bims-meglyc 2025-03-09 papers

Issue of 2025–03–09
four papers selected by
Silvia Radenkovic, UMC Utrecht

J Neuromuscul Dis. 2025 Mar 04. 22143602251314767

Recent advances in the clinical spectrum and pathomechanisms associated with X-linked myopathy with excessive autophagy and other VMA21-related disorders.

Ilaria Cocchiararo, Perrine Castets.

X-linked myopathy with excessive autophagy (XMEA) is a rare neuromuscular disorder caused by mutations in the VMA21 gene, encoding a chaperone protein present in the endoplasmic reticulum (ER). In yeast and human, VMA21 has been shown to chaperone the assembly of the vacuolar (v)-ATPase proton pump required for the acidification of lysosomes and other organelles. In line with this, VMA21 deficiency in XMEA impairs autophagic degradation steps, which would be key in XMEA pathogenesis. Recent years have witnessed a surge of interest in VMA21, with the identification of novel mutations causing a congenital disorder of glycosylation (CDG) with liver affection, and its potent implication in cancer predisposition. With this, VMA21 deficiency has been further linked to defective glycosylation, lipid metabolism dysregulation and ER stress. Moreover, the identification of two VMA21 isoforms, namely VMA21-101 and VMA21-120, has opened novel avenues regarding the pathomechanisms leading to XMEA and VMA21-CDG. In this review, we discuss recent advances on the clinical spectrum associated with VMA21 deficiency and on the pathophysiological roles of VMA21.

Keywords: VMA21; X-linked myopathy with excessive autophagy; autophagic vacuolar myopathies

DOI: https://doi.org/10.1177/22143602251314767

Zool Res. 2025 Mar 18. pii: 2095-8137(2025)02-0313-12. [Epub ahead of print]46(2): 313-324

Knockout of the fcsk gene in zebrafish causes neurodevelopmental defects.

Zhen-Xing Liu, Ting-Ting Zou, Hui-Hui Liu, Hai-Bo Jia, Xian-Qin Zhang.

Congenital disorders of glycosylation (CDG) are a cluster of monogenic disorders resulting from defects in glycosylation. FCSK encodes fucokinase, an enzyme that catalyzes the phosphorylation of L-fucose to generate fucose-1-phosphate, an important step in fucosylation. Mutations in FCSK lead to CDG with an autosomal recessive inheritance pattern, primarily manifesting as developmental delay, hypotonia, and brain abnormalities. However, no fcsk mutant animal models have yet been established. This study constructed the first fcsk knockout ( fcsk -/-) zebrafish model using CRISPR/Cas9 technology. Notably, fcsk -/- zebrafish exhibited impaired growth, characterized by delayed epiboly and DNA accumulation during early embryonic development, as well as brain atrophy in adulthood. Larval-stage fcsk -/- zebrafish displayed locomotor deficits and increased susceptibility to pentylenetetrazole-induced seizures. In adulthood, fcsk -/- zebrafish showed neurodevelopmental abnormalities, including increased anxiety, decreased aggression, reduced social preference, and impaired memory. Additionally, total protein fucosylation was markedly reduced in fcsk -/- zebrafish, accompanied by decreased expression of pofut2, which encodes protein O-fucosyltransferase 2, an enzyme involved in the fucosylation salvage pathway. Apoptotic activity was elevated in the midbrain-hindbrain boundary (MHB) of fcsk -/- zebrafish. Supplementation with GDP-L-fucose or the human FCSK gene restored developmental defects and total protein fucosylation in fcsk -/- zebrafish. RNA sequencing revealed dysregulated gene expression associated with glycosylation, apoptosis, and neurodegenerative diseases. These findings suggest that fcsk -/- zebrafish exhibit neurodevelopmental disorders, providing the first fcsk gene knockout animal model and offering a platform for investigating the molecular underpinnings of the disease and facilitating drug screening efforts.

Keywords: Behavior; Congenital disorders of glycosylation; RNA sequencing; Zebrafish; fcsk

DOI: https://doi.org/10.24272/j.issn.2095-8137.2024.229

Mol Genet Metab. 2025 Mar 03. pii: S1096-7192(25)00066-6. [Epub ahead of print]144(4): 109075

Beyond sialylation: Exploring the multifaceted role of GNE in GNE myopathy.

Beatriz L Pereira, Mariana Barbosa, Pedro Granjo, Hanns Lochmüller, Paula A Videira.

Defects in sialic acid metabolism disrupt the sialylation of glycoproteins and glycolipids, contributing to a spectrum of diseases, including GNE myopathy (GNEM). This rare disorder is caused by mutations in the GNE gene that encodes for a bifunctional enzyme required for sialic acid biosynthesis, resulting in progressive muscle atrophy and weakness. There is no approved treatment for GNEM, and the number of affected individuals is underestimated. Although hyposialylation is considered the hallmark of GNEM, evidence showed lack of consistent correlation with GNEM severity and unveiled additional roles of GNE that contribute to the onset and/or progression of GNEM. Recent findings indicate that these mechanisms extend beyond glycosylation, encompassing cytoskeletal dynamics, oxidative stress, and muscle regeneration pathways. Understanding how GNE mutations result in a cascade of cellular and molecular dysregulations is crucial for developing targeted therapies aimed at improving the quality of life of patients. This review comprehensively examines GNEM's pathophysiology, clinical presentation, and therapeutic strategies, highlighting key findings on non-canonical GNE functions that account to GNEM clinical outcomes and emerging therapeutic targets. We propose future research directions to explore alternative target pathways that can ultimately support clinical development.

Keywords: Drug target development; GNE myopathy; Metabolic defects; Muscle atrophy; Sialic acid

DOI: https://doi.org/10.1016/j.ymgme.2025.109075

Biochem J. 2025 Mar 05. 482(5): 295-307

Aldose reductase, fructose and fat production in the liver.

Peter Delannoy, Dean R Tolan, Miguel A Lanaspa, Iñigo San Millán, So Young Bae, Richard J Johnson.

There is an increasing interest in the role of fructose as a major driver of non-alcoholic fatty liver disease (NAFLD), and it is linked closely with the intake of sugar. However, there has also been the recognition that fructose can be produced directly from intracellular glucose via the evolutionarily conserved polyol pathway whose access is governed by aldose reductase (AR). The purpose of this article is to review the biochemistry of AR and the role of the polyol pathway in opening fructose metabolism. This article provides a new perspective about AR and the other key enzymes surrounding the decision to divert glucose into the polyol pathway which suggests that the production of endogenous fructose may be of much greater significance than historically viewed. There are important aspects of the regulation of the polyol pathway and its committal step catalyzed by AR, which supports the notion that fructose-uric acid pathway is activated by elevated glucose with the downstream consequence of NAFLD and perhaps other chronic metabolic diseases.

Keywords: aldose reductase; fructose; glucokinase; polyol pathway; sorbitol; warburg

DOI: https://doi.org/10.1042/BCJ20240748