bims-meglyc 2024-11-17 papers

Issue of 2024‒11‒17
five papers selected by
Silvia Radenkovic, UMC Utrecht

Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2024 Nov 10. 41(11): 1349-1355

[Clinical features and genetic analysis of a child with Congenital disorder of glycosylation due to novel variants of COG6 gene].

Liyu Zhang, Ying Yang, Fengyu Che, Benchang Li, Lidangzhi Mo, Guoxia Wang, Jiangang Zhao.

OBJECTIVE: To analyze the clinical characteristics of a child with Congenital disorder of glycosylation due to compound heterozygous variants of COG6 gene (COG6-CDG).METHODS: A child who was admitted to Xi'an Children's Hospital on January 10, 2023 was selected as the study subject. Clinical data were collected. Pathogenic variants were analyzed by whole exome sequencing, and candidate variants were verified by Sanger sequencing, in vitro experiments and bioinformatic analysis. This study was approved by the Medical Ethics Committee of Xi'an Children's Hospital (Ethics No. 20230101).
RESULTS: The child, a 1-month-8-day-old male, was admitted for diarrhea and weight loss for one month. He had presented with cholestasis, diarrhea, facial dysmorphism, poor response, bilateral Simian crease, and brain atrophy. After discharge, he had continued to have high fever, feeding difficulty, and deceased finally. Whole exome sequencing results showed that he had harbored compound heterozygous variants of the COG6 gene, namely c.807delT (p.F269Lfs*37) and c.1746+1G>C (p.Gly565_Met582del). Sanger sequencing verified that the variants were inherited from his father and mother, respectively. In vitro experiments verified that the c.1746+1G>C variant could affect the mRNA splicing and produce a truncated protein, whilst the c.807delT variant could significantly reduce gene expression at both mRNA and protein levels. Based on the guidelines from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP), the variants were classified as pathogenic (PVS1+PM3+PM2_Supporting) and likely pathogenic (PVS1+PM2_Supporting), respectively.
CONCLUSION: The c.807delT (p.F269Lfs*37) and c.1746+1G>C (p.Gly565_Met582del) compound heterozygous variants of the COG6 gene probably underlay the pathogenesis of this child. Above finding has enriched the mutational spectrum of COG6-CDG and provided a basis for the genetic counseling for this family.

DOI: https://doi.org/10.3760/cma.j.cn511374-20240318-00177

J Inherit Metab Dis. 2024 Sep;47(5): 935-944

Assessing age of onset and clinical symptoms over time in patients with heterozygous pathogenic DHDDS variants.

I J J Muffels, M Sadek, T Kozicz, E Morava.

Mono-allelic DHDDS variants are associated with seizures, intellectual disability, and movement disorders. The age of onset and progression rates of symptoms vary greatly among patients, spanning from infancy to late adulthood. Yet, the reasons behind this clinical variability and the underlying pathophysiological mechanisms of the disease have remained elusive. We investigated the age of onset and the progression of symptoms over time in 59 patients with heterozygous DHDDS variants, drawing from medical literature and incorporating five previously unreported cases from the FCDGC Natural History Study. Clinical symptoms typically emerged early in life. Ataxia, tremor, dystonia, and dyskinesia manifested slightly later in childhood. Global developmental delay usually presented as the initial symptom. We observed diverse rates of symptom accumulation over time: some patients exhibited the full spectrum of symptoms in early childhood, while others developed novel symptoms well into adulthood. Interestingly, neither the sex nor the underlying DHDDS variants correlated with the age of symptom onset or specific clinical symptoms. Additionally, we found that 19% of patients presented with autism spectrum disorder. This study offers insight into the age of symptom onset and the rate of symptom accumulation in patients with DHDDS variants. We found no correlation between the age of onset and progression of clinical symptoms with specific DHDDS variants or patient sex. Autism spectrum disorder is common in patients and warrants attention in clinical management.

Keywords: CDG; DHDDS; congenital disorders of glycosylation; congenital movement disorders; dolichol synthesis; neurodevelopmental delay and epilepsy

DOI: https://doi.org/10.1002/jimd.12769

Elife. 2024 Nov 13. pii: e90376. [Epub ahead of print]13

Rescuable sleep and synaptogenesis phenotypes in a Drosophila model of O-GlcNAc transferase intellectual disability.

Ignacy Czajewski, Bijayalaxmi Swain, Jiawei Xu, Laurin McDowall, Andrew T Ferenbach, Daan M F van Aalten.

O-GlcNAcylation is an essential intracellular protein modification mediated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Recently, missense mutations in OGT have been linked to intellectual disability, indicating that this modification is important for the development and functioning of the nervous system. However, the processes that are most sensitive to perturbations in O-GlcNAcylation remain to be identified. Here, we uncover quantifiable phenotypes in the fruit fly Drosophila melanogaster carrying a patient-derived OGT mutation in the catalytic domain. Hypo-O-GlcNAcylation leads to defects in synaptogenesis and reduced sleep stability. Both these phenotypes can be partially rescued by genetically or chemically targeting OGA, suggesting that a balance of OGT/OGA activity is required for normal neuronal development and function.

Keywords: D. melanogaster; developmental biology; genetics; genomics

DOI: https://doi.org/10.7554/eLife.90376

Science. 2024 Nov 08. 386(6722): 667-672

Regulated N-glycosylation controls chaperone function and receptor trafficking.

Mengxiao Ma, Ramin Dubey, Annie Jen, Ganesh V Pusapati, Bharti Singal, Evgenia Shishkova, Katherine A Overmyer, Valérie Cormier-Daire, Juliette Fedry, L Aravind, Joshua J Coon, Rajat Rohatgi.

One-fifth of human proteins are N-glycosylated in the endoplasmic reticulum (ER) by two oligosaccharyltransferases, OST-A and OST-B. Contrary to the prevailing view of N-glycosylation as a housekeeping function, we identified an ER pathway that modulates the activity of OST-A. Genetic analyses linked OST-A to HSP90B1, an ER chaperone for membrane receptors, and CCDC134, an ER luminal protein. During its translocation into the ER, an N-terminal peptide in HSP90B1 templates the assembly of a translocon complex containing CCDC134 and OST-A that protects HSP90B1 during folding, preventing its hyperglycosylation and degradation. Disruption of this pathway impairs WNT and IGF1R signaling and causes the bone developmental disorder osteogenesis imperfecta. Thus, N-glycosylation can be regulated by specificity factors in the ER to control cell surface receptor signaling and tissue development.

DOI: https://doi.org/10.1126/science.adp7201

Nat Comput Sci. 2024 Nov 11.

MassiveFold: unveiling AlphaFold's hidden potential with optimized and parallelized massive sampling.

Nessim Raouraoua, Claudio Mirabello, Thibaut Véry, Christophe Blanchet, Björn Wallner, Marc F Lensink, Guillaume Brysbaert.

Massive sampling in AlphaFold enables access to increased structural diversity. In combination with its efficient confidence ranking, this unlocks elevated modeling capabilities for monomeric structures and foremost for protein assemblies. However, the approach struggles with GPU cost and data storage. Here we introduce MassiveFold, an optimized and customizable version of AlphaFold that runs predictions in parallel, reducing the computing time from several months to hours. MassiveFold is scalable and able to run on anything from a single computer to a large GPU infrastructure, where it can fully benefit from all the computing nodes.

DOI: https://doi.org/10.1038/s43588-024-00714-4