bims-meglyc 2026-04-19 papers

Issue of 2026–04–19
four papers selected by
Silvia Radenkovic, UMC Utrecht

IUBMB Life. 2026 Apr;78(4): e70101

Lipo-Glc-1,6-P2: A Bioprecursor Prodrug for Phosphomannomutase-2 Congenital Disorder of Glycosylation.

Federica Sodano, Maria Monticelli, Bruno Hay Mele, Barbara Rolando, Loretta Lazzarato, Angela De Simone, Vincenza Andrisano, Debora Paris, Maria Grazia Rimoli, Maria Vittoria Cubellis, Giuseppina Andreotti.

Phosphomannomutase-2 (PMM2) deficiency leads to the prominent Congenital Disorder of Glycosylation (CDG), a rare disease currently lacking effective treatment options. The complete absence of PMM2 activity is incompatible with life, and all patients carry at least one missense destabilising variant that allows residual enzymatic function. This makes PMM2-CDG amenable to pharmacological chaperone treatment. Glucose-1,6-bisphosphate (Glc-1,6-P2) is PMM2's natural activator and stabiliser, but its clinical application is severely limited due to its unfavourable physicochemical profile. Here, we applied the bioprecursor prodrug strategy to design and synthesise Lipo-Glc-1,6-P2, a novel prodrug with good stability and oral bioavailability. Its advantageous physicochemical profile was confirmed through metabolomics-based studies in fibroblasts derived from PMM2-CDG patient.

Keywords: PMM2‐CDG; glucose‐1,6‐bisphosphate; pharmacological chaperone; prodrug approach; protein–ligand binding

DOI: https://doi.org/10.1002/iub.70101

Mol Genet Metab. 2026 Apr 06. pii: S1096-7192(26)00398-7. [Epub ahead of print]148(2): 110115

Truncated N-glycans destabilize POMT1 and POMT2 but do not limit cellular O-mannosylation in HEK293 cells.

Daniel Sturm, Christina Hölscher, Ivan Andújar Martínez, Andreas Harst, Andriana Konstantinidi, Shahidul Alam, Robert Burock, Sergey Y Vakhrushev, Marcus Hoffmann, Thomas Ruppert, Erdmann Rapp, Adnan Halim, Christian Thiel, Sabine Strahl.

Protein O-mannosylation is initiated by the ER-resident enzymes POMT1 and POMT2, both of which carry multiple N-glycans essential for solubility and activity. Although congenital disorders of glycosylation type I (CDG-I) disrupt the early N-glycosylation process, their impact on POMT biogenesis and O-mannosylation has remained unclear. Here, we show that ALG3-dependent elongation of the N-glycan precursor is required to maintain normal abundance of POMT1 and POMT2. In ALG3-deficient HEK293 cells, POMTs carry truncated Man5-type N-glycans and their steady-state protein levels are reduced by more than half, despite unchanged transcript levels. In vitro, reduced POMT abundance resulted in a proportional decrease in mannosyltransferase activity. However, O-mannosylation in cells remained unaffected: α-dystroglycan displayed normal matriglycan extension and a highly O-mannosylated KIAA1549 reporter showed unaltered site occupancy and core structures. These data indicate that POMT activity operates with substantial catalytic reserve under basal conditions, sufficient to tolerate significant reduction in enzyme levels without impairing substrate modification. Our work identifies ALG3-mediated N-glycan maturation as a determinant of POMT stability, highlights buffering capacity that preserves substrate O-mannosylation despite reduced enzyme abundance, and provides a mechanistic framework for how N-glycosylation defects could modulate POMT-dependent glycosylation in disease.

Keywords: ALG3; KIAA1549; N-glycosylation; O-mannosylation; POMT1; POMT2

DOI: https://doi.org/10.1016/j.ymgme.2026.110115

Cells. 2026 Mar 27. pii: 596. [Epub ahead of print]15(7):

Reversible Metabolic and Liver Disease in Complex III Deficiency: Novel Variants Expand the Reported UQCRC2-Associated Phenotype.

Graeme Preston, Ibrahim Shammas, Filippo Pinto E Vairo, Anna Ligezka, Carlos Alberto de Moura Aschoff, Fabiano Poswar, Ida Vanessa D Schwartz, Tamas Kozicz, Eva Morava.

INTRODUCTION: Ubiquinol-cytochrome c reductase core protein II (UQCRC2) encodes a core subunit of the mitochondrial electron transport chain (ETC) complex III (CIII). Biallelic pathogenic variants in UQCRC2 have been associated with mitochondrial disease characterized by lactic acidosis, developmental delay, hepatopathy, and episodic metabolic decompensation.
METHODS: We reviewed the biochemical phenotypes of 14 individuals possessing UQCRC2 variants, including two novel cases. We performed biochemical studies of mitochondrial respiration and oxidative phosphorylation (OXPHOS) complex measurements in patient-derived fibroblasts.
RESULTS: We report reduced CIII activity in a majority of individuals possessing variants in UQCRC2, as well as biochemical findings consistent with impaired mitochondrial energy metabolism, though impairments in mitochondrial respiration were variable. The two previously unreported, unrelated patients possessing the likely pathogenic missense variant c.361T>C, p.Tyr121His in UQCRC2 in trans with a 16p12.2 microdeletion encompassing UQCRC2 showed milder phenotypes, less severe metabolic decompensations, and no long-term neurological impairments. Both individuals display reduced CIII activity and mitochondrial respiratory dysfunction.
DISCUSSION: These data expand the current understanding of genotypes associated with UQCRC2-associated mitochondrial disease to include the novel 16p12.2 microdeletion. These data also highlight the consistent biochemical phenotype associated with UQCRC2-associated mitochondrial disease, and the need for consistent biochemical and respiratory assessment of individuals possessing UQCRC2 variants to further our understanding of this phenotype.

Keywords: OXPHOS; Seahorse; complex III; hyperammonemia; microdeletion 16p12.2; mitochondrial

DOI: https://doi.org/10.3390/cells15070596