bims-meglyc 2025-07-13 papers

Issue of 2025–07–13
five papers selected by
Silvia Radenkovic, UMC Utrecht

Mol Genet Metab. 2025 Jul 03. pii: S1096-7192(25)00177-5. [Epub ahead of print]145(4): 109186

Dolichol synthesis defects: a cautionary note on the use of statins.

Matthew P Wilson, Eva Morava.

Keywords: Congenital disorders of glycosylation; Dolichol; HMGCR; Statins

DOI: https://doi.org/10.1016/j.ymgme.2025.109186

Cells. 2025 Jul 07. pii: 1036. [Epub ahead of print]14(13):

Structural and Functional Characterization of N-Glycanase-1 Pathogenic Variants.

Antje Banning, Lukas Hoeren, Isis Atallah, Ralph Orczyk, David Jacquier, Diana Ballhausen, Ritva Tikkanen.

NGLY1 deficiency is a congenital disorder of deglycosylation, caused by pathogenic variants of the NGLY1 gene. It manifests as global developmental delay, hypo- or alacrima, hypotonia, and a primarily hyperkinetic movement disorder. The NGLY1 enzyme is involved in deglycosylation of misfolded N-glycosylated proteins before their proteasomal degradation and in the activation of transcription factors that control the expression of proteasomal subunits. Here, we have characterized the pathogenic NGLY1 variants found in three Swiss NGLY deficiency patients, as well as the most common pathogenic NGLY1 variant, Arg401*, found in about 20% of patients. Our functional and structural assessments of these variants show that they cause a profound reduction in NGLY1 activity, severely reduced expression of NGLY1 protein, and misprocessing of the transcription factor NFE2L1. Furthermore, transcription of proteasomal subunits and NGLY1 mRNA splicing are impaired by some of these variants. Our in silico structural analysis shows that the Arg390Gln substitution results in destabilization of NGLY1 structure due to a loss of an ionic interaction network of Arg390 and potentially impairment of protein-protein interactions. Our results provide important information on the functional and structural effects of pathogenic NGLY1 variants and pave the way for structure-based development of personalized treatment options.

Keywords: ERAD; N-Glycosylation; congenital disorders of deglycosylation; developmental delay; proteasome; protein misfolding

DOI: https://doi.org/10.3390/cells14131036

bioRxiv. 2025 Jul 04. pii: 2025.07.01.662580. [Epub ahead of print]

PGM1 deficiency disrupts sarcomere and mitochondrial function in a stem-cell cardiomyocyte model.

Silvia Radenkovic, Graeme Preston, Rohit Budhraja, Irena Muffels, Anna Ligezka, Nathan P Staff, Ron Hrstka, Biijina Balakrishnan, Rameen Shah, Sanne Verberkmoes, Ibrahim Shammas, Inez Bosnyak, Kyle M Stiers, Kent Lai, Lesa J Beamer, Akhilesh Pandey, Eva Morava, Tamas Kozicz.

Background: Phosphoglucomutase-1 (PGM1) plays a pivotal role in glycolysis, glycogen metabolism, and glycosylation. Pathogenic variants in PGM1 cause PGM1-congenital disorder of glycosylation (PGM1-CDG), a multisystem disorder with cardiac involvement. While glycosylation abnormalities in PGM1-CDG are treatable with galactose, cardiomyopathy does not improve suggesting a glycosylation-independent pathomechanism. Recently, mitochondrial abnormalities have been shown in a heart of a PGM1-deficicient patient and PGM1-mouse model. In addition, PGM1 has been associated with LDB3 (ZASP/Cypher), a sarcomeric Z-disk protein also associated with cardiomyopathy. However, the cardiac-specific role of PGM1 remains poorly understood, and targeted therapies for PGM1-related cardiomyopathy are currently lacking.
Methods: Induced pluripotent stem cell-derived cardiomyocytes (iCMs) were generated from PGM1-deficient patient fibroblasts. Multielectrode array (MEA) recordings, untargeted (glyco)proteomics, and pathway analysis were performed to assess functional and molecular changes. Key findings were validated using tracer metabolomics and mitochondrial respiration assays.
Results: PGM1-deficient iCMs exhibited reduced beating frequency, impaired contractility, and prolonged contraction kinetics. Proteomic analyses revealed depletion of Z-disk components, including LDB3. AlphaFold3 structural modeling predicted a direct interaction between PGM1 and LDB3, implicating PGM1 in Z-disk integrity, which was confirmed in vitro . In addition, mitochondrial proteins were severely depleted, prompting us to investigate mitochondrial function. Functional validation confirmed extensive metabolic rewiring, energy depletion, and severely impaired mitochondrial respiration. Finally, the in silico drug repurposing identified possible therapeutic options that could target PGM1-deficient cardiomyopathy.
Conclusion: PGM1 is a key regulator of cardiomyocyte function, linking sarcomeric Z-disk integrity with mitochondrial metabolism. These mechanistic insights offer a foundation for developing targeted therapies for PGM1-CDG and potentially other cardiomyopathies involving Z-disk dysfunction.
Graphical abstract:

DOI: https://doi.org/10.1101/2025.07.01.662580

Sci Rep. 2025 Jul 08. 15(1): 24471

Simone Treccarichi, Mirella Vinci, Lara Cirnigliaro, Angela Messina, Angelo Palmigiano, Fabio Pettinato, Antonino Musumeci, Valeria Chiavetta, Salvatore Saccone, Luisa Sturiale, Francesco Calì, Rita Barone.

Glycosylation is a post-translational modification essential for proper protein folding and function, with significant roles in diverse biological processes, including neurogenesis. MAN2A2 enzyme is required for proper N-glycan trimming/maturation in the N-glycosylation pathway. Whole-exome sequencing of a trio revealed two potentially causative variants in the MAN2A2 gene in a patient with autism spectrum disorder (ASD) and cognitive delay. The first variant, c.1679G > A (p.Arg560Gln), was inherited from the unaffected father. It is located within the alpha-mannosidase middle functional domain, a region essential for mannose metabolism and alpha-mannosidase enzymatic activity. The second variant, c.3292C > T (p.Gln1098Ter), was inherited from the mother and it generated a premature stop codon. These variants resulted in a compound heterozygous condition in the patient. Prediction using the DOMINO tool suggested an autosomal recessive inheritance pattern. Notably, the MAN2A2 gene is highly expressed in several brain regions. The encoded enzyme, an alpha-mannosidase, is localized to the Golgi apparatus, the cellular organelle where the processing and maturation of N-glycans occurs. In silico analyses consistently classified both variants as likely pathogenic, supported by structural prediction analyses that indicated significant disruptions in protein architecture. Glycosylation analyses demonstrated impaired N-glycosylation, evidenced by the accumulation of immature serum glycoprotein N-glycans including disease-specific hybrid-type species. Further investigations are essential to elucidate the role of this gene in ASD and cognitive delay.

Keywords: MAN2A2 gene; N-glycans; Congenital disorders of glycosylation; Golgi apparatus; MAN2A1/MAN2A2 alpha-mannosidase; Whole exome sequencing

DOI: https://doi.org/10.1038/s41598-025-09400-5

J Hum Genet. 2025 Jul 08.

VarMeter: a prediction method for the impact of glycogene variants.

Shiho Ohno, Noriyoshi Manabe, Tadashi Kaname, Shoko Nishihara, Yoshiki Yamaguchi.

The clinical relevance of glycans, which play a wide array of physiological roles, is underscored by the emergence of congenital disorders of glycosylation, a group of rare inherited diseases caused by defects in glycan-related genes (glycogenes). Biochemical studies of recombinant proteins and phenotypic analyses in knockout mice are revealing critical insights into the roles of various glycosyltransferases, glycosidases, and glycan-binding proteins. However, the biological functions of numerous glycogenes and their role in disease remain incompletely understood, partly due to human-specific functions that are not recapitulated in model organisms, and partly due to the structural diversity and complexity of glycan modifications, which are difficult to fully assess by conventional methods. A promising complementary strategy is the systematic assessment of human genetic variants, particularly missense mutations, to infer functional consequences. Recent developments in protein structure prediction, exemplified by AlphaFold, are facilitating the development of structure-based approaches to variant interpretation. In this review, we discuss current methodologies for predicting the impact of missense variants using structural information, and introduce VarMeter, a computational framework incorporating 3D structural parameters that has been successfully applied to the prediction of pathogenic variants in the ClinVar database. We also describe VarMeter2, an updated version that integrates AlphaFold-derived pLDDT confidence scores and Mahalanobis distance analysis to improve prediction accuracy, demonstrating its ability to predict pathogenic variants of four glycan-related proteins. These tools offer a novel avenue for uncovering previously unrecognized functions of glycogenes and their links to disease, and contribute to the clinical interpretation of genetic variation.

DOI: https://doi.org/10.1038/s10038-025-01364-8