O-GlcNAcylation modulates expression and abundance of N-glycosylation machinery in an inherited glycosylation disorder DOI Creative Commons

Courtney Matheny-Rabun,

Sneha S. Mokashi, Silvia Radenkovic

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(11), P. 114976 - 114976

Published: Nov. 1, 2024

Core components of the N-glycosylation pathway are known, but metabolic and post-translational mechanisms regulating this in normal disease states remain elusive. Using a multi-omic approach zebrafish, we discovered mechanism whereby O-GlcNAcylation directly impacts expression abundance two rate-limiting proteins N-linked glycosylation pathway. We show model an inherited disorder PMM2-CDG, congenital disorders that phosphomannomutase deficiency is associated with increased levels UDP-GlcNAc protein O-GlcNAcylation. O-GlcNAc modification increases transcript both NgBR Dpagt1 pmm2

Language: Английский

Identifying Targets of Selection in Laboratory Evolution Experiments DOI

Artemiza A. Martínez,

Gregory I. Lang

Journal of Molecular Evolution, Journal Year: 2023, Volume and Issue: 91(3), P. 345 - 355

Published: Feb. 21, 2023

Language: Английский

Citations

13
Congenital disorders of glycosylation: narration of a story through its patents DOI Creative Commons
Maria Monticelli,

Tania D’Onofrio,

Jaak Jaeken

et al.

Orphanet Journal of Rare Diseases, Journal Year: 2023, Volume and Issue: 18(1)

Published: Aug. 29, 2023

Abstract Congenital disorders of glycosylation are a group more than 160 rare genetic defects in protein and lipid glycosylation. Since the first clinical report 1980 PMM2-CDG, most common CDG worldwide, research made great strides, but nearly all them still missing cure. diagnosis has been at rapid pace since introduction whole-exome/whole-genome sequencing as diagnostic tool. Here, we retrace history by analyzing patents associated with topic. To this end, explored Espacenet database, extracted list patents, then divided into three major groups: (1) Drugs/therapeutic approaches for CDG, (2) Drug delivery tools (3) Diagnostic CDG. Despite enormous scientific progress experienced last 30 years, tools, drugs, biomarkers urgently needed.

Language: Английский

Citations

10
Treatment of congenital disorders of glycosylation: An overview DOI Creative Commons
Dulce Quelhas, Jaak Jaeken

Molecular Genetics and Metabolism, Journal Year: 2024, Volume and Issue: 143(1-2), P. 108567 - 108567

Published: Aug. 18, 2024

Language: Английский

Citations

3
Identification of CNTN2 as a genetic modifier of PIGA-CDG in a family with incomplete penetrance and in Drosophila DOI
Holly J. Thorpe, Brent S. Pedersen, Miranda Dietze

et al.

The American Journal of Human Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

Citations

0
Beneficial effects of Glc-1,6-P2 modulation on mutant phosphomannomutase-2 DOI Creative Commons
Maria Monticelli, Debora Paris, Maria Chiara Monti

et al.

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Journal Year: 2025, Volume and Issue: unknown, P. 119948 - 119948

Published: March 1, 2025

Language: Английский

Citations

0
A comprehensive update of genotype–phenotype correlations in PMM2-CDG: insights from molecular and structural analyses DOI Creative Commons
Tiago Oliveira, Ricardo Ferraz, Luı́sa Azevedo

et al.

Orphanet Journal of Rare Diseases, Journal Year: 2025, Volume and Issue: 20(1)

Published: April 30, 2025

Language: Английский

Citations

0
Systematic Review: Drug Repositioning for Congenital Disorders of Glycosylation (CDG) DOI Open Access
Sandra Brasil, Mariateresa Allocca, Salvador C. M. Magrinho

et al.

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(15), P. 8725 - 8725

Published: Aug. 5, 2022

Advances in research have boosted therapy development for congenital disorders of glycosylation (CDG), a group rare genetic affecting protein and lipid glycosylphosphatidylinositol anchor biosynthesis. The (re)use known drugs novel medical purposes, as drug repositioning, is growing both common disorders. latest innovation concerns the rational search repositioned molecules which also benefits from artificial intelligence (AI). Compared to traditional methods, repositioning accelerates overall discovery process while saving costs. This particularly valuable diseases. AI tools proven their worth diagnosis, disease classification characterization, ultimately availability biomarkers reliable models critical new drugs, especially heterogeneous diseases such CDG. work reviews literature related CDG, discovered by serendipity or through systemic approach. Recent advances are outlined well stakeholders' views on

Language: Английский

Citations

13
Experimental evolution for cell biology DOI Creative Commons
Jana Helsen, Gavin Sherlock, G.K. Dey

et al.

Trends in Cell Biology, Journal Year: 2023, Volume and Issue: 33(11), P. 903 - 912

Published: May 15, 2023

Evolutionary cell biology explores the origins, principles, and core functions of cellular features regulatory networks through lens evolution. This emerging field relies heavily on comparative experiments genomic analyses that focus exclusively extant diversity historical events, providing limited opportunities for experimental validation. In this opinion article, we explore potential laboratory evolution to augment evolutionary toolbox, drawing inspiration from recent studies combine with biological assays. Primarily focusing approaches single cells, provide a generalizable template adapting protocols fresh insight into long-standing questions in biology.

Language: Английский

Citations

7
Exploring ligand interactions with human phosphomannomutases using recombinant bacterial thermal shift assay and biochemical validation DOI Creative Commons
Maria Monticelli, Bruno Hay Mele,

Demi Marie Wright

et al.

Biochimie, Journal Year: 2024, Volume and Issue: 222, P. 123 - 131

Published: March 6, 2024

PMM2-CDG, a disease caused by mutations in phosphomannomutase-2, is the most common congenital disorder of glycosylation. Yet, it still lacks cure. Targeting phosphomannomutase-2 with pharmacological chaperones or inhibiting phosphatase activity phosphomannomutase-1 to enhance intracellular glucose-1,6-bisphosphate have been proposed as therapeutical approaches. We used Recombinant Bacterial Thermal Shift Assay assess binding substrate analog and specific an FDA-approved drug - clodronate. also deepened clodronate enzyme assays silico docking. Our results confirmed selective shed light on such binding.

Language: Английский

Citations

1
Evolutionary rate covariation is pervasive between glycosylation pathways and points to potential disease modifiers DOI Open Access
Holly J. Thorpe, Raghavendran Partha, Jordan Little

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 5, 2024

Mutations in glycosylation pathways, such as N-linked glycosylation, O-linked and GPI anchor synthesis, lead to Congenital Disorders of Glycosylation (CDG). CDGs typically present with seizures, hypotonia, developmental delay but display large clinical variability symptoms affecting every system the body. This suggests modifier genes might influence phenotypes. Because similar physiology symptoms, there are likely common genetic modifiers between CDGs. Here, we use evolution a tool identify CDG genes. Protein is evolutionarily conserved from yeast mammals. Evolutionary rate covariation (ERC) identifies proteins evolutionary rates that indicate shared biological functions pathways. Using ERC, identified strong signatures same different Genome-wide analysis showing significant ERC synthesis revealed ncRNA modification DNA repair proteins. We also patterns based on cellular sub-localization enzymes. Functional testing highest scoring candidates validated interactions novel disease pathways allows for rapid prioritization potential modifiers, which can provide better understanding pathophysiology therapeutic targets.

Language: Английский

Citations

1