Dystroglycan and dystroglycanopathies: Report of the 187th ENMC Workshop 11–13 November 2011, Naarden, The Netherlands

Abstract

The 187th ENMC Workshop on dystroglycan and dystroglycanopathies in Naarden from 11th to 13th November 2011, brought together 20 researchers from seven different countries (Germany, Italy, The Netherlands, Sweden, Switzerland, UK and USA) working on the clinical and basic aspects of the post-translational modification of dystroglycan. Topics included the pathophysiology in patients, animal models of dystroglycanopathies, and cellular approaches addressing the effects of post-translational modification on dystroglycan function in a variety of systems. Specific issues which were addressed included factors that might determine the development of central nervous system involvement in patients, if current cell and animal models of the dystroglycanopathies are appropriate for the study of the disease and their utility for therapeutic screening and whether dystroglycan signalling pathways in the cytoskeleton, cancer and polarity can provide new insight into the dystroglycanopathies. Dystroglycan is a core and essential component of the dystrophin glycoprotein complex of muscle and brain. With one rare exception [1], no primary mutations are known in dystroglycan itself, presumed to be due to embryonic lethality. However mutations have been identified in a number of genes involved in the post-translational modification of dystroglycan giving rise to a large number of secondary dystroglycanopathies. The post translational modification of dystroglycan by either glycosylation, phosphorylation or proteolysis has profound effects on the functional capabilities of dystroglycan. Several forms of neuromuscular disease are now known to be associated with mutations in genes including; POMT1, POMT2, POMGnt1, LARGE, fukutin, fukutin related protein (FKRP) and most recently DMP2 and DMP3. All encode for proteins that are either putative or determined glycosyltransferases or in the case of fukutin and FKRP proteins that are of unknown function but are nonetheless necessary for α-dystroglycan glycosylation lending support to the idea that the aberrant post-translational modification of proteins represents an important mechanism of pathogenesis in the muscular dystrophies [2–4]. One key characteristic of the muscle of patients with mutations in these genes is a marked hypoglycosylation of α-dystroglycan [5–7] which has led to the suggestion of dystroglycanopathies as a general term to describe these conditions. α-Dystroglycan is a central component of the dystrophin associated complex and is expressed in a number of different tissues including the brain. Its abnormal glycosylation affects its interaction with members of the extracellular matrix, including laminin, perlecan, neurexin and agrin within the basement membrane. This reduction in ligand binding within the basement membrane is thought to underlie both the muscular dystrophy and the structural brain defects. Mutations in POMT1/2 [7,8], POMGnT1 [9], fukutin [10]), fukutin-related protein (FKRP) [11], LARGE [12,13] are responsible for a spectrum of clinical phenotypes that ranges from Walker–Warburg syndrome (WWS), Muscle–Eye–Brain disease (MEB), Fukuyama-type muscular dystrophy (FCMD), congenital muscular dystrophy (CMD) types MDC1C and MDC1D and the limb girdle type 2 variants with onset in childhood or adult life (LGMD2I, LGMD2L, and LGMD2N) [14–17]. At the severe end of the spectrum these diseases are associated with central nervous system involvement that present as cortical malformations (polymicrogyria and cobblestone lissencephaly) and ocular defects in addition to muscular dystrophy. Interestingly the phenotype of patients belonging to this group of disorders depends not so much on the specific gene primarily affected (i.e. POMT1, POMT2, POMGnT1, LARGE, FKRP or fukutin) but rather the severity of the specific mutation and presumably its effect on the structure and thus the function of the gene product [16]. Whilst the hypoglycosylation of α-dystroglycan is the key pathogenic defect in the dystroglycanopathies, other posttranslational modifications such as phosphorylation and proteolysis have been recorded that also have profound consequences for dystroglycan function [18]. Indeed there is evidence to suggest that some of these latter modifications may also be consequent on the former. For example in many adenocarcinomas where α-dystroglycan is hypoglycosylated due to downregulation of LARGE [19], there are associated changes: phosphorylation and proteolysis in β-dystroglycan [20,21]. Although studied less extensively in muscle, it is extremely likely that secondary post-translational modification of β-dystroglycan is an important part of the aetiology of the dystroglycanopathies.