Dataset Information

GMPPB-congenital disorders of glycosylation associate with decreased enzymatic activity of GMPPB.

ABSTRACT: The congenital disorders of glycosylation (CDG) are a family of metabolic diseases in which glycosylation of proteins or lipids is deficient. GDP-mannose pyrophosphorylase B (GMPPB) mutations lead to CDG, characterized by neurological and muscular defects. However, the genotype-phenotype correlation remains elusive, limiting our understanding of the underlying mechanism and development of therapeutic strategy. Here, we report a case of an individual presenting congenital muscular dystrophy with cerebellar involvement, who presents two heterozygous GMPPB mutations (V111G and G214S). The V111G mutation significantly decreases GMPPB's enzymatic activity. By measuring enzymatic activities of 17 reported GMPPB mutants identified in patients diagnosed with GMPPB-CDG, we discover that all tested GMPPB variants exhibit significantly decreased enzymatic activity. Using a zebrafish model, we find that Gmppb is required for neuronal and muscle development, and further demonstrate that enzymatic activity of GMPPB mutants correlates with muscular and neuronal phenotypes in zebrafish. Taken together, our findings discover the importance of GMPPB enzymatic activity for the pathogenesis of GMPPB-CDG, and shed light for the development of additional indicators and therapeutic strategy.

SUBMITTER: Liu Z

PROVIDER: S-EPMC8607393 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Congenital myasthenic syndromes are inherited disorders that arise from impaired signal transmission at the neuromuscular junction. Mutations in at least 20 genes are known to lead to the onset of these conditions. Four of these, ALG2, ALG14, DPAGT1 and GFPT1, are involved in glycosylation. Here we identify a fifth glycosylation gene, GMPPB, where mutations cause congenital myasthenic syndrome. First, we identified recessive mutations in seven cases from five kinships defined as congenital myasthenic syndrome using decrement of compound muscle action potentials on repetitive nerve stimulation on electromyography. The mutations were present through the length of the GMPPB, and segregation, in silico analysis, exon trapping, cell transfection followed by western blots and immunostaining were used to determine pathogenicity. GMPPB congenital myasthenic syndrome cases show clinical features characteristic of congenital myasthenic syndrome subtypes that are due to defective glycosylation, with variable weakness of proximal limb muscle groups while facial and eye muscles are largely spared. However, patients with GMPPB congenital myasthenic syndrome had more prominent myopathic features that were detectable on muscle biopsies, electromyography, muscle magnetic resonance imaging, and through elevated serum creatine kinase levels. Mutations in GMPPB have recently been reported to lead to the onset of muscular dystrophy dystroglycanopathy. Analysis of four additional GMPPB-associated muscular dystrophy dystroglycanopathy cases by electromyography found that a defective neuromuscular junction component is not always present. Thus, we find mutations in GMPPB can lead to a wide spectrum of clinical features where deficit in neuromuscular transmission is the major component in a subset of cases. Clinical recognition of GMPPB-associated congenital myasthenic syndrome may be complicated by the presence of myopathic features, but correct diagnosis is important because affected individuals can respond to appropriate treatments.

Dataset Information

GMPPB-congenital disorders of glycosylation associate with decreased enzymatic activity of GMPPB.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets