bims-meglyc 2025-01-12 papers

bims-meglyc

Biomed News

on Metabolic disorders affecting glycosylation

Issue of 2025–01–12
nine papers selected by
Silvia Radenkovic, UMC Utrecht

SLC10A7 regulates O-GalNAc glycosylation and Ca2+ homeostasis in the secretory pathway: insights into SLC10A7-CDG.
Congenital disorders of glycosylation type 1A associated with cerebral hemorrhagic infarction: illustrative case.
In-Depth Phenotyping of PIGW-Related Disease and Its Role in 17q12 Genomic Disorder.
SLC35A2 loss of function variants affect glycomic signatures, neuronal fate, and network dynamics.
ALG8-CDG: Advances in Molecular and Prenatal Phenotyping Facilitate Prenatal Diagnosis and Genetic Counseling.
The Metabolic Treatabolome and Inborn Errors of Metabolism Knowledgebase therapy tool: Do not miss the opportunity to treat!
Untargeted metabolomics analysis as a potential screening tool for 3-methylglutaconic aciduria syndromes.
TRAPPopathies: Severe Multisystem Disorders Caused by Variants in Genes of the Transport Protein Particle (TRAPP) Complexes.
Genetic gradual reduction of OGT activity unveils the essential role of O-GlcNAc in the mouse embryo.

Cell Mol Life Sci. 2025 Jan 08. 82(1): 40

SLC10A7 regulates O-GalNAc glycosylation and Ca2+ homeostasis in the secretory pathway: insights into SLC10A7-CDG.

Zoé Durin, Aurore Layotte, Willy Morelle, Marine Houdou, Antoine Folcher, Dominique Legrand, Dirk Lefeber, Natalia Prevarskaya, Julia Von Blume, Valérie Cormier-Daire, François Foulquier.

  Glycans are known to be fundamental for many cellular and physiological functions. Congenital disorders of glycosylation (CDG) currently encompassing over 160 subtypes, are characterized by glycan synthesis and/or processing defects. Despite the increasing number of CDG patients, therapeutic options remain very limited as our knowledge on glycan synthesis is fragmented. The emergence of CDG resulting from defects in ER/ Golgi homeostasis makes this even more difficult. SLC10A7 belongs to the SLC10 protein family, known as bile acid and steroid transport family, exhibiting a unique structure. It shows a ubiquitous expression and is linked to negative calcium regulation in cells. The mechanisms by which SLC10A7 deficiency leads to Golgi glycosylation abnormalities are unknown. The present study identifies major O-glycosylation defects in both SLC10A7 KO HAP1 cells and SLC10A7-CDG patient fibroblasts and reveals an increased ER and Golgi calcium contents. We also show that the abundance of COSMC and C1GALT1 is altered in SLC10A7-CDG patient cells, as well as the subcellular Golgi localization of the Ca2+-binding Cab45 protein. Finally, we demonstrate that supraphysiological manganese supplementation suppresses the deficient electrophoretic mobility of TGN46 by an aberrant transfer of GalNAc residues, and reveal COSMC Mn2+ sensitivity. These findings provide novel insights into the mechanisms of Golgi glycosylation defects in SLC10A7-deficient cells. They show that SLC10A7 is a key Golgi transmembrane protein maintaining the tight regulation of Ca2+ homeostasis in the ER and Golgi compartments, both essential for glycosylation.

Keywords:  CDG; Glycosylation; O-GalNAc; SLC10A7

DOI:  https://doi.org/10.1007/s00018-024-05551-2
J Neurosurg Case Lessons. 2025 Jan 06. pii: CASE23729. [Epub ahead of print]9(1):

Congenital disorders of glycosylation type 1A associated with cerebral hemorrhagic infarction: illustrative case.

Yu Nomura, Takahiro Morita, Kota Ueno, Ryota Watanabe, Takeshi Katagai, Kenichiro Asano, Atsushi Saito.

   BACKGROUND: Cases of congenital disorders of glycosylation (CDGs) are rare, and the occurrence of hemorrhagic infarction is also rare. The etiology is unclear.
OBSERVATIONS: A 3-year-old Asian boy with CDG type 1A was hospitalized with pneumonia. Consciousness disturbance and hemiplegia appeared after high fever and were associated with disseminated intravascular coagulation. Magnetic resonance (MR) images showed subcortical hemorrhagic infarction due to anterior superior sagittal sinus occlusion. Follow-up computed tomography revealed the enlargement of a right frontal lobe hematoma with a midline shift. The authors performed emergency craniotomy for hematoma evacuation. The postoperative course was favorable, with improvements in consciousness and hemiplegia. Patients with CDG type 1A have various types of coagulation disorders and sometimes develop several thrombotic and bleeding events; however, there has only been one reported case of CDG with concomitant intracranial hemorrhagic infarction. The authors detected sinus thrombosis on MR images for the first time in a patient with CDG.
LESSONS: In patients with CDGs, abnormalities in the coagulation-fibrinolysis system can cause various neurological symptoms, such as intracranial bleeding, cerebral ischemia, and stroke-like episodes. In Asian infants with suspected cerebral venous sinus thrombosis, it is advisable to conduct examinations that include imaging modalities, such as MR venography and/or contrast-enhanced T1-weighted imaging, to confirm complications. https://thejns.org/doi/10.3171/CASE23729.

Keywords:  coagulation disorder; congenital disorders of glycosylation type 1A; glycoprotein; hemorrhagic infarction; venous thrombosis

DOI:  https://doi.org/10.3171/CASE23729
Biomolecules. 2024 Dec 18. pii: 1626. [Epub ahead of print]14(12):

In-Depth Phenotyping of PIGW-Related Disease and Its Role in 17q12 Genomic Disorder.

Agnese Feresin, Mathilde Lefebvre, Emilie Sjøstrøm, Caterina Zanus, Elisa Paccagnella, Irene Bruno, Erica Valencic, Anna Morgan, Alberto Tommasini, Christel Thauvin, Allan Bayat, Giorgia Girotto, Luciana Musante.

  Glycosylphosphatidylinositol (GPI) biosynthesis defect 11 (GPIBD11), part of the heterogeneous group of congenital disorders of glycosylation, is caused by biallelic pathogenic variants in PIGW. This rare disorder has previously been described in only 12 patients. We report four novel patients: two sib fetuses with congenital anomalies affecting several organs, including the heart; a living girl with tetralogy of Fallot, global developmental delay, behavioral abnormalities, and atypic electroencephalography (EEG) without epilepsy; a girl with early-onset, treatment-resistant seizures, developmental regression, and recurrent infections, that ultimately passed away prematurely due to pneumonia. We also illustrate evolving facial appearance and biochemical abnormalities. We identify two novel genotypes and the first frameshift variant, supporting a loss-of-function pathogenic mechanism. By merging our cohort with patients documented in the literature, we deeply analyzed the clinical and genetic features of 16 patients with PIGW-related disorder, revealing a severe multisystemic condition deserving complex management and with uncertain long-term prognosis. We consider the role of PIGW within the critical 17q12 region, which is already associated with genomic disorders caused by deletion or duplication and characterized by variable expressivity. Finally, we discuss PIGW dosage effects and a second hit hypothesis in human development and disease.

Keywords:  17q12 genomic disorder; GPIBD11; PIGW; epilepsy; fetus; heart malformation

DOI:  https://doi.org/10.3390/biom14121626
bioRxiv. 2024 Dec 27. pii: 2024.12.27.630524. [Epub ahead of print]

SLC35A2 loss of function variants affect glycomic signatures, neuronal fate, and network dynamics.

Dulcie Lai, Paulina Sosicka, Damian J Williams, MaryAnn E Bowyer, Andrew K Ressler, Sarah E Kohrt, Savannah J Muron, Peter B Crino, Hudson H Freeze, Michael J Boland, Erin L Heinzen.

  SLC35A2 encodes a UDP-galactose transporter essential for glycosylation of proteins and galactosylation of lipids and glycosaminoglycans. Germline genetic SLC35A2 variants have been identified in congenital disorders of glycosylation and somatic SLC35A2 variants have been linked to intractable epilepsy associated with malformations of cortical development. However, the functional consequences of these pathogenic variants on brain development and network integrity remain elusive. In this study, we use an isogenic human induced pluripotent stem cell-derived neuron model to comprehensively interrogate the functional impact of loss of function variants in SLC35A2 through the integration of cellular and molecular biology, protein glycosylation analysis, neural network dynamics, and single cell electrophysiology. We show that loss of function variants in SLC35A2 result in disrupted glycomic signatures and precocious neurodevelopment, yielding hypoactive, asynchronous neural networks. This aberrant network activity is attributed to an inhibitory/excitatory imbalance as characterization of neural composition revealed preferential differentiation of SLC35A2 loss of function variants towards the GABAergic fate. Additionally, electrophysiological recordings of synaptic activity reveal a shift in excitatory/inhibitory balance towards increased inhibitory drive, indicating changes occurring specifically at the pre-synaptic terminal. Our study is the first to provide mechanistic insight regarding the early development and functional connectivity of SLC35A2 loss of function variant harboring human neurons, providing important groundwork for future exploration of potential therapeutic interventions.

Keywords:  epilepsy; glycosylation; human stem cells; neural network; neurodevelopment

DOI:  https://doi.org/10.1101/2024.12.27.630524
QJM. 2025 Jan 10. pii: hcaf006. [Epub ahead of print]

ALG8-CDG: Advances in Molecular and Prenatal Phenotyping Facilitate Prenatal Diagnosis and Genetic Counseling.

Yanlin Huang, Lihua Yu, Juan Zhu, Yunan Wang, Rui Zhang, Jianhong Chen, Cuiqing Huang, Ling Li, Hongke Ding, Jian Lu, Yan Zhang, Li Du.

   BACKGROUND: ALG8-congenital disorder of glycosylation (ALG8-CDG) is a rare inherited metabolic disorder leading to severe multisystem manifestations, with no reported prenatal patients to date.
METHODS: We describe two fetuses from a single family with ALG8-CDG presenting with prenatal hydrops, undergoing comprehensive prenatal ultrasound, umbilical cord blood biochemistry, autopsy, placental pathology, and genetic testing.
RESULTS: Prenatal ultrasound revealed fetal hydrops, skeletal anomalies, cardiac developmental abnormalities, cataracts, echogenic kidneys and bowel, oligohydramnios, choroid plexus cysts, and intrauterine growth restriction. Umbilical cord blood biochemistry demonstrated fetal anemia, coagulation disorders, and abnormal liver and kidney function. Autopsy confirmed fetal hydrops and associated anomalies. A novel compound heterozygous mutation comprising the missense variant c.754T>C (p.Ser252Pro) and a partial exonic deletion (deletion of exons 1-2) in the ALG8 gene was identified in fetus P2.
CONCLUSIONS: This study represents the first prenatal diagnosis of ALG8-CDG, comprehensively delineating the prenatal phenotypic spectrum. Prenatal ultrasound, umbilical cord blood biochemistry, and placental pathology findings aid in the assessment of prenatal manifestations, invaluable for prenatal diagnosis, genetic counseling, and potential interventions in future patients.

Keywords:   ALG8 gene; Congenital disorder of glycosylation; fetal hydrops; molecular genetic diagnosis; prenatal phenotype

DOI:  https://doi.org/10.1093/qjmed/hcaf006
J Inherit Metab Dis. 2025 Jan;48(1): e12835

The Metabolic Treatabolome and Inborn Errors of Metabolism Knowledgebase therapy tool: Do not miss the opportunity to treat!

Bibiche den Hollander, Eva M M Hoytema van Konijnenburg, Brittany Hewitson, Jan C van der Meijden, Berith M Balfoort, Brad Winter, Annelieke R Müller, Wyeth W Wasserman, Carlos R Ferreira, Clara D van Karnebeek.

  Inborn errors of metabolism (IEMs) are rare genetic conditions with significant morbidity and mortality. Technological advances have increased therapeutic options, making it challenging to remain up to date. A centralized therapy knowledgebase is needed for early diagnosis and targeted treatment. This study aimed to identify all treatable IEMs through a scoping literature review, followed by data extraction and analysis according to the Treatabolome principles. Knowledge of treatable IEMs, therapeutic categories, efficacy, and evidence was integrated into the Inborn Errors of Metabolism Knowledgebase (IEMbase), an online database encompassing all IEMs. The study identified 275 treatable IEMs, 18% of all currently known 1564 IEMs, according to the International Classification of Inherited Metabolic Disorders. Disorders of fatty acid and ketone body metabolism had the highest treatability (67%), followed by disorders of vitamin and cofactor metabolism (60%), and disorders of lipoprotein metabolism (42%). The most common treatment strategies were pharmacological therapy (34%), nutritional therapy (34%), and vitamin and trace element supplementation (12%). Treatment effects were most commonly observed in nervous system abnormalities (34%), metabolism/homeostasis abnormalities (33%), and growth (7%). Predominant evidence sources included case reports with evidence levels 4 (48%) and 5 (12%), and individual cohort studies with evidence level 2b (12%). Our study generated the Metabolic Treatabolome 2024. IEMs are the largest group of monogenic disorders amenable to disease-modifying therapy. With drug repurposing efforts and advancements in gene therapies, this number will expand. IEMbase now provides up-to-date, comprehensive information on clinical and biochemical symptoms and therapeutic options, empowering patients, families, healthcare professionals, and researchers in improving patient outcomes.

Keywords:  ICIMD; IEMbase; IMD; Treatabolome; inborn error of metabolism; treatable IEM

DOI:  https://doi.org/10.1002/jimd.12835
Mol Genet Metab. 2024 Dec 30. pii: S1096-7192(24)00893-X. [Epub ahead of print]144(3): 109009

Untargeted metabolomics analysis as a potential screening tool for 3-methylglutaconic aciduria syndromes.

Charles R DiFalco, Charul Gijavanekar, Yue Wang, Alexandra N Grace, Keren Machol, Lisa Emrick, Ning Liu, Elizabeth Mizerik, Laura Mackay, Hongzheng Dai, Liesbeth Vossaert, Fan Xia, Sarah H Elsea, Fernando Scaglia.

  The 3-methylglutaconic aciduria (3-MGA-uria) syndromes comprise a heterogeneous group of inborn errors of metabolism defined biochemically by detectable elevation of 3-methylglutaconic acid (3-MGA) in the urine. In type 1 (or primary) 3-MGA-uria, distal defects in the leucine catabolism pathway directly cause this elevation. Secondary 3-MGA-uria syndromes, however, are unrelated to leucine metabolism-specific defects but share a common biochemical phenotype of elevated 3-MGA. It is currently thought that this accumulation is due to an underlying buildup of acetyl-CoA in the mitochondria from impaired function of the TCA cycle with ensuing formation of trans-3-methylglutaconyl CoA and its subsequent byproducts, including 3-MGA. In these disorders, urine 3-MGA levels are known to be fluctuant and at times undetectable by standard urine organic acid analysis (UOA), thereby reducing the utility of this biochemical screening method. Here, we retrospectively evaluated a cohort of nine patients with confirmed 3-MGA-uria syndromes. It was observed that UOA analysis obtained from three separate patients did not identify detectable 3-MGA levels. This inherent limitation highlights the need for a more sensitive clinical modality. Untargeted metabolomics profiling is a rapidly emerging technology that is being used to detect and characterize biochemical abnormalities in many inborn errors of metabolism. Untargeted metabolomics profiling performed on plasma samples in this cohort identified significant elevations of 3-MGA in all nine individuals. This high degree of clinical sensitivity demonstrates the promising potential for untargeted metabolomics analysis as both an effective biochemical screening tool for 3-MGA-uria syndromes and a functional method to assist with validation of genomic variants of uncertain significance in these disorders.

Keywords:  3-methylglutaconic aciduria; Mitochondrial disorders; Untargeted metabolomics

DOI:  https://doi.org/10.1016/j.ymgme.2024.109009
Int J Mol Sci. 2024 Dec 12. pii: 13329. [Epub ahead of print]25(24):

TRAPPopathies: Severe Multisystem Disorders Caused by Variants in Genes of the Transport Protein Particle (TRAPP) Complexes.

Riley Hall, Vallari Sawant, Jinchao Gu, Tim Sikora, Ben Rollo, Silvia Velasco, Jinkuk Kim, Nava Segev, John Christodoulou, Nicole J Van Bergen.

  The TRAPP (TRAnsport Protein Particle) protein complex is a multi-subunit complex involved in vesicular transport between intracellular compartments. The TRAPP complex plays an important role in endoplasmic reticulum-to-Golgi and Golgi-to-plasma membrane transport, as well as autophagy. TRAPP complexes comprise a core complex, TRAPPI, and the association of peripheral protein subunits to make two complexes, known as TRAPPII and TRAPPIII, which act as Guanine Nucleotide Exchange Factors (GEFs) of Rab11 and Rab1, respectively. Rab1 and Rab11 are GTPases that mediate cargo selection, packaging, and delivery during pre- and post-Golgi transport in the secretory pathway. Rab1 is also required for the first step of macroautophagy, a cellular recycling pathway. Pathogenic variants in genes encoding protein subunits of the TRAPP complex are associated with a range of rare but severe neurological, skeletal, and muscular disorders, collectively called TRAPPopathies. Disease-causing variants have been identified in multiple subunits of the TRAPP complex; however, little is known about the underlying disease mechanisms. In this review, we will provide an overview of the current knowledge surrounding disease-associated variants of the TRAPP complex subunits, propose new insights into the underlying disease pathology, and suggest future research directions into the underlying disease mechanisms.

Keywords:  Rab GTPase; TRAPP complex; autophagy; human genetics; intracellular trafficking; neurological disease; pediatrics

DOI:  https://doi.org/10.3390/ijms252413329
PLoS Genet. 2025 Jan;21(1): e1011507

Genetic gradual reduction of OGT activity unveils the essential role of O-GlcNAc in the mouse embryo.

Sara Formichetti, Agnieszka Sadowska, Michela Ascolani, Julia Hansen, Kerstin Ganter, Christophe Lancrin, Neil Humphreys, Mathieu Boulard.

The reversible glycosylation of nuclear and cytoplasmic proteins (O-GlcNAcylation) is catalyzed by a single enzyme, namely O-GlcNAc transferase (OGT). The mammalian Ogt gene is X-linked, and it is essential for embryonic development and for the viability of proliferating cells. We perturbed OGT's function in vivo by creating a murine allelic series of four single amino acid substitutions, reducing OGT's catalytic activity to a range of degrees. The severity of the embryonic lethality was proportional to the extent of impairment of OGT's catalysis, demonstrating that the O-GlcNAc modification itself is required for early development. We identified hypomorphic Ogt alleles that perturb O-GlcNAc homeostasis while being compatible with embryogenesis. The analysis of the transcriptomes of the mutant embryos at different developmental stages suggested a sexually-dimorphic developmental delay caused by the decrease in O-GlcNAc. Furthermore, a mild reduction of OGT's enzymatic activity was sufficient to loosen the silencing of endogenous retroviruses in vivo.

DOI: https://doi.org/10.1371/journal.pgen.1011507