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

Springer Science and Business Media LLC - Tập 2 Số 1 - 2021
Zhe Liu1, Yan Wang1, Fan Yang1, Yang Qin1, Xianming Mo2, Ezra Burstein3, Da Jia1, Xiaoxiao Cai1, Yingfeng Tu1
1Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, 610041, China
2Department of Pediatric Surgery and Laboratory of Stem Cell Biology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
3Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA

Tóm tắt

AbstractThe 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.

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