Efficient reversal of muscular phenotypes of GMPPB-dystroglycanopathy


Pre-Clinical Research

Poster Number: T353


Ziwei Fu, phD, Fudan university

It has been found lately that diverse forms of congenital muscular dystrophy are congenital disorders of glycosylation, composing a clinically heterogeneous group of disorders collectively referred to as dystroglycanopathy (DGP). Recently, clinical cases have been reported in patients with muscular dystrophy with mutations in guanosine diphosphate mannose (GDP – mannose) pyrophosphorylase B (GMPPB), most of which are of compound mutations. However, it is not clear if and how GMPPB mutations or variations in GDP-mannose levels directly contribute to muscular dystrophy, nor did the molecular mechanisms affecting disease progression being identified. To establish the role of GMPPB in muscular dystrophy, we constructed GMPPB mutant mouse lines and found that two of these alterations are lethal in the homozygous forms. Besides, a heterozygous GMPPB mouse line exhibited reduced muscle strength, decreased locomotor ability, elevated creatine kinase levels and increased number of central nuclei. We further show that the ability of muscle regeneration in these mice is decreased post muscle injury. Reduced myotube diameter and fusion index are evident in GMPPB mutant myoblasts and muscle stem cells isolated from heterozygous mice upon induction of muscle differentiation. To identify the pathways mediating impaired muscle development in GMPPB-deficient contexts, we conducted genomic studies and found that Wnt/beta-catenin pathway undergoes significant alterations. Ectopic activation of Wnt signaling alleviates the block of muscle differentiation in GMPPB-deficient cells. Additionally, the muscle regeneration post muscle injury is restored in vivo by pharmacological activation of Wnt signaling, as well as by AAV gene replacement therapy. Overall, these findings provide direct evidence supporting that GMPPB loss-of-function leads to onset of dystroglycanopathy diseases, and further extend understanding of the role of GMPPB in the disease progression. Gene therapy and Wnt pathway activating agents are potential effective intervention routes for these pathological conditions and further preclinical DGP studies are warranted.