220th ENMC workshop: Dystroglycan and the dystroglycanopathies Naarden, The Netherlands, 27–29 May 2016

Brown, S.; Winder, Steve J.

doi:10.1016/j.nmd.2016.12.010

Cited by 8 publications

(3 citation statements)

References 22 publications

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“…These steps are followed by (iii) gene sequencing to identify mutations in the abovementioned 18 genes [4][5][6][7]. Despite recent advances, the efficiency of accurate genetic and molecular diagnoses is rather low-only 36% in children and 22% in adults [4,8]. It was experimentally validated that in the sarcolemma of muscle fibers, Dg arranges various protein complexes even in the absence of both dystrophin and utrophin [9], supporting the idea about a broader role for Dg, apart from being a core DGC component.…”

Section: Introductionmentioning

confidence: 99%

Profiling of the muscle-specific dystroglycan interactome reveals the role of Hippo signaling in muscular dystrophy and age-dependent muscle atrophy

Yatsenko

Kucherenko

Xie

et al. 2020

BMC Med

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Background: Dystroglycanopathies are a group of inherited disorders characterized by vast clinical and genetic heterogeneity and caused by abnormal functioning of the ECM receptor dystroglycan (Dg). Remarkably, among many cases of diagnosed dystroglycanopathies, only a small fraction can be linked directly to mutations in Dg or its regulatory enzymes, implying the involvement of other, not-yet-characterized, Dg-regulating factors. To advance disease diagnostics and develop new treatment strategies, new approaches to find dystroglycanopathy-related factors should be considered. The Dg complex is highly evolutionarily conserved; therefore, model genetic organisms provide excellent systems to address this challenge. In particular, Drosophila is amenable to experiments not feasible in any other system, allowing original insights about the functional interactors of the Dg complex. Methods: To identify new players contributing to dystroglycanopathies, we used Drosophila as a genetic muscular dystrophy model. Using mass spectrometry, we searched for muscle-specific Dg interactors. Next, in silico analyses allowed us to determine their association with diseases and pathological conditions in humans. Using immunohistochemical, biochemical, and genetic interaction approaches followed by the detailed analysis of the muscle tissue architecture, we verified Dg interaction with some of the discovered factors. Analyses of mouse muscles and myocytes were used to test if interactions are conserved in vertebrates. Results: The muscle-specific Dg complexome revealed novel components that influence the efficiency of Dg function in the muscles. We identified the closest human homologs for Dg-interacting partners, determined their significant enrichment in disease-associations, and verified some of the newly identified Dg interactions. We found that Dg associates with two components of the mechanosignaling Hippo pathway: the WW domain-containing proteins Kibra and Yorkie. Importantly, this conserved interaction manages adult muscle size and integrity.

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Section: Introductionmentioning

confidence: 99%

Profiling of the muscle-specific dystroglycan interactome reveals the role of Hippo signaling in muscular dystrophy and age-dependent muscle atrophy

Yatsenko

Kucherenko

Xie

et al. 2020

BMC Med

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“…Defective O-linked glycosylation of a-dystroglycan is a common pathological hallmark associated with number of genetic syndromes, encompassing symptoms from muscular dystrophies to ocular defects, cognitive deficits, and structural cortical malformations (cobblestone lissencephaly) in the central nervous system (CNS). This group of autosomal recessive disorders are commonly referred to as secondary dystroglycanopathies [2,3]. Currently, there is no cure for dystroglycanopathies.…”

Section: Introductionmentioning

confidence: 99%

A new patient‐derived iPSC model for dystroglycanopathies validates a compound that increases glycosylation of α‐dystroglycan

et al. 2019

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Dystroglycan, an extracellular matrix receptor, has essential functions in various tissues. Loss of a-dystroglycan-laminin interaction due to defective glycosylation of a-dystroglycan underlies a group of congenital muscular dystrophies often associated with brain malformations, referred to as dystroglycanopathies. The lack of isogenic human dystroglycanopathy cell models has limited our ability to test potential drugs in a human-and neural-specific context. Here, we generated induced pluripotent stem cells (iPSCs) from a severe dystroglycanopathy patient with homozygous FKRP (fukutin-related protein gene) mutation. We showed that CRISPR/Cas9-mediated gene correction of FKRP restored glycosylation of a-dystroglycan in iPSCderived cortical neurons, whereas targeted gene mutation of FKRP in wild-type cells disrupted this glycosylation. In parallel, we screened 31,954 small molecule compounds using a mouse myoblast line for increased glycosylation of a-dystroglycan. Using human FKRP-iPSCderived neural cells for hit validation, we demonstrated that compound 4-(4-bromophenyl)-6-ethylsulfanyl-2-oxo-3,4-dihydro-1 H-pyridine-5-carbonitrile (4BPPNit) significantly augmented glycosylation of a-dystroglycan, in part through upregulation of LARGE1 glycosyltransferase gene expression. Together, isogenic human iPSC-derived cells represent a valuable platform for facilitating dystroglycanopathy drug discovery and therapeutic development.

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“…Disorders due to mutations in dystroglycan, or in the genes encoding the proteins and enzymes involved in the glycosylation of α-dystroglycan are collectively known as dystroglycanopathies. The dystroglycanopathies are described as a group of diseases caused by the loss or reduced binding of α-dystroglycan to its extracellular ligands, such as laminin, agrin, neurexins, perlecans, pikachurin, and Slit (Brown and Winder, 2017). Mutations in these proteins share the clinical features of dystroglycanopathies, which widens the horizons of how crucial and selective the role of Dg is in various kinds of MDs.…”

Section: Introductionmentioning

confidence: 99%

Roles of miR-137 in Muscular Dystrophy and Muscular Dystrophy-Related Phenotypes in Drosophila melanogaster

Shruti¹

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Muscular dystrophies (MDs) are a group of diseases that cause muscular and neurological disorders in human patients. They are associated with a multi-component complex called the Dystrophin Glycoprotein Complex (DGC). The DGC connects the extracellular matrix to the cytoskeleton and is well-conserved in animals. Perturbation of this complex is associated with various kinds of MDs, leading to a diverse range of muscle and nervous system abnormalities. Dystroglycan (Dg) is a central DGC component, mutations of which are associated with a heterogeneous group of MDs also known as dystroglycanopathies.MiRNAs are small, noncoding RNAs that function in posttranscriptional gene regulation and often represses their target mRNAs. Previous work has shown that similar to MD, stress itself causes muscle degeneration, and altered miRNA expression profiles have been detected in dystrophic as well as stressed wild type flies. These results indicate that miRNAs influence a common regulatory pathway between stress and MD. Though much is known about the DGC and its relevance to MDs, the molecular and genetic pathways underlying MD pathogenesis remain largely unknown.To understand the role of miRNAs in DGC signaling and their contribution to MDs, in particular during stress, we screened several miRNAs that are predicted to target multiple components of the DGC study their potential roles in MD development, particularly upon various stresses. We found that miR-137, miR-966, and miR-927 affect muscle integrity upon stress and aging. Our study further reveals that miR-966 and miR-137 are required more during adult muscle maintenance than developing muscles. MiR-137, in particular, is a stress-responsive miRNA, as the severity of the phenotypes related to muscle maintenance progressed in a stress-and age-dependent manner.We further show that levels of Dg must be regulated to sustain healthy muscle, and this regulation includes targeting of Dg by miR-137. The Dg-miR-137 interaction is required to address negative effects of stress in adult muscle maintenance. Our results also demonstrate that a perturbed blood-testis barrier (BTB) in testes is a novel phenotype related to MD, and miR-137 regulates the expression of Dg in early somatic cells of Drosophila testes to maintain the BTB. Our results highlight the importance of miRNAs in the regulation of the DGC and MD, particularly on muscle maintenance that is accelerated upon stress. various kinds of disorders ranging from bacterial infections, metabolic disorders to aging, and cancer. Therefore, Drosophila melanogaster is an ideal model for studying the DGC, identifying its novel functions, interacting components, and factors involved in the physiological and molecular dynamics of its signaling and regulatory systems. Many of the core components of the DGC are evolutionarily conserved but with less diversity. Drosophila has only two syntrophins: syntrophin-like-1 (Syn1) homologous to α1/β1/β2-syntrophins, and syntrophin-like-2 (Syn2) homologous to γ1/γ2-syntrophins in mammals. Dystrophin (...

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220th ENMC workshop: Dystroglycan and the dystroglycanopathies Naarden, The Netherlands, 27–29 May 2016

Cited by 8 publications

References 22 publications

Profiling of the muscle-specific dystroglycan interactome reveals the role of Hippo signaling in muscular dystrophy and age-dependent muscle atrophy

Profiling of the muscle-specific dystroglycan interactome reveals the role of Hippo signaling in muscular dystrophy and age-dependent muscle atrophy

A new patient‐derived iPSC model for dystroglycanopathies validates a compound that increases glycosylation of α‐dystroglycan

Roles of miR-137 in Muscular Dystrophy and Muscular Dystrophy-Related Phenotypes in Drosophila melanogaster

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