bims-meglyc 2025-04-20 papers

Issue of 2025–04–20
eight papers selected by
Silvia Radenkovic, UMC Utrecht

Mol Genet Metab Rep. 2025 Jun;43 101212

Outcome of creatine supplementation therapy in phosphoglucomutase-1 deficiency associated congenital disorders of glycosylation: Novel insights.

Anastasia Ambrose, Morganne McCabe, Clara Hung, Iveta Sosova, Peter Seres, Saadet Mercimek-Andrews.

Background: Biallelic pathogenic variants in PGM1 result in phosphoglucomutase 1 (PGM1) deficiency that is one of the congenital disorders of glycosylation (CDG) (PGM1-CDG). Phenotypic spectrum includes congenital malformations, and muscular, cardiac, hepatic, endocrine and hematologic phenotypes. Current treatment consists of D-galactose therapy that results in clinical and biochemical improvements. To improve fatigue, and exercise intolerance, we started creatine supplementation therapy.
Material and methods: We reviewed electronic patient chart. We applied Nijmegen Pediatric CDG Rating Scale (NPCRS) and The Functional Assessment of Chronic Illness Therapy Fatigue scale (FACIT-F). We measured creatine metabolism biomarkers.
Results: This is a 29-year-old female with PGM1-CDG, confirmed diagnosis by clinical exome sequencing. She has been treated with D-galactose therapy which did not improve her fatigue and exercise intolerance. She was started on creatine supplementation therapy at the age of 27 years which led to decreased daytime sleeping, increased exercise capacity and improvements in her NPCRS, and FACIT-F. Her plasma guanidinoacetate was low. She had elevated urine galactitol on D-galactose therapy.
Discussion: PGM1-CDG associated myopathy is likely due to combination of several factors including abnormal muscle carbohydrate metabolism, abnormal N-glycosylation of proteins involved in the muscle functions and creatine transport and altered muscle energy homeostasis. It was previously shown that creatine supplementation therapy improves myopathy in patients with mitochondrial cytopathies. We think that the use of creatine supplementation therapy coincided with improvements in fatigue and exercise intolerance subjectively and objectively in our patient.

Keywords: Congenital disorders of glycosylation; Creatine; Fatigue; PGM1-CDG; Phosphoglucomutase-1; The PGM1 gene

DOI: https://doi.org/10.1016/j.ymgmr.2025.101212

Hum Mutat. 2024 ;2024 8813121

Genotype/Phenotype Relationship: Lessons From 137 Patients With PMM2-CDG.

We report on the largest single dataset of patients with PMM2-CDG enrolled in an ongoing international, multicenter natural history study collecting genetic, clinical, and biological information to evaluate similarities with previous studies, report on novel findings, and, additionally, examine potential genotype/phenotype correlations. A total of 137 participants had complete genotype information, representing 60 unique variants, of which the most common were found to be p.Arg141His in 58.4% (n = 80) of participants, followed by p.Pro113Leu (21.2%, n = 29), and p.Phe119Leu (12.4%, n = 17), consistent with previous studies. Interestingly, six new variants were reported, comprised of five missense variants (p.Pro20Leu, p.Tyr64Ser, p.Phe68Cys, p.Tyr76His, and p.Arg238His) and one frameshift (c.696del p.Ala233Argfs∗100). Patient phenotypes were characterized via the Nijmegen Progression CDG Rating Scale (NPCRS), together with biochemical parameters, the most consistently dysregulated of which were coagulation factors, specifically antithrombin (below normal in 79.5%, 93 of 117), in addition to Factor XI and protein C activity. Patient genotypes were classified based upon the predicted pathogenetic mechanism of disease-associated mutations, of which most were found in the catalysis/activation, folding, or dimerization regions of the PMM2 enzyme. Two different approaches were used to uncover genotype/phenotype relationships. The first characterized genotype only by the predicted pathogenic mechanisms and uncovered associated changes in biochemical parameters, not apparent using only NPCRS, involving catalysis/activation, dimerization, folding, and no protein variants. The second approach characterized genotype by the predicted pathogenic mechanism and/or individual variants when paired with a subset of severe nonfunctioning variants and uncovered correlations with both NPCRS and biochemical parameters, demonstrating that p.Cys241Ser was associated with milder disease, while p.Val231Met, dimerization, and folding variants with more severe disease. Although determining comprehensive genotype/phenotype relationships has previously proven challenging for PMM2-CDG, the larger sample size, plus inclusion of biochemical parameters in the current study, has provided new insights into the interplay of genetics with disease. Trial Registration: NCT03173300.

Keywords: PMM2; congenital disorders of glycosylation; genetic variations; genotype/phenotype correlations; inherited metabolic disorders; natural history; phosphomannomutase 2-CDG

DOI: https://doi.org/10.1155/2024/8813121

Hum Mutat. 2024 ;2024 9857442

COG6-CDG: Two Novel Variants and Milder Phenotype in a Chinese Patient.

Xue-Yuan Zhang, Jing Zhang, Yi Lu.

Here, we present a Han Chinese pediatric girl highly suspected of congenial disorder of glycosylation type IIL (CDG2L; OMIM#614576). Her clinical symptoms include transferase abnormal, liver cirrhosis, hemogram, coagulopathy, growth retardation, intellectual disability, frequent infections, and enamel hypoplasia. Trio-genome sequencing identified in COG6 a paternal variant c.1672C>T (p.Gln558Ter) and a maternal variant c.153+392A>G (p.?). Reverse transcription-polymerase chain reaction (RT-PCR) using mRNA isolated from peripheral blood confirmed the pathogenicity of both variants. The paternal variant resulted in nonsense-mediated mRNA decay. The maternal variant generated two aberrant COG6 transcripts with 154 bp overlap and was predicted to result in a frameshift at the same position, leading to generation of a premature termination codon. They might result in synthesis of a truncated form of COG6. Thus, the patient was genetically diagnosed.

DOI: https://doi.org/10.1155/2024/9857442

Front Mol Biosci. 2025 ;12 1563384

Cytosolic UDP-Gal biosynthetic machinery is required for dimerization of SLC35A2 in the Golgi membrane and its interaction with B4GalT1.

Wojciech Wiertelak, Artem Pavlovskyi, Mariusz Olczak, Dorota Maszczak-Seneczko.

Glycosylation is a vital post-translational modification involving the addition of sugars to proteins and lipids, facilitated by glycosyltransferases and dependent on nucleotide sugar donors like UDP-galactose (UDP-Gal). This study examines how disruptions in UDP-Gal synthesis affect protein-protein interactions critical for glycosylation. Using CRISPR/Cas9, we generated HEK293T cell lines lacking key enzymes of the Leloir pathway: UDP-galactose 4'-epimerase (GALE), galactose-1-phosphate uridylyltransferase (GALT), or both. The knockout of GALE led to a significant reduction in intracellular UDP-Gal levels and altered N-glycan profiles, indicating impaired galactosylation. Through the NanoBiT assay, we observed that knocking out GALE alone or both GALE and GALT diminished the ability of the UDP-Gal transporter SLC35A2 to form homomers and to interact with the beta-1,4-galactosyltransferase 1 (B4GALT1). These findings suggest that the nucleotide sugar availability and/or the presence of the corresponding enzymes in the cytoplasm influences the formation of protein complexes involved in glycosylation in the Golgi apparatus, potentially affecting the glycosylation process itself. Our study highlights the dynamic nature of the glycosylation machinery and suggests that the interactions between glycosylation proteins are responsive to changes in nucleotide sugar levels. This opens new avenues for understanding the mechanisms underlying glycosylation and for investigating congenital glycosylation disorders.

Keywords: B4GALT1; Golgi apparatus; SLC35A2; UDP-galactose; glycosylation; protein-protein interactions

DOI: https://doi.org/10.3389/fmolb.2025.1563384

Annu Rev Nutr. 2025 Apr 18.

Progress in Understanding the Regulation of Glucose and Fructose Metabolism.

Meng Zhao, Jameel Lone, Saranya Reghupaty, Karen Yasmin Linde-Garelli, Katrin J Svensson.

Hexoses, including glucose, fructose, and galactose, are six-carbon monosaccharides that play fundamental roles in mammalian metabolism, with glucose serving as the primary energy source and fructose and galactose metabolized through pathways converging with glucose metabolism. While glucose metabolism has been extensively studied over the past hundred years, the mechanisms of fructose metabolism and uptake, the transporters involved, and its roles in physiology and disease are far less explored. Recent data also suggest that excessive fructose intake can have detrimental effects on metabolic organs, including the liver. Emerging studies have uncovered novel regulatory mechanisms in glucose and fructose metabolism, including the role of posttranslational modifications of transporters and enzymes, and the discovery of regulators of transporters. Here, we highlight new findings on the regulation of glucose and fructose transporters and integrate recent molecular and clinical insights into how glucose and fructose contribute to metabolic diseases.

DOI: https://doi.org/10.1146/annurev-nutr-111824-012939

Pediatr Neurol. 2025 Mar 25. pii: S0887-8994(25)00076-1. [Epub ahead of print]167 89-95

Glycosylphosphatidylinositol Biosynthesis Defect Due To Novel Biallelic Pathogenic Variants in PIGW.

BACKGROUND: Inherited glycosylphosphatidylinositol (GPI) deficiencies are a heterogeneous group of inherited disorders of glycosylation, caused by mutations in genes involved in GPI-anchored proteins (GPI-AP) biosynthesis. PIGW is a gene known to be involved in the early steps of the GPI-anchor biosynthesis, as well as functional studies for most patients. Biallelic mutations in PIGW have been previously linked to hyperphosphatasia with mental retardation syndrome 5, also known as glycosylphosphatidylinositol biosynthesis defect 11 (GPIBD11).
METHODS: We report seven individuals, including two fetuses from six unrelated families. Whole exome sequencing and chromosome analysis were performed, with variant interpretation based on ACMG and AMP guidelines. Magnetic resonance imaging (MRI) was also conducted on some of the patients. Blood samples were collected from patients to analyze GPI-AP expression using flow cytometry on markers like CD16, CD24, and FLAER. Functional analyses were performed using PIGW KO HEK 293 cells generated with CRISPR/Cas9 technology. The cells were transfected with rat Pigw cDNA that contained patient variants. The restoration of GPI-AP expression was measured by flow cytometry. Western blotting was used to assess protein expression.
RESULTS: Affected patients exhibited a wide range of clinical features. Some patients presented classic GPIBD11 symptoms like developmental delay, hyperphosphatasia, and intellectual disability. Other patients showed atypical or milder phenotypes. The magnetic resonance imaging scans revealed variable neurological abnormalities in the affected individuals. Whole exome sequencing results identified PIGW mutations in all patients, which confirms the genetic basis of the disorder. Flow cytometry analysis of blood samples from patients P1, P4, and P5 using various markers showed a significant reduction in GPI-AP expression. The CD16 marker decreased to 1.8% in P1 and 21% in P5 compared to controls. CD24 was reduced to 22% in P1 granulocytes. Also, a minor decrease in CD14 on monocytes was observed in P4, as well as a slight reduction in the expression of FLAER in lymphocytes. Functional studies on PIGW-deficient CHO cells and HEK293 cells, using flow cytometry, showed that GPI-AP expression is affected by the PIGW variants. Western blotting showed reduced PIGW protein expression, except for P153L and R36G, which were similar to wild-type levels.
CONCLUSIONS: To date, six patients and two fetuses with biallelic variants in PIGW have been reported. Here, we describe five new patients and two fetuses harboring homozygous or compound heterozygous variants in the PIGW gene. Our results illustrate the clinical variability of GPIBD11, highlighting the importance of broad genomic sequencing assays for patients who do not show typical symptoms. Therefore, our study expands the clinical and molecular spectrum of PIGW-associated disorder.

Keywords: GPI-anchored proteins; Glycosylphosphatidylinositol biosynthesis defect 11 (GPIBD11); Hyperphosphatasia with mental retardation syndrome 5 (HPMRS5); Phosphatidyl inositol glycan class W (PIGW)

DOI: https://doi.org/10.1016/j.pediatrneurol.2025.03.012

bioRxiv. 2025 Apr 03. pii: 2025.04.01.646556. [Epub ahead of print]

The glycosyltransferase ALG3 is an AKT substrate that regulates protein N-glycosylation.

Adrija J Navarro-Traxler, Laura Ghisolfi, Evan C Lien, Alex Toker.

The PI3K/AKT signaling pathway is frequently dysregulated in cancer and controls key cellular processes such as survival, proliferation, metabolism and growth. Protein glycosylation is essential for proper protein folding and is also often deregulated in cancer. Cancer cells depend on increased protein folding to sustain oncogene-driven proliferation rates. The N-glycosyltransferase asparagine-linked glycosylation 3 homolog (ALG3), a rate-limiting enzyme during glycan biosynthesis, catalyzes the addition of the first mannose to glycans in an alpha-1,3 linkage. Here we show that ALG3 is phosphorylated downstream of the PI3K/AKT pathway in both growth factor-stimulated cells and PI3K/AKT hyperactive cancer cells. AKT directly phosphorylates ALG3 in the amino terminal region at Ser11/Ser13. CRISPR/Cas9-mediated depletion of ALG3 leads to improper glycan formation and induction of endoplasmic reticulum stress, the unfolded protein response, and impaired cell proliferation. Phosphorylation of ALG3 at Ser11/Ser13 is required for glycosylation of cell surface receptors EGFR, HER3 and E-cadherin. These findings provide a direct link between PI3K/AKT signaling and protein glycosylation in cancer cells.

DOI: https://doi.org/10.1101/2025.04.01.646556