bims-meglyc 2026-04-05 papers

Issue of 2026–04–05
five papers selected by
Silvia Radenkovic, UMC Utrecht

Mol Genet Metab. 2026 Mar 25. pii: S1096-7192(26)00193-9. [Epub ahead of print]148(2): 109910

Biochemical genetic testing for congenital disorders of glycosylation after sequencing produces equivocal results.

Matthew J Schultz, Kristen L Liedtke, Coleman T Turgeon, Dietrich Matern, Patricia L Hall.

Congenital disorders of glycosylation (CDG) are a large, rapidly expanding group of inherited disorders with variable phenotypes. More than 200 CDGs have been reported, many in only a small number of patients. Untargeted next-generation sequencing methods have led to the discovery of most CDGs, shortening the time to diagnosis in many cases. However, novel missense variants are frequently identified, and genotypes involving variants of uncertain significance often require additional testing. Our laboratory has received an increased number of referrals for CDG biochemical genetic testing, particularly for transferrin and apolipoprotein CIII isoform profiles, after variants in genes associated with the glycosylation pathway have initially been identified by molecular genetic testing. In this study, we quantified this practice and its outcomes by conducting a retrospective review of cases submitted to our laboratory for biochemical genetic testing from January 2022 through March 2025. Equivocal or uncertain molecular genetic testing results for a gene associated with a CDG were submitted for 89 patients from 87 families at the time that biochemical genetic testing was ordered. Molecular findings were reported for 52 different genes, of which PMM2 (n = 13), MAN1B1 (n = 6), and ALG13 (n = 6) were the most frequent. Two patients were excluded from further analysis due to the presence of variants in multiple genes associated with CDGs. For 23 of the 87 patients (26.4%), the CDG suspected on the basis of genotype could be supported or confirmed by biochemical genetic testing. For another 36 patients (41.4%), the suspected CDG could be excluded due to normal results, and for 16 patients (18.4%), a definitive diagnosis could not be established because the available biochemical genetic tests were not expected to be informative. In 11 cases (12.6%), the outcome was uncertain. In conclusion, health care professionals should be judicious when seeking biochemical genetic confirmation of genotypes suggestive of a CDG. Although molecular findings of uncertain significance require confirmation, not all CDGs can be identified with currently available biochemical genetic testing.

Keywords: MAN1B1-CDG; Next-generation sequencing; PMM2-CDG

DOI: https://doi.org/10.1016/j.ymgme.2026.109910

Adv Exp Med Biol. 2026 ;1491 249-272

Cytosolic Peptide: N-Glycanase (NGLY1)-from Basic Biology to Genetic Disorder, NGLY1 Deficiency.

Haruhiko Fujihira, Tadashi Suzuki.

The cytosolic peptide:N-glycanase (PNGase, NGLY1 in mammals) is an enzyme that removes N-glycans from misfolded glycoproteins. NGLY1 contributes to cytosolic glycan degradation (non-lysosomal glycan degradation) and is one of the quality control systems for newly synthesized proteins, i.e., ER-associated degradation (ERAD). NGLY1 is also responsible for the activation of a transcription factor, NFE2L1, which participates in several stress responses, including regulation of proteasome subunit expression and oxidative stress. In 2012, NGLY1 deficiency, a human genetic disorder caused by the biallelic mutations in the NGLY1 gene, was discovered. Since then, research on the physiological functions of NGLY1 and the pathogenic mechanism of NGLY1 deficiency has expanded rapidly. Here, we will briefly overview the early history of NGLY1 research and then introduce its versatile functions. We will also provide mechanistic insights into the pathogenesis of NGLY1 deficiency based on studies using model animals, such as worms, flies, and rodents.

Keywords: Genetic disorder; Model animal/cell analyses; NGLY1

DOI: https://doi.org/10.1007/978-3-032-04153-1_16

Adv Exp Med Biol. 2026 ;1491 207-219

Lysosomal Neuraminidase 1 (NEU1): Its Unique Molecular Characters and Therapeutic Approaches for Deficiencies.

Kohji Itoh, Jun Tsukimoto.

Neuraminidase 1 (NEU1) is a lysosomal sialidase that removes terminal α-bound sialic acid from sialylglycoconjugates and contributes to ubiquitous catabolism of sialylglycoconjugates and immunoregulatory functions. Different from other human sialidases, including NEU2 to NEU4, NEU1 is first produced as an N-glycosylated precursor protein, which binds to its protective protein/cathepsin A (CTSA) and then forms a lysosomal multienzyme complex (LMC) with β-galactosidase 1 (GLB1) in the rough endoplasmic reticulum (RER) lumen. NEU1 trafficking to lysosomes and intralysosomal activation under acidic pH conditions essentially requires association with CTSA, which carries terminal mannose 6-phosphate (M6P)-type N-glycan to bind with cation-dependent (CD) M6P receptor (CD-M6PR) in the Golgi apparatus via endosomes. In contrast, the single NEU1 gene overexpression in mammalian cells results in NEU1 protein crystallization in the RER owing to self-aggregation at a relatively low intrinsic CTSA level. Two NEU1 deficiencies, sialidosis (SiD) and galactosialidosis (GS), are caused by autosomal recessive NEU1 and CTSA gene mutations, respectively. These untreatable disorders are associated with excessive storage of sialylglycans in neurovisceral organs and systemic symptoms. We produced a new GS model mouse by introducing a homozygous Ctsa IVS6+1g/a mutation into the murine gene locus, leading to partial exon 6 skipping and simultaneous deficiency of Ctsa and Neu1. The GS mice exhibited clinical symptoms similar to those seen in juvenile/adult GS patients, including myoclonic seizures, suppressed behavior, a gargoyle-like face, edema, proctoptosis owing to Neu1 deficiency, and sialylglycan accumulation related to neurovisceral inflammation. Evaluating the efficacy of a novel therapy utilizing GS and SiD model mice and overcoming the human NEU1 gene product shortage will be necessary for a novel, effective treatment for NEU1 deficiencies.

Keywords: Galactosialidosis; Gene therapy; Immune disease; In cellulo crystallization; Inflammation; Lysosomal disease; Lysosomal neuraminidase ; Neu1-deficient model mouse; Sialidosis; Sialyloligosaccharide

DOI: https://doi.org/10.1007/978-3-032-04153-1_13

Adv Exp Med Biol. 2026 ;1491 59-87

Biosynthesis and Regulation of Laminin-Binding O-Mannosyl Glycans Related to Muscular Dystrophy.

Rieko Imae, Hiroshi Manya, Tamao Endo.

Glycosylation is an important post-translational protein modification involved in various biological processes. Glycans are divided into two types: Asn-linked N-glycans and Ser/Thr-linked O-glycans. O-mannosyl glycans are a unique group of O-glycans in mammals that play critical roles in the skeletal muscle and the brain. The plasma membrane-localized glycoprotein α-dystroglycan (α-DG) is modified with a laminin-binding O-mannosyl glycan. Defects in this glycan synthesis result in the loss of α-DG laminin-binding and cause a group of congenital muscular dystrophies with neuronal abnormalities, collectively termed dystroglycanopathy. Considerable efforts have been devoted to elucidating the laminin-binding O-mannosyl glycan structure. Recently, the complete structure of the glycan and its biosynthetic enzymes have been revealed. Pathological analyses of dystroglycanopathy in patients and mouse models have clarified the physiological functions of this glycan. In this review, we describe the structures, biosynthetic mechanisms, and functions of O-mannosyl glycans in mammals, with a focus on the laminin-binding O-mannosyl glycan. In addition, we summarize recent progress in the regulatory mechanisms of laminin-binding O-mannosyl glycan biosynthesis.

Keywords: Dystroglycanopathy; Laminin; O-mannosyl glycan; α-Dystroglycan

DOI: https://doi.org/10.1007/978-3-032-04153-1_6

Adv Exp Med Biol. 2026 ;1491 21-32

Roles of Core Fucosylation in Neuroinflammation and Its Possibility for Application.

Xing Xu, Tomohiko Fukuda, Jianguo Gu.

Core fucosylation, a critical post-translational modification mediated by α1,6-fucosyltransferase (Fut8), is vital in regulating cellular functions and signaling pathways. This glycosylation process is particularly significant in the context of the central nervous system (CNS), where it influences neurodevelopment, synaptic functionality, and the neuroinflammatory response. Aberrations in core fucosylation have been implicated in the pathogenesis of various neuroinflammatory conditions, underscoring its potential as a therapeutic target for neurological disorders. Core fucosylation affects several important signaling molecules and receptors, such as the transforming growth factor-β (TGF-β) receptor, vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), integrins, and glycoprotein 130 (gp130). These molecules are essential for maintaining CNS homeostasis and responding to injury or disease. Furthermore, the dysregulation of core fucosylation has been associated with altered microglial and astrocytic responses to inflammatory stimuli, affecting the progression of neurodegenerative diseases. The modulation of core fucosylation pathways presents a promising avenue for developing novel therapeutic strategies to control neuroinflammation and improve outcomes in patients with neurodegenerative disorders. In conclusion, the intricate relationship between core fucosylation and neuroinflammation offers insights into the molecular mechanisms underlying CNS pathologies and highlights the importance of further research in this area to identify new targets for therapeutic intervention.

Keywords: Central nervous system; Core fucosylation; Immune system; Neuroinflammation

DOI: https://doi.org/10.1007/978-3-032-04153-1_3