bims-meglyc 2024-12-22 papers

Issue of 2024–12–22
four papers selected by
Silvia Radenkovic, UMC Utrecht

Neurochem Res. 2024 Dec 14. 50(1): 60

Peng Gao, Haoran Chen, Yangyang Sun, Xin Qian, Tao Sun, Yuhan Fan, Jing Zhang.

The ALG13 gene encodes a subunit of the uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) transferase enzyme, which plays a key role in the N-linked glycosylation pathway. This pathway involves the attachment of carbohydrate structures to asparagine (Asn) residues in proteins within the endoplasmic reticulum, by which N-glycosylated proteins produced participate a wide range of processes such as electrical gradients formation and neurotransmission. Mutations in the ALG13 gene have been identified as a causative factor for congenital disorders of glycosylation (CDG) and have been frequently associated with epilepsy in affected individuals. Several studies have demonstrated a strong correlation between abnormal N-glycosylation due to ALG13 deficiency and the onset of epilepsy. Despite these findings, the precise role of ALG13 in the pathogenesis of epilepsy remains unclear. This review provides a comprehensive overview of the current literature on ALG13-related disorders, with a focus on recent evidence regarding its role in epilepsy development and progression. Future research directions are also proposed to further elucidate the molecular mechanisms underlying this association.

Keywords: ALG13 ; Congenital disorder in glycosylation; Epilepsy; Gene mutation; N-glycosylation

DOI: https://doi.org/10.1007/s11064-024-04300-y

Life Sci Alliance. 2025 Mar;pii: e202403118. [Epub ahead of print]8(3):

Defective glycosylation and ELFN1 binding of mGluR6 congenital stationary night blindness mutants.

Mustansir Pindwarawala, Faiyaz Ak Abid, Jaeeun Lee, Michael L Miller, Juliet S Noppers, Andrew P Rideout, Melina A Agosto.

Synaptic transmission from photoreceptors to ON-bipolar cells (BCs) requires the postsynaptic metabotropic glutamate receptor mGluR6, located at BC dendritic tips. Binding of the neurotransmitter glutamate initiates G protein signaling that regulates the TRPM1 transduction channel. mGluR6 also interacts with presynaptic ELFN adhesion proteins, and these interactions are important for mGluR6 synaptic localization. The mechanisms of mGluR6 trafficking and synaptic targeting remain poorly understood. In this study, we investigated mGluR6 missense mutations from patients with congenital stationary night blindness (CSNB), which is associated with loss of synaptic transmission to ON-BCs. We found that multiple CSNB mutations in the extracellular ligand-binding domain of mGluR6 impart a trafficking defect leading to lack of complex N-glycosylation but efficient plasma membrane insertion, suggesting a Golgi bypass mechanism. These mutants fail to bind ELFN1, consistent with lack of a necessary modification normally acquired in the Golgi. The same mutants were mislocalized in bipolar cells, explaining the loss of function in CSNB. The results reveal a key role of Golgi trafficking in mGluR6 function, and suggest a role of the extracellular domain in Golgi sorting.

DOI: https://doi.org/10.26508/lsa.202403118

Cell Mol Life Sci. 2024 Dec 16. 82(1): 4

Golgi pH elevation due to loss of V-ATPase subunit V0a2 function correlates with tissue-specific glycosylation changes and globozoospermia.

Johannes Kopp, Denise Jahn, Guido Vogt, Anthi Psoma, Edoardo Ratto, Willy Morelle, Nina Stelzer, Ingrid Hausser, Anne Hoffmann, Miguel Rodriguez de Los Santos, Leonard A Koch, Björn Fischer-Zirnsak, Christian Thiel, Wilhelm Palm, David Meierhofer, Geert van den Bogaart, François Foulquier, Andreas Meinhardt, Uwe Kornak.

Loss-of-function variants in ATP6V0A2, encoding the trans Golgi V-ATPase subunit V0a2, cause wrinkly skin syndrome (WSS), a connective tissue disorder with glycosylation defects and aberrant cortical neuron migration. We used knock-out (Atp6v0a2-/-) and knock-in (Atp6v0a2RQ/RQ) mice harboring the R755Q missense mutation selectively abolishing V0a2-mediated proton transport to investigate the WSS pathomechanism. Homozygous mutants from both strains displayed a reduction of growth, dermis thickness, and elastic fiber formation compatible with WSS. A hitherto unrecognized male infertility due to globozoospermia was evident in both mouse lines with impaired Golgi-derived acrosome formation and abolished mucin-type O-glycosylation in spermatids. Atp6v0a2-/- mutants showed enhanced fucosylation and glycosaminoglycan modification, but reduced levels of glycanated decorin and sialylation in skin and/or fibroblasts, which were absent or milder in Atp6v0a2RQ/RQ. Atp6v0a2RQ/RQ mutants displayed more abnormal migration of cortical neurons, correlating with seizures and a reduced O-mannosylation of α-dystroglycan. While anterograde transport within the secretory pathway was similarly delayed in both mutants the brefeldin A-induced retrograde fusion of Golgi membranes with the endoplasmic reticulum was less impaired in Atp6v0a2RQ/RQ. Measurement of the pH in the trans Golgi compartment revealed a shift from 5.80 in wildtype to 6.52 in Atp6v0a2-/- and 6.25 in Atp6v0a2RQ/RQ. Our findings suggest that altered O-glycosylation is more relevant for the WSS pathomechanism than N-glycosylation and leads to a secondary dystroglycanopathy. Most phenotypic and cellular properties correlate with the different degrees of trans Golgi pH elevation in both mutants underlining the fundamental relevance of pH regulation in the secretory pathway.

Keywords: Cutis laxa; Globozoospermia; Glycosylation; Golgi; Neuronal migration; Spermiogenesis; V-ATPase; Vesicular trafficking; pH-regulation

DOI: https://doi.org/10.1007/s00018-024-05506-7

Nutrients. 2024 Nov 30. pii: 4154. [Epub ahead of print]16(23):

Nutritional Management of Patients with Inborn Errors of Metabolism.

María-Luz Couce, Isidro Vitoria.

Inborn errors of metabolism (IEM) are a large group of single-gene disorders resulting from enzyme defects in biochemical and metabolic pathways [...].

DOI: https://doi.org/10.3390/nu16234154