The 3rd ENMC workshop on Dystroglycan and the Dystroglycanopathies

The 3rd ENMC workshop on Dystroglycan and the Dystroglycanopathies

Location: Hoofddorp

Organizers

Prof Kevin Campbell (Iowa City, USA) and Dr. Volker Straub (Newcastle upon Tyne, UK)

We are grateful to the LGMD2i Fund for contributing to travel expenses for speakers from non-ENMC member countries.

Description

The 257^th ENMC Workshop entitled ‘Dystroglycan and the Dystroglycanopathies’ was a hybrid workshop that took place from the 10^th – 12^th June 2022 in Hoofddorp, The Netherlands. The 17 participants were a multidisciplinary group comprising clinical and basic scientists from seven different countries (Denmark, France, Germany, The Netherlands, UK, and USA) including a patient and carer and a representative from a patient organization.

Background

Dystroglycan is a core and essential component of the dystrophin-glycoprotein complex of muscle and brain, making vital links between the cytoskeleton and laminin in the extracellular matrix. Perturbations in the ability of dystroglycan to interact with laminin have severe implications for human disease. These diseases have collectively been termed dystroglycanopathies. In rare, isolated instances they involve primary mutations of dystroglycan itself, but more frequently are associated with mutations in genes involved in the post-translational modification of dystroglycan: the secondary dystroglycanopathies, but also the so-called tertiary dystroglycanopathies arising from mutations in metabolic enzymes and other proteins that are involved more generally in multiple glycosylation pathways and cellular roles that in turn also impinge on dystroglycan function. A heightened clinical awareness of the spectrum of these diseases coupled with greater use of exome sequencing has led to the identification of several new genes involved in dystroglycan glycosylation and other pathways relevant for dystroglycan function. Furthermore, detailed biochemical and cell biological analyses have finely mapped the biosynthetic pathways leading to the glycosylation of dystroglycan that enable it to bind to laminin. Our understanding of dystroglycan function has also developed considerably in the decade since we proposed the inaugural workshop on this topic, and clinical trials in LGMD2i (LGMDR9) are imminent.

This wealth of information has led to a new understanding of how the defective interaction between of dystroglycan and laminin leads to disease. For example we now have insight on the process of glycosylation of a crucial component of dystroglycan called “matriglycan” , where the like-acetylglucosaminyltransferase-1 (LARGE1) enzyme adds repeating disaccharide of alternating xylose and glucuronic acid . This allows dystroglycan to function as the predominant extracellular matrix receptor in skeletal muscle and brain. Matriglycan is indeed a scaffold for multiple laminin-G (LG) domain-containing extracellular matrix proteins (e.g. laminin, agrin, and perlecan) and it has the remarkable capacity to be tuned during skeletal muscle development and regeneration. Defects in matriglycan synthesis result in the dystroglycanopathies, which include both congenital and limb-girdle muscular dystrophies,  that can also be accompanied by structural brain and eye abnormalities. Moreover, in addition to our understanding of the glycosylation of dystroglycan, much insight has also been gained into the functional roles of dystroglycan, not only in the bran and muscle, but also in other cells types, and the implication that the defective processing of this protein has with respect to role in Lassa fever virus infections.

There are nevertheless several incompletely understood aspects of this group of disorders.. Indeed symptoms range from relatively mild late-onset muscular dystrophy, to perinatally lethal severe muscular dystrophy with significant neurological abnormalities. Even within the disease spectrum relating to a single gene, there is considerable variation in phenotype depending on the actual mutation.

Aims

The aims of this workshop, therefore, are to bring together researchers working on the clinical and basic aspects of the post-translational modification of dystroglycan, whether it is in relation to the pathophysiology of patients, animal models of dystroglycanopathies, or cellular systems addressing the effects of these modifications on dystroglycan function. In addition, natural history and epidemiology data for dystroglycanopathies and clinical trial plans were addressed. Specific issues that were addressed are as follows:

Regulation of matriglycan synthesis in the dystroglycanopathies

Functional roles of dystroglycan in the brain and the lessons to be learned from neuroscience, both basic and clinical.

How can we reconcile the genotype with phenotype, can functional consequences be reconciled with disease severity and how can we use this information for future therapeutic development?

Are current cellular and animal models of the dystroglycanopathies appropriate for the study of the disease and are they useful for therapeutic screening.

Gene transfer studies in dystroglycan animal models

The potential for new avenues for therapeutic intervention, and for new biomarkers.

How can we make better use of natural history and epidemiology data for dystroglycanopathies

Trial Readiness and Clinical Trials

Addressing the perspectives of patients and care givers, in order to provide valuable insight into the importance of finding a therapy for this group of diseases, particularly to basic scientists who have no direct contact with patients

Achievements

During the workshop reviewed a broad range of topics relevant to the dystroglycanopathies, from patient registries and clinical diagnostic approaches to the functional role of dystroglycan in muscle and brain, as well as potential new therapeutic approaches to treat the dystroglycanopathies. There were presentations from a dystroglycanopathy patient, and representative of the organization Cure CMD, also gave his perspective. These presentations provided a valuable insight into the importance of finding a therapy for this group of diseases, particularly to basic scientists who have no direct contact with patients.

The following key conclusions were reached:

• A greater appreciation of how disease mechanisms can lead to the identification of new treatment modalities and therapeutic interventions.
• Identification of knowledge gaps or shortcomings in tools (models) to study basic and preclinical aspects of the dystroglycanopathies.
• Potential reconciliation the genotype with phenotype conundrum and how we use this information therapeutically.
• How do the myriad post-translational modifications of dystroglycan affect function? The potential for new avenues for therapeutic intervention.

Participants

Kevin Campbell (Iowa, USA), Gustavo Dziewczapolski (California, USA), Meredith James (Newcastle Upon Tyne, UK), Nicholas Johnson (Virginia, USA) Dirk Lefeber (Nijmegen, The Netherlands), Matthew Lefkowitz (Virginia, USA), Monika Liljedahl (Sweden), Qi Long Lu (Charlotte, USA), José Martin-Nieto (Alicante, Spain), Francesco Muntoni (London, UK), Isabelle Richard (Évry-Courcouronnes, France), Tanya Stojkovic (Paris, France), Volker Straub (Newcastle upon Tyne, UK), Yvan Torrente (Milan, Italy), Lance Wells (Georgia, USA), Kevin Wright (Oregon, USA), John Vissing (Copenhagen, Denmark)

A full report will be published in  Neuromuscular Disorders (pdf).