GMPPB-congenital disorders of glycosylation associate with decreased enzymatic activity of GMPPB.
GMPPB-congenital disorders of glycosylation associate with decreased enzymatic activity of GMPPB.
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GMPPB-先天性糖基化障碍与 GMPPB 酶活性降低相关
DOI：
10.1186/s43556-021-00027-2
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发表时间：
2021-05-10
影响因子：
4
通讯作者：
Tu Y
中科院分区：
文献类型：
--
作者：
Liu Z;Wang Y;Yang F;Yang Q;Mo X;Burstein E;Jia D;Cai XT;Tu Y
先天性糖基化障碍（CDG）是蛋白质或脂质糖基化缺陷的代谢性疾病家族。GDP-甘露糖焦磷酸化酶B（GMPPB）突变导致以神经和肌肉缺陷为特征的CDG。然而，基因型-表型相关性仍然难以捉摸，限制了我们对潜在机制的理解和治疗策略的发展。在这里，我们报告的情况下，个人提出先天性肌营养不良症小脑参与，谁提出了两个杂合子GMPPB突变（V111 G和G214 S）。V111 G突变显著降低了GMPPB的酶活性。通过测量在诊断为GMPPB-CDG的患者中鉴定的17个报告的GMPPB突变体的酶活性，我们发现所有测试的GMPPB变体均表现出显著降低的酶活性。使用斑马鱼模型，我们发现，GMPPB是所需的神经元和肌肉的发展，并进一步证明，GMPPB突变体的酶活性与肌肉和神经元的表型在斑马鱼。总之，我们的研究结果发现了GMPPB酶活性对GMPPB-CDG发病机制的重要性，并为开发其他指标和治疗策略提供了依据。
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.