bims-meglyc 2026-07-26 papers

Issue of 2026–07–26
four papers selected by
Silvia Radenkovic, UMC Utrecht

Biometals. 2026 Jul 22.

Functional characterization of a novel ZIP8 variant causing impaired manganese homeostasis and congenital disorders of glycosylation.

Hitomi Fujishiro, Naoya Morisada, Nao Mitani, Rina Nakayama, Natsuki Goto, Yukina Nishito, Taiho Kambe, Nobuhiko Okamoto, Yoshinao Wada, Yusuke Ishida, Hisato Suzuki, Kandai Nozu, Kenjiro Kosaki, Seiichiro Himeno, Daigo Sumi.

ZIP8, encoded by SLC39A8, mediates cellular uptake of divalent metal ions, including manganese (Mn). Mutations in SLC39A8 cause a congenital disorder of glycosylation (CDG) associated with Mn deficiency (SLC39A8-CDG). Here, we report a novel case of SLC39A8-CDG harboring a previously unreported mutation (p.F206I) in the transmembrane domain 3 (TMD3). The patient showed markedly low serum Mn levels and abnormal glycosylation. To evaluate the functional consequences of this variant, we generated cells expressing hZIP8-F206I. Mn, cadmium, and zinc uptake levels in cells expressing hZIP8-F206I were approximately half of those in cells expressing wild-type hZIP8. The mutant hZIP8 also showed reduced plasma membrane localization. These findings suggest that this previously unreported mutation in TMD3 significantly impairs ZIP8-mediated metal transport, leading to CDG.

Keywords: Congenital disorder of glycosylation; Manganese; Metal transporter; SLC39A8; ZIP8

DOI: https://doi.org/10.1007/s10534-026-00862-2

Mol Genet Metab Rep. 2026 Sep;48 101336

Tissue-specific expression and regulation of congenital disorders of glycosylation genes: A GTEx-based in silico study.

Cátia J Neves, António Gomes, Rita A Lourenço, Mariana Barbosa, Ana R Grosso, Paula A Videira.

Congenital disorders of glycosylation (CDGs) are rare metabolic diseases characterized by clinical heterogeneity, yet the molecular basis for their tissue-specific manifestations remains poorly understood. Because affected tissues are rarely accessible for biopsy, the baseline transcriptional and regulatory landscape of CDG-causative genes in healthy human tissues offers a valuable, complementary perspective on tissue vulnerability. Here, we performed an in silico study of the expression, allelic regulation, expression quantitative trait loci (eQTLs), and associations with immune cell compositions of 12 CDG-causative genes across healthy human tissues using multi-omics datasets from the Adult GTEx project. The selected panel includes the most prevalent multisystem CDGs (PMM2-, ALG6-, ALG1-, SLC35A2-, ALG13-, SRD5A3-, MAN1B1-, DPAGT1-CDG), three immune-relevant CDGs classified as inborn errors of immunity (MOGS-, PGM3-, VPS13B-CDG), and the autosomal recessive form of GNE-CDG (GNE-CDG (ar); GNE myopathy) as a tissue-restricted contrast. CDG-causative genes were broadly but heterogeneously expressed, with substantial inter-individual variation. Tissues frequently affected in the corresponding disorders did not consistently display the highest baseline gene expression, underscoring that higher gene expression alone is a poor indicator of tissue susceptibility. Allele-specific analyses revealed five distinct allelic expression patterns across individuals and identified tissue-specific deviations from balanced biallelic expression for several genes, most notably SRD5A3, PGM3, VPS13B, and GNE. Tissue-specific eQTLs affecting CDG genes were frequently located in intronic enhancers of unrelated genes or intergenic regions, revealing a complex, predominantly distal regulatory architecture. Several eQTLs overlapped GWAS Catalog traits and ClinVar entries relevant to the corresponding CDG phenotypes, including PMM2 eQTLs associated with reduced PMM2 gene levels. Finally, correlations between CDG-causative gene expression and immune cell composition recapitulated known immune phenotypes from blood and suggested additional tissue-dependent roles for glycosylation in immune modulation, that warrant functional validation. Together, these findings demonstrate that CDG-causative genes operate within diverse transcriptional, allelic, and regulatory contexts across human tissues. Our in silico framework provides an interpretable candidates and foundational reference for interpreting tissue vulnerability in CDG and underscore the need for global analyses to fully understand organ-specific disease mechanisms.

Keywords: Allelic expression; Congenital disorders of glycosylation; Immunity; In silico; Regulation; Transcriptomics; eQTL

DOI: https://doi.org/10.1016/j.ymgmr.2026.101336

Expert Rev Proteomics. 2026 Jul 23. 1-14

Clinical proteomics in inborn errors of metabolism: from biomarker discovery to implementation.

Michela Geminiani, Alfonso Trezza, Anna Visibelli, Rebecca Finetti, Pierfrancesco Mastroeni, Bianca Roncaglia, Ottavia Spiga, Annalisa Santucci.

INTRODUCTION: Inborn errors of metabolism (IEMs) are rare, heterogeneous disorders traditionally diagnosed through genetic testing, enzyme assays, and metabolite measurements. However, these tools often do not fully explain phenotypic variability, organ involvement, disease progression, or treatment response. Clinical proteomics provides a complementary functional layer by capturing changes in protein abundance, proteoforms, post-translational modifications (PTM), and biological pathways, offering insights beyond genotype- and metabolite-based approaches.
AREAS COVERED: This review examines the role of high-resolution mass spectrometry and computational proteomics in biomarker discovery and clinical decision-making for IEMs. It focuses on their contribution to diagnosis, variant interpretation, patient stratification, and treatment monitoring. Disease-specific applications are discussed, with the strongest evidence in lysosomal storage disorders, mitochondrial diseases, congenital disorders of glycosylation, and selected neurodegenerative or renal metabolic conditions. The literature search was performed in PubMed, Scopus, Web of Science, and Google Scholar, covering peer-reviewed articles available up to 2026, with emphasis on methodological advances and translational applications in clinical proteomics for IEMs.
EXPERT OPINION: Proteomics will not replace established diagnostic tools, but it can help address clinically actionable questions in selected contexts. Translation into clinical practice will require standardized workflows, multicenter validation, clinically anchored endpoints, and integration with other omics approaches.

Keywords: Clinical proteomics; bioinformatics; biomarker discovery; inborn errors of metabolism; mass spectrometry; multi-omics; rare diseases

DOI: https://doi.org/10.1080/14789450.2026.2709148

Mol Genet Metab. 2026 Jul 17. pii: S1096-7192(26)00502-0. [Epub ahead of print]149(1-2): 110219

Endogenous fructose production in patients and mice with aldolase B deficiency.

Amée M Buziau, Nynke Simons, Dean R Tolan, Florian Caiment, Jean L J M Scheijen, Marjo P van de Waarenburg, Casper G Schalkwijk, Martijn C G J Brouwers.

BACKGROUND: Hereditary fructose intolerance (HFI) is an inborn error of fructose metabolism caused by aldolase B deficiency (ALDOB). Patients with HFI require lifelong adherence to a fructose-restricted diet. However, despite strict dietary restriction, both HFI patients and mice with Aldob-/- exhibit hepatocellular accumulation of fructose 1-phosphate (F1P) and intrahepatic lipids (IHL). We studied whether endogenously produced fructose could account for these observations.
METHODS: We first measured serum fructose levels during a 75 g oral glucose tolerance test (OGTT) in patients with HFI (n = 14) and matched healthy controls (n = 14). Furthermore, we quantified the incorporation of 13C6-glucose into F1P in Aldob-/- mice (n = 4) and wildtype mice (n = 4). Next, we examined the effects of inhibition of endogenous fructose production in Aldob-/- mice. Aldob-/- mice were treated for 9 days with an aldose reductase inhibitor (ARi; n = 9) or vehicle (n = 9) under fructose-free dietary conditions.
RESULTS: Serum fructose concentrations increased significantly at 30 and 60 min compared to baseline in patients with HFI and controls (P < 0.05), indicating glucose-derived fructose production. Similar, 13C6-glucose was incorporated into F1P in Aldob-/- mice and wildtype mice. ARi-treatment significantly reduced hepatic fructose levels in Aldob-/- mice (P = 0.002), confirming effective inhibition of the polyol pathway, but did not reduce IHL content (P = 0.71).
CONCLUSIONS: Although endogenous fructose production contributes to circulating and hepatic fructose levels in Aldob-/-, inhibition of the polyol pathway does not reduce hepatic steatosis in Aldob-/- mice under fructose-free conditions.

Keywords: Aldolase B; Endogenous fructose production; Hereditary fructose intolerance; Intrahepatic lipid; Metabolic disease; Polyol pathway

DOI: https://doi.org/10.1016/j.ymgme.2026.110219