The overall objectives of this proposal are to improve our basic understanding of how dystroglycan binds laminin, and to explore the effectiveness of expressing LARGE and applying drugs of several classes in treating dystroglycan-related muscular dystrophies. In particular, the role of a novel post-translational phosphate modification?an O-linked mannose that is part of the laminin-binding glycan structure of alpha-dystroglycan?in laminin binding will be investigated. Also, new antibodies that recognize only immature alpha-DG with a terminal phosphate modification will be developed and used to evaluate the post-translational modification status of alpha-DG in tissues or cells collected from individuals with various types of dystroglycanopathies (by immunofluorescence, immunoblotting, and radioisotope-labeling). These studies will improve our understanding of the modifications required for dystroglycan to serve as a laminin receptor, and advance patient diagnosis by improving biomarker correlations with clinical severity. In vitro experiments with patient cells have suggested that overexpression of the glycosyltransferase LARGE can bypass alpha-dystroglycan glycosylation defects in a broad range of dystroglycanopathies. This hypothesis will be corroborated In vivo by assessing the ability to prevent disease in different dystroglycanopathy mouse models through either systemic or muscle-specific expression of the Large transgene. This will provide a better understanding of the feasibility and likelihood of success of broadly applying a LARGE-based therapy to the genetically diverse group of dystroglycanopathies. Furthermore, existing clinical drugs will be tested for their potential to ameliorate disease in dystroglycanopathy mouse models. The group of drugs to be tested includes a premature stop-codon readthrough drug (PTC124), as well as steroids (Prednisone) and PDES inhibitors (Sildenafil);the latter two compounds have already shown promise in the treatment of non-dystroglycan related muscular dystrophies. The effectiveness of these treatments will be explored using a combination of cell culture and in vivo mouse studies and measuring dystroglycan function, muscle physiology and pathology. The proposed research will provide a platform for new therapeutic avenues, some of which it will be possible to implement directly in the care of dystroglycanopathy patients

Public Health Relevance

This project outline represents an opportunity to maximize the basic science expertise that contributes to the University of lowa MDCRC to achieve our goal of translating our research discoveries into clinical applications for the diagnosis and treatment of dystroglycan-related muscular dystrophy. Our basic science and translational approach on dystroglycanopathy mouse models will provide the groundwork for future clinical trials in dystroglycanopathy patients.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center--Cooperative Agreements (U54)
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University of Iowa
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Bönnemann, Carsten G; Wang, Ching H; Quijano-Roy, Susana et al. (2014) Diagnostic approach to the congenital muscular dystrophies. Neuromuscul Disord 24:289-311
Inamori, Kei-ichiro; Willer, Tobias; Hara, Yuji et al. (2014) Endogenous glucuronyltransferase activity of LARGE or LARGE2 required for functional modification of ?-dystroglycan in cells and tissues. J Biol Chem 289:28138-48
Chauveau, Claire; Bonnemann, Carsten G; Julien, Cedric et al. (2014) Recessive TTN truncating mutations define novel forms of core myopathy with heart disease. Hum Mol Genet 23:980-91
Wallace, Stephanie E; Conta, Jessie H; Winder, Thomas L et al. (2014) A novel missense mutation in POMT1 modulates the severe congenital muscular dystrophy phenotype associated with POMT1 nonsense mutations. Neuromuscul Disord 24:312-20
Willer, Tobias; Inamori, Kei-Ichiro; Venzke, David et al. (2014) The glucuronyltransferase B4GAT1 is required for initiation of LARGE-mediated ?-dystroglycan functional glycosylation. Elife 3:
Crockett, Cameron D; Ruggieri, Alessandra; Gujrati, Meena et al. (2014) Late adult-onset of X-linked myopathy with excessive autophagy. Muscle Nerve 50:138-44
Goddeeris, Matthew M; Wu, Biming; Venzke, David et al. (2013) LARGE glycans on dystroglycan function as a tunable matrix scaffold to prevent dystrophy. Nature 503:136-40
Cirak, Sebahattin; Foley, Aileen Reghan; Herrmann, Ralf et al. (2013) ISPD gene mutations are a common cause of congenital and limb-girdle muscular dystrophies. Brain 136:269-81
Yang, Amy C; Ng, Bobby G; Moore, Steven A et al. (2013) Congenital disorder of glycosylation due to DPM1 mutations presenting with dystroglycanopathy-type congenital muscular dystrophy. Mol Genet Metab 110:345-51
Stevens, Elizabeth; Carss, Keren J; Cirak, Sebahattin et al. (2013) Mutations in B3GALNT2 cause congenital muscular dystrophy and hypoglycosylation of *-dystroglycan. Am J Hum Genet 92:354-65

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