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

Zhe Liu,Ezra Burstein,Xianming Mo,Da Jia,Yingfeng Tu,Qin Yang,Yan Wang,Xiao-Tang Cai,Fan Yang

doi:10.1186/s43556-021-00027-2

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.

Highlights

The congenital disorders of glycosylation (CDG), a heterogeneous category of disorders, lead to malfunction of multiple organs, especially the nervous system, muscles, and intestines in affected individuals [1,2,3]
Identification of novel GDP-mannose pyrophosphorylase B (GMPPB) mutations in a patient affected by congenital muscular dystrophies (CMD) with cerebellar involvement The patient was a 1-year old Chinese male, who was diagnosed with CMD with cerebellar involvement (CMD-CRB)
We report two novel GMPPB mutations in a patient diagnosed with CMD

Summary

Introduction

The congenital disorders of glycosylation (CDG), a heterogeneous category of disorders, lead to malfunction of multiple organs, especially the nervous system, muscles, and intestines in affected individuals [1,2,3]. Patients with CDG display a wide spectrum of clinical phenotypes, including but not limited to ataxia, seizures, cerebellar hypoplasia, liver diseases, limb-girdle muscular dystrophies (LGMD), and severe congenital muscular dystrophies (CMD) with eye and brain abnormalities [1, 2, 4, 5]. GMPPB mutations-associated phenotypic spectrum ranges from LGMD, to congenital myasthenic syndrome (CMS), to severe CMD with eye and brain symptoms [10,11,12,13,14,15,16,17,18]. Given the essential role of GMPPB in catalyzing the formation of GDP-mannose, we hypothesize that the enzymatic activity of GMPPB mutants may correlate with the development of GMPPB-CDG

Methods

Results

Conclusion