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.

Three siblings with variable degrees of neuromuscular involvement and congenital sideroblastic anemia: A peculiar phenotype and a surprise genotypic explanation

“…In our report, the two patients with this homozygous variant presented with an earlier onset of muscle weakness and showed moderate improvement in muscle weakness on anticholinesterase inhibitors unlike the report above. This supports the previous reports that noted that there is no clear genotypephenotype correlation in patients with GMPPB-MDDG (Liu et al, 2021).…”

Consequences of GMPPB deficiency for neuromuscular development and maintenance

“…Disease associated GMPPB variants include missense, nonsense and frameshift mutations ( Astrea et al, 2018 ; Tian et al, 2019 ) and are considered to result in GMPPB loss-of-function. Functional studies reported decreased enzymatic activities of approximately up to 90% ( Liu et al, 2021 ). Here, we show that the total loss of GMPPB activity by disrupting the catalytic nucleotide transferase domain results in embryonic lethality in mice suggesting a pivotal role of GMPPB activity for early development.…”

“…GMPPB is crucial for the conversion of mannose-1-phosphate and guanosine triphosphate into GDP-mannose, which is required as a mannose donor for glycosylation ( Ning and Elbein, 2000 ). Bi-allelic mutations in GMPPB are associated with variable disorders such as muscular dystrophy and other neurological symptoms including intellectual disability ( Carss et al, 2013 ; Belaya et al, 2015 ; Liu et al, 2021 ). Additional symptoms such as cerebellar hypoplasia, seizures, or cardiac involvement are reported for some patients.…”

“…Previous morpholino-based knockdown studies in zebrafish suggested that GMPPB is required for the development of motor neurons and myofibers ( Carss et al, 2013 ; Liu et al, 2021 ; Zheng et al, 2021 ). Here, we report that the KO of GMPPB in mice results in early embryonic lethality, suggesting that protein mannosylation is essential for embryonic development and that the loss of GMPPB to provide activated mannose cannot be compensated during early development.…”

Altered mannose metabolism in chronic stress and depression is rapidly reversed by vitamin B12

“…It has been shown that reduced GMPPB abundance leads to decreased GDP-mannose levels and thus affects neuronal and muscle development ( 4 , 31 , 32 ). For example, motor neurons were shortened ( 4 ), and an early marker of pan-neuronal cells was remarkably decreased in GMPPB knockdown zebrafish ( 33 ).…”