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<p>Dystroglycanopathies (DGPs) are a group of autosomal recessive neuromuscular diseases with significant clinical and genetic heterogeneity. They originate due to defects in the O-mannosyl glycosylation of α-dystroglycan (α-DG), a prominent linker between the intracellular cytoskeleton and the extracellular matrix (ECM). Fundamentally, such interactions are crucial for the integrity of muscle fibers and neuromuscular synapses, where their defects are mainly associated with muscle and brain dysfunction. To date, biallelic variants in 18 genes have been associated with DGPs, where the underlying cause is still undefined in a significant proportion of patients. Glycosylation of α-DG generates three core motifs where the core M3 is responsible for interaction with the basement membrane. Consistently, all gene defects that corrupt core M3 maturation have been identified as causes of DGPs. <i>POMGNT1</i> which stimulates the generation of core M1 is also associated with DGPs, as it plays a central role in core M3 processing. Other genes involved in the glycosylation of α-DG seem unrelated to DPGs. The current review illustrates the <i>O</i>-mannosylation pathway of α-DG highlighting the functional properties of related genes and their contribution to the progression of DPGs. Different classes of DPGs are also elaborated characterizing the clinical features of each distinct type and phenotypes associated with each single gene. Finally, current therapeutic approaches with favorable outcomes are addressed. Potential achievements of preclinical and clinical studies would introduce effective curative therapies for this group of disorders in the near future.</p>

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Malformations of Core M3 on α-Dystroglycan Are the Leading Cause of Dystroglycanopathies

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  • 发表日期：

    2025年2月25日

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  • Wessam Sharaf-Eldin

摘要

Dystroglycanopathies (DGPs) are a group of autosomal recessive neuromuscular diseases with significant clinical and genetic heterogeneity. They originate due to defects in the O-mannosyl glycosylation of α-dystroglycan (α-DG), a prominent linker between the intracellular cytoskeleton and the extracellular matrix (ECM). Fundamentally, such interactions are crucial for the integrity of muscle fibers and neuromuscular synapses, where their defects are mainly associated with muscle and brain dysfunction. To date, biallelic variants in 18 genes have been associated with DGPs, where the underlying cause is still undefined in a significant proportion of patients. Glycosylation of α-DG generates three core motifs where the core M3 is responsible for interaction with the basement membrane. Consistently, all gene defects that corrupt core M3 maturation have been identified as causes of DGPs. POMGNT1 which stimulates the generation of core M1 is also associated with DGPs, as it plays a central role in core M3 processing. Other genes involved in the glycosylation of α-DG seem unrelated to DPGs. The current review illustrates the O-mannosylation pathway of α-DG highlighting the functional properties of related genes and their contribution to the progression of DPGs. Different classes of DPGs are also elaborated characterizing the clinical features of each distinct type and phenotypes associated with each single gene. Finally, current therapeutic approaches with favorable outcomes are addressed. Potential achievements of preclinical and clinical studies would introduce effective curative therapies for this group of disorders in the near future.