Biology subjects

Muffels, I. J. J.

Publications and source records attributed to Muffels, I. J. J..

2 recordsLinked to original sources

bioRxiv2025

Mono-allelic p.R37H Dehydrodolichyl Diphosphate Synthase variants lead to protein glycosylation defects, aberrant lipid profiles and interneuron scarcity in a novel mouse model of progressive epileptic encephalopathy.

Developmental delay and seizures with or without movement abnormalities (OMIM 617836) caused by heterozygous pathogenic variants in the DHDDS gene (DHDDS-CDG) is a rare genetic disease that belongs to the progressive encephalopathy spectrum. It results in cognitive delay in affected children, accompanied by myoclonus, seizures, ataxia and tremor, which worsens over time. DHDDS encodes a subunit of a DHDDS/NUS1 cis-prenyltransferase (cis-PTase), a branch point enzyme of the mevalonate pathway essential for N-linked glycosylation. We describe the first mouse model of this disease, DhddsR37H+/-strain, heterozygous for the human recurrent de novo c.110G>A:p.R37H pathogenic variant. DhddsR37H+/- mice present with seizures, myoclonus and memory deficits associated with reduced density or/and maturity of inhibitory interneurons in the cortex. Multiomics analyses of mouse CNS tissues, together with the enzymatic/structural characterization of the R37H DHDDS mutant protein, reveal that the variant produces a catalytically inactive enzyme and results in a brain dolichol deficit, aberrant glycosylation of brain glycoproteins, including those involved in synaptic transmission and major perturbations in the CNS proteome and lipidome. Acetazolamide, a carbonic anhydrase inhibitor clinically approved for treatment of glaucoma, epilepsy, and intracranial hypertension, and successfully used "off-label" to treat genetic movement disorders, reduces seizure susceptibility to pentylenetetrazol in DhddsR37H+/- mice, suggesting potential therapeutic value of using this drug in human DHDDS-CDG patients. Together, our results define cis-PTase as a master regulator of CNS development and function and establish that its monoallelic debilitating variants cause a novel congenital disorder of glycosylation associated with aberrant levels of neuronal proteins and lipids.

neuroscience↗

bioRxiv2025

Predicting disease-overarching therapeutic approaches for Congenital Disorders of Glycosylation using multi-OMICS

BackgroundCongenital Disorders of Glycosylation (CDG) are a rapidly expanding group of inherited metabolic diseases caused by defects in glycosylation. Although over 190 genetic defects have been identified, effective treatments remain available for only a few. We hypothesized that integrative analysis of multi-omics datasets from individuals with various CDG could uncover common molecular signatures and highlight shared therapeutic targets. MethodsWe compiled all publicly available RNA sequencing, proteomics and glycoproteomics datasets from patients with PMM2-CDG, ALG1-CDG, SRD5A3-CDG, NGLY1-CDDG, ALG13-CDG and PGM1-CDG, spanning different tissues, including induced cardiomyocytes, human cortical organoids, fibroblasts, and lymphoblasts. Differential expression and glycosylation analyses were performed, followed by Gene Set Enrichment Analysis (GSEA) to identify commonly dysregulated pathways. We then applied the EMUDRA drug prediction algorithm to prioritize candidate compounds capable of reversing these shared molecular signatures. ResultsWe identified four glycoproteins with consistent differential glycosylation across all eight glycoproteomics datasets. Six glycosylation sites and glycan structures were recurrently altered across CDG and showed partial correction with treatment. Pathway analysis revealed shared disruptions in autophagy, vesicle trafficking, and mitochondrial function. EMUDRA predicted several repurposable drug classes, including muscle relaxants, antioxidants, beta-adrenergic agonists, antibiotics, and NSAIDs, that could reverse key pathway abnormalities, particularly those involving autophagy and N-glycosylation. ConclusionMost dysregulated pathways were shared across CDG, suggesting the potential for common therapeutic strategies. Several candidate drugs targeting these shared abnormalities emerged from integrative analysis and warrant validation in future in vitro studies.

genetics↗