Dystroglycanopathies: coming into focus
Introduction
A reduction in α-dystroglycan's ligand-binding capacity resulting from its aberrant glycosylation is now a well-documented phenomenon characterising a growing subset of muscular dystrophies. The term ‘dystroglycanopathies’ has been ascribed to these genetically heterogeneous disorders that frequently include central nervous system pathology and encompass a striking range of clinical severity. At the most severe end of the clinical spectrum are the conditions Walker–Warburg syndrome (WWS), muscle–eye–brain disease (MEB) and Fukuyama congenital muscular dystrophy (FCMD) [1, 2, 3]. These conditions are characterised by congenital muscular dystrophy (CMD) with severe structural brain and eye abnormalities, which in WWS results in early infantile death [4]. Conversely, individuals at the mildest end of the clinical spectrum may present in adult life with limb girdle muscular dystrophy (LGMD) and without associated brain or eye involvement [5]. A number of intermediate phenotypes between these aforementioned extremes have also been described with the best characterised being MDC1C, due to defects in FKRP, in which affected children do not typically have brain or eye involvement despite the relative severe skeletal muscle involvement [5]. Diagnosis of dystroglycanopathies is established upon the detection of hypoglycosylated α-dystroglycan at the sarcolemma of skeletal muscle fibres by immunolabelling and/or on Western blot (Figure 1) [6]. Whereas genetic defects in DAG1 (encoding dystroglycan) itself have not yet been identified in human disease, defects in eight putative and demonstrated glycosyltransferases, or accessory proteins of glycosyltransferases, implicated in the glycosylation of α-dystroglycan have been shown to cause a dystroglycanopathy phenotype (Table 1) [1, 2, 3, 4, 5, 7••, 8].
Causative mutations were originally identified in homogenous disease categories in patients from discrete geographic regions. The original data indicated a complete correlation between mutations in specific genes and discrete clinical phenotypes. This is best represented by the research performed on patients with FCMD and MEB. FCMD was described within the Japanese population where, in the majority of cases, it is caused by a 3 kb retrotransposal insertion in the 3′ UTR of the FKTN gene, a mutation endemic to Japan [2]. MEB was originally described within an isolated Finnish population in association with mutations in POMGNT1 [3]. More recently, these tight associations have been blurred as a more complex picture has emerged between gene defect and clinical phenotype.
This review will focus discussion on those studies aimed at characterising the dystroglycanopathy patient population and revealing the molecular and cellular dysfunctions underlying muscular dystrophies with defective glycosylation of dystroglycan.
Section snippets
Genotype–phenotype correlations: additional parameters
Until recently no information has been available regarding the relative contribution of individual causative genes or the genotype–phenotype correlations within large cohorts of dystroglycanopathy patients. Over the past few years, however, a number of studies of large cohorts have been performed by us and others to address this. These studies have firmly established that the clinical spectrum associated with mutations in specific causative dystroglycanopathy genes is in fact far wider than
Dystroglycanopathies meet congenital disorders of glycosylation
In July 2009 Lefeber et al. reported a patient with an intriguing molecular defect presenting with mild muscular dystrophy, dilated cardiomyopathy and stroke-like episodes with no associated brain or eye involvement [7••]. A reduction in immunoreactivity to IIH6 was seen on immunohistochemistry from a skeletal muscle biopsy. Transferrin isoelectric focusing revealed an abnormal profile suggesting a CDG type I pattern consistent with a disorder in N-glycosylation and a defect in the endoplasmic
Aggressive carcinoma cells and B3GNT1
The processing of dystroglycan also affects its function as a cellular receptor for human pathogens and has implications in the progression of cancer [16, 17, 18]. Multiple post-translational modifications of dystroglycan have been identified in carcinoma cells, which are thought to modulate the composition and function of dystroglycan. Bao et al. recently reported an association between the reduction in laminin-binding glycans and the decreased expression of β3GNT1 in aggressive carcinoma cell
Hypoglycosylation in the chicken
Hypoglycosylation of α-dystroglycan has previously been demonstrated in a naturally occurring muscular dystrophy in the chicken [21]. This was observed using the same monoclonal antibody routinely used in the diagnosis of dystroglycanopathy humans [21, 22]. Linkage studies identified a homozygous region spanning approximately 1 Mb on chicken chromosome 2q and containing only seven genes [23]. A single homozygous missense alteration (c.1321G>A; p.Arg441Gln) was identified in the gene encoding
The identification of novel causative dystroglycanopathy genes
Over the past few years the identification of novel genetic defects in dystroglycanopathy patients has been hindered by the extensive genetic and clinical heterogeneity present in these disorders [4]. To compound these issues, as studies of common founder mutations and large informative pedigrees are exhausted, the detection of rarely mutated genes becomes more challenging. We investigated whether mutations in WWP1 or β3GNT1 were present in our cohort of molecularly undiagnosed patients. No
Characterising the glycosylation of α-dystroglycan
Dystroglycan is an integral component of the dystrophin–glycoprotein complex and functions in a diverse range of cellular processes including development, signalling and adhesion [25, 26]. The binding of α-dystroglycan to its extracellular matrix ligands is strictly dependent on the glycosylation status of α-dystroglycan [6, 27]. This extensive glycosylation is species specific, tissue specific and developmentally regulated [28, 29]. Although a number of different glycans have been identified
Dystroglycanopathy animal models
A number of both naturally occurring and targeted animal models defective in genes implicated in the pathway of glycosylation have been developed. These models recapitulate various aspects of the clinical and pathological features of dystroglycanopathy in humans [35]. Of particular interest, a number of new FKRP animal models have recently been reported. The downregulation of FKRP in zebrafish embryos causes alterations in somatic structure and muscle fibre organisation as well as defects in
Avenues for therapy
In 2004, Campbell and co-workers reported that the function of LARGE could be exploited as a viable therapeutic strategy for dystroglycanopathy patients [40]. The overexpression of human LARGE in the Largemyd mouse model (via intramuscular injection) not only ameliorated muscle pathology but also was well tolerated. Unexpectedly, the overexpression of LARGE in patient cell lines with FKTN, POMGNT1 and POMT1 mutations also resulted in increased glycosylation (production of the IIH6 antigen).
Conclusion
Significant progress has been made in characterising these genetically and clinically heterogeneous disorders of aberrant glycosylation of dystroglycan. Further work is needed to determine the role of glycans in ligand binding and determine the exact glycan composition in different tissues, developmental stages and pathological conditions. Additional information regarding the pathways underlying dystroglycanopathies will aid in the diagnosis, treatment and the development of novel therapeutic
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
The authors would like to thank both the Muscular Dystrophy Campaign and the National Commissioning Group for their support, Dr S. Torelli and Dr C. Jimenez-Mallebrera for providing the images used in Figure 1 and Miss E. Stevens for her helpful discussion regarding this manuscript Both ARF and CG are Muscular Dystrophy Campaign fellows. FM is supported by the Great Ormond Street Hospital Children's Charity.
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