2I, MIM607155), therefore this disease is allelic with MDC1C (28). The spectrum of LGMD2I phenotypes is quite wide; a large proportion of patients share a common mutation (C826A; Leu276Ileu) and phenotypic severity is often correlated with the second allelic mutation (29). Although initially FKRP mutations were not associated with brain abnormalities (27–30), mutations in FKRP have recently been described in two patients with a pattern of muscle involvement identical to MDC1C but including mental retardation and cerebellar cysts (31).

FKRP is predicted to be a type II membrane protein and is targeted to the medial Golgi apparatus through its N-terminal and transmembrane domains (26). Overexpression of FKRP containing a missense mutation identified in MDC1C (P448L) caused the protein to be inefficiently trafficked to the Golgi apparatus (26). Although the function of the protein is unknown, like fukutin it is predicted to be a phospholigand transferase (27).

Large
Large encodes a putative, bifunctional glycosyltransferase (32,33). A loss of function mutation is responsible for the myodystrophy (myd) mouse (34). Although initial investigations of the myd phenotype highlighted the skeletal muscle aspect of the disease (35,36), we and others have shown that the heart, retinal, peripheral and central nervous systems are also involved (37–39). Homozygous myd mice display a severe, progressive muscular dystrophy and a mild cardiomyopathy. Neuronal migration abnormalities are present in the brain, particularly the cortex and cerebellum (38,39). These resemble the brain abnormalities observed in fukutin-deficient mice (24). Although morphologically the eyes and retina appear normal, electroretinograms showed a normal a-wave but increased implicit times and decreased amplitudes of the b-wave, suggesting altered signal processing in the downstream retinal circuitry (38).

Large has an N-terminal transmembrane anchor, typical of glycosyltransferases. It also has a coiled coil motif and two putative catalytic regions (32,34). The two catalytic domains are not closely related to each other, each showing homology to a different family of glycosyltransferases. The proximal domain is related to bacterial -glycosyltransferases involved in synthesis of lipopolysaccharides or lipooligosaccharides (40). The distal domain is most closely related to iGnT, required for synthesis of the poly-N-acetyllactosamine backbone (Galß14GlcNAcß13)_n found on N- and O-glycans and glycolipids (41).

	ABNORMAL GLYCOSYLATION OF DYSTROGLYCAN

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The overlapping phenotypes of these muscular dystrophies suggest that the glycosylation proteins might act in a common pathway. Using immunoblot assays of total protein extracts, we observed a selective deficiency of -dystroglycan (-DG) in the myd mouse, which we speculated might reflect altered glycosylation of the protein (34). A deficiency in -DG is now known to be a common feature of all these glycosylation-deficient muscular dystrophies; in most cases this has been observed as a loss of immunoreactivity with one or both of the two commercially available monoclonal antibodies, VIA4-1 and IIH6 (11,27,28,34,42,43).

More recently, an antibody to hypoglycosylated -DG generated by Kevin Campbell's group in Iowa was shown to identify a reduced molecular weight form of -DG in skeletal muscle from FCMD and WWS patients and from myd mice (39). Again, this was interpreted as hypoglycosylation -DG, although it is unclear why mutations in three different glycosylation enzymes should result in the same sized form of -DG. It is possible that aberrantly modified -DG is susceptible to proteolysis and the fragment is a common breakdown product.

Dystroglycan function
Dystroglycan is a central component of the DGC in the sarcolemmal muscle membrane (Fig. 1). Its main function is in maintaining sarcolemmal integrity by linking cytoskeletal actin (via dystrophin) to components of the extracellular matrix (via -DG). Ligands for -DG include the laminin-1 and -2 chains, agrin, perlecan and neurexin (44,45). Mutations in almost all of the genes encoding components of the DGC or proteins that interact with the complex have been implicated in inherited forms of human muscular dystrophy or in animal models (1–5), although genetic forms of muscular dystrophy are not exclusively associated with the DGC (46). The complex is not confined to skeletal muscle, as some DGC components are associated with dystroglycan and dystrophin isoforms in other tissues including brain, peripheral nerve, retina and kidney (47–50).

View larger version (26K): [in this window] [in a new window]   Figure 1. Schematic diagram of the skeletal muscle dystrophin-associated protein complex (DGC) (not drawn to scale). In skeletal muscle the DGC is composed of dystrophin, the dystroglycan complex of - and ß-subunits, the sarcoglycans and sarcospan, and ß1 syntrophins and dystrobrevin. N-glycosylation is indicated by purple circles, O-glycosylation by yellow circles. Up to one-half of the molecular mass of -dystroglycan is accounted for by carbohydrate. Mutations in genes encoding most of these components results in muscular dystrophy phenotypes in human and/or animal models. Laminins consist of heterotrimers of , ß and chains. -Dystroglycan binds to the laminin 2 chain, the predominant chain in skeletal muscle, linking the DGC to the extracellular matrix. This binding requires carbohydrate structures on -dystroglycan, presumed to be part of the O-glycosylation.

 
Dystroglycan (Dag1) null mice are embryonic lethal due to very early defects in basement membrane assembly (51). Chimeric mice generated from Dag1^-/- ES cells developed a progressive muscular dystrophy as the skeletal muscles lacked dystroglycan (52). Cre-LoxP technology has been used to produce conditional knockouts of dystroglycan. Loss of Dag1 in differentiated skeletal muscle produced a relatively mild dystrophic phenotype as the satellite cells in this model are able to express dystroglycan successfully and regenerate muscle fibres (53). Elimination of dystroglycan from the CNS produced a phenotype with striking similarities to WWS, MEB, FCMD and the myd mouse with disruption of cortical layering, fusion of cerebral hemispheres and aberrant migration of granule cells (54). In combination with the evidence of altered glycosylation of -DG, this implicates an important role for dystroglycan in the muscle and brain phenotypes of the glycosylation-deficient muscular dystrophies.

Dystroglycan glycosylation
Dystroglycan is post-translationally cleaved into - and ß-subunits (55,56). The 43 kDa ß-subunit, which is N-glycosylated, migrates at the expected mass in all the glycosylation-deficient muscular dystrophies, indicating that the precursor protein is synthesized and cleaved normally. In the myd mouse, immunoblotting of muscle proteins treated with N-glycanases indicates that glycosylation of ß-dystroglycan is not affected (unpublished data). Although it has a predicted weight of 72 kDa, on polyacrylamide gels -DG migrates as a heterogeneous band of much larger mass due to extensive glycosylation (55). The amount and type of protein glycosylation varies between tissues and developmental stages, with the apparent molecular mass varying between about 120 kDa in brain and peripheral nerve to >150 kDa in skeletal and cardiac muscle (44,57–59).

-DG is modified by both N- and O-linked glycosylation (57). The protein is a dumbbell-shaped molecule with two globular domains separated by a central rod thought to be the O-glycosylated mucin-like domain (60). There is evidence for a requirement for sialylated O-glycans on -DG for binding to many of its ligands, including laminin, agrin, neurexin and perlecan (44,61). In MEB, FCMD and the myd mouse, binding of -DG to laminin, agrin and neurexin is defective (38,39). The monoclonal antibody IIH6, which recognizes a carbohydrate epitope on -DG, can block the interaction with laminin (58,62). The loss or reduction of binding by this antibody in conjunction with the predicted activities of POMT1 and POMGnT1, strongly suggests that defects in synthesis of O-linked sugars on -DG underlies the muscular dystrophy phenotypes described here. In addition, there is evidence (at least in myd mice) that N-glycosylation is not affected; mass spectrometry analysis of the profile of N-glycans showed no difference between the brains of myd and control mice (63). Furthermore, treatment of dystroglycan with N-glycanases does not alter its ligand binding activity, nor its immunoreactivity to the VIA4-1 and IIH6 monoclonal antibodies (58).

Several groups have isolated and sequenced glycans from purified -DG (reviewed and discussed in detail in ref. 64). Because this type of analysis requires significant amounts of protein as starting material, these studies have been carried out on sheep brain (65), cow peripheral nerve (66) and rabbit skeletal muscle (67). In each case, the same O-linked -mannose structure was identified (NeuAc2,3Galß1,4GlcNAcß1,2Man-Ser/Thr). Consequently, this structure has been the focus of much attention in recent literature, particularly as sialylated O-linked sugars have been implicated in the laminin-binding activity of dystroglycan (68). POMT1 is a good candidate for the initial attachment of the mannose to dystroglycan, while POMGnT1 is likely to add the GlcNAc residue (16,17). It has been suggested that fukutin, Large and FKRP function in the synthesis of this tetrasaccharide, although this is only conjecture. It should also be noted that not all the O-linked sugars on -DG are attached via mannose; a substantial proportion contain the more common structure Galß1,3GalNAc-Ser/Thr (66,67).

	CONCLUSIONS AND PERSPECTIVES

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Phenotypic spectrum of glycosylation-deficient muscular dystrophies
Clinically, WWS, MEB and FCMD can be difficult to differentiate. In a screen of 30 patients diagnosed as WWS, severe FCMD or MEB, seven had mutations in POMGnT1 (18). This highlights the need to consider all three genes when screening for mutations in these diseases. Of the glycosylation genes identified thus far, mutations in FKRP are associated with the greatest phenotypic variation. However, this might not reflect any biological function but might be a consequence of screening a wider phenotypic spectrum of patients than for the other gene; the coding region of FKRP is contained within a single exon (27) simplifying mutation detection. The extensive amount of clinical and genotypic data accumulating for FKRP should prove useful in identifying functionally important regions of the protein and establishing genotype–phenotype correlations. For example, patients clinically diagnosed with MDC1C tend to carry two missense mutations or are compound heterozygotes for a nonsense and a missense mutation, while the common Leu276Ile changes are invariably associated with LGMD2I (29). The relatively mild nature of the myd phenotype (38) is quite surprising; it is possible that functional redundancy between Large and related glycosyltransferases can compensate in some tissues (33).

Role for aberrant dystroglycan glycosylation in muscular dystrophy
Disruption of the laminin-binding activity of -DG, through aberrant glycosylation, seems a plausible mechanism for muscular dystrophy. Absence or abnormalities in laminins are associated with CMD phenotypes similar to those described here (69–71). Furthermore, the brain abnormalities in WWS, MEB, FCMD and myd reflect closely the effects of deletion of dystroglycan in the CNS (54). Although a direct action of POMT1 and POMGnT1 on dystroglycan in vivo has not been demonstrated, these enzymes are likely to be involved in the addition of O-mannosyl sugars to the protein. In mouse, dystroglycan, fukutin and POMGnT1 are co-expressed in late embryonic and early postnatal cerebellar neurons and glial cells (72). Co-expression of FKRP and dystroglycan in CHO cells alters the post-translational processing of -DG (26). However, it seems very unlikely that these five glycosylation enzymes identified so far each have the sole function of glycosylation of -DG. Different target specificities could account for differences in phenotypes between the diseases. For example, significant morphological ocular abnormalities are only associated with mutations in POMT1, POMGnT1 and fukutin, suggesting that other targets for these enzymes play a role in normal eye development.

Future perspectives
Important questions still to be addressed in this field include the definition of the biochemical activities of most of these enzymes. This will help to define the glycans required for -DG ligand interaction. Although technically difficult, glycan analysis of -DG from disease tissue to define the precise change in glycans would also be valuable in addressing this problem. As these muscular dystrophies are not due to structural abnormalities, potential therapeutic implications include enzyme replacement via gene therapy, upregulation of compensating glycosyltransferases or use of glycan analogues to restore laminin binding.

	ACKNOWLEDGEMENTS

 
The authors thank Chris Moore and Jenny McLaughlan for comments on the manuscript. Funding from The Wellcome Trust and The Muscular Dystrophy Association, USA, is gratefully acknowledged.

	NOTE ADDED IN PROOF

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Since submission of this review, a case of muscular dystrophy associated with mutations in the human LARGE gene has been reported (F. Muntoni, personal communication).

	FOOTNOTES

 
^* 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{at}nottingham.ac.uk

Present address: Department of Cellular and Molecular Medicine, Howard Hughes Medical Institute, University of California San Diego, California 92093, USA.

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