bims-meglyc 2024-09-15 papers

Issue of 2024–09–15
four papers selected by
Silvia Radenkovic, UMC Utrecht

Seizure. 2024 Jul 26. pii: S1059-1311(24)00220-6. [Epub ahead of print]121 235-242

Identification of two novel variants in ALG11 causing congenital disorder of glycosylation.

Peiwei Zhao, Xiankai Zhang, Zhengrong Duan, Chunhui Wan, Lei Zhang, Sukun Luo, Hongmin Zhu, Xuelian He.

BACKGROUND: Congenital disorders of glycosylation (CDG) represent a heterogeneous group of rare inherited metabolic disorders due to abnormalities in protein or lipid glycosylation pathways, affecting multiple systems, and frequently being accompanied by neurological symptoms. ALG11-CDG, also known as CDG-1p, arises from a deficiency in a specific mannosyltransferase encoded by the ALG11 gene. To date, only 17 cases have been documented, and these patients have prominent clinical phenotypes, including seizures, developmental delay, and microcephaly.
METHODS: We describe a novel case of a four-month-old boy from a Chinese family exhibiting developmental delay, seizures, and microcephaly. Trio whole-exome sequencing (WES) and subsequent Sanger sequencing were employed to identify the potential genetic cause, and functional study was performed to evaluate the pathogenicity of genetic variant identified.
RESULTS: Trio WES unveiled novel compound heterozygous variants: c.1307G>T (p.G436V) and c.1403G>A (p.R468H) within exon 4 of the ALG11 gene, inherited from the father and mother, respectively. Subsequent in vitro functional analysis revealed decreased stability of the mutant protein and concurrent hypoglycosylation of GP130, a hyperglycosylated protein.
CONCLUSIONS: Our findings not only expand the clinical and variant spectrum of ALG11-CDG, but also emphasize the importance of WES as a first-tier genetic test in determining the molecular diagnosis.

Keywords: ALG11; Congenital disorders of glycosylation; GP130; Microcephaly; Seizure

DOI: https://doi.org/10.1016/j.seizure.2024.07.020

Glycobiology. 2024 Sep 10. pii: cwae070. [Epub ahead of print]

(Key1-001) congenital disorders of glycosylation: Glycobiology at the bedside.

Andrew C Edmondson.

Congenital disorders of glycosylation (CDG) are a group of rare monogenic human disorders caused by defects in the genes encoding the proteins that generate, attach, and modify glycans, thus disrupting cellular glycosylation machinery. Over 200 CDG caused by disruptions of 189 different genes are currently known. The multi-system disease manifestations of the CDG disorders highlight the importance of glycosylation across the organ systems. Clinical manifestations of CDG tend to group among genes contributing to the same glycosylation pathways, suggesting shared pathophysiology related to the glycosylation disruptions. However, the underlying glycosylation disruptions and pathophysiologic mechanisms responsible for specific CDG clinical manifestations have been determined for only a few hypoglycosylated proteins. The Frontiers in CDG Consortium (FCDGC) is an international network of clinical sites, laboratories, and patient advocacy groups established in 2019 to improve clinical symptoms, quality of life, and life expectancy for individuals with CDG. FCDGC seeks to answer decades of unresolved questions, address knowledge gaps, develop and validate new biochemical diagnostic techniques and therapeutic biomarkers, and explore novel therapeutic options for CDG. Over the past 5 years, FCDGC has launched a Natural History Study with over 300 CDG patients, discovered novel biomarkers suggesting new mechanisms of disease, and launched clinical trials aiming to restore appropriate glycosylation and targeting newly identified potential mechanisms of disease. Technical advances in glycobiology are making it increasingly possible to comprehensively catalog glycoproteomic data and to probe functional impact of altered glycosylation. My laboratory applies glycoproteomic technologies to samples from human subjects and genetic model systems to identify glycosylation abnormalities and unlock new insights from translational glycobiology. Current findings and accomplishments highlight the ongoing bottlenecks and knowledge gaps at intersections of glycobiology and clinical care requiring further investigation.

DOI: https://doi.org/10.1093/glycob/cwae070

PLoS Genet. 2024 Sep 11. 20(9): e1011406

Evolutionary rate covariation is pervasive between glycosylation pathways and points to potential disease modifiers.

Holly J Thorpe, Raghavendran Partha, Jordan Little, Nathan L Clark, Clement Y Chow.

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

DOI: https://doi.org/10.1371/journal.pgen.1011406

Cells. 2024 Aug 26. pii: 1430. [Epub ahead of print]13(17):

iPSC-Derived Cardiomyocytes as a Disease Model to Understand the Biology of Congenital Heart Defects.

Chithra K Pushpan, Subramanyan Ram Kumar.

The discovery of human pluripotent stem cells (hiPSCs) and advances in DNA editing techniques have opened opportunities for personalized cell-based therapies for a wide spectrum of diseases. It has gained importance as a valuable tool to investigate genetic and functional variations in congenital heart defects (CHDs), enabling the customization of treatment strategies. The ability to understand the disease process specific to the individual patient of interest provides this technology with a significant advantage over generic animal models. However, its utility as a disease-in-a-dish model requires identifying effective and efficient differentiation protocols that accurately reproduce disease traits. Currently, iPSC-related research relies heavily on the quality of cells and the properties of the differentiation technique In this review, we discuss the utility of iPSCs in bench CHD research, the molecular pathways involved in the differentiation of cardiomyocytes, and their applications in CHD disease modeling, therapeutics, and drug application.

Keywords: TOF; cardiomyocyte; congenital heart diseases; disease model; iPSC

DOI: https://doi.org/10.3390/cells13171430