Mice with the mono-allelic p.R37H Dhdds variant show aberrant glycosylation and interneuron deficits

Clicks: 16
ID: 328401
2026
Free PDF
Article Quality & Performance Metrics
Overall Quality
Not rated
Combines reader engagement with the AI quality analysis. This article has not been analysed, so there is no overall score — reader engagement is measured and shown alongside.
AI Quality Assessment
Not analyzed
Readership in this journal
Emerging

Ranked #328 of 455 articles by views in Brain research

Most read Least read

Bar heights use a square-root scale. Only the 120 most-read articles are drawn; the journal has 455 in total.

Mint this article as an NFT
Not yet minted

Create a permanent, verifiable on-chain record of this article on the Scimatic Network. The NFT is held in your Journament account, and you can withdraw it to your own wallet at any time.

5 SUSD one-off · no wallet required
Sign in to mint
Abstract
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.
Reference Key
openalex_W7212272006 Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Afitz Da Silva, Merrick S. Fallah, Samuel Boris Tene Tadoum, Mehrnaz Fazeli, Irena J J Muffels, Siyan Wang, François Grenier, Rohit Budhraja, Luisa Sturiale, Angela Messina, Moshe Giladi, Mahsa Taherzadeh, Éric Bonneil, Shaukat Khan, Danielle te Vruchte, Yojiro Yamanaka, Graziella Di Cristo, Fadi F. Hamdan, Frances M. Platt, Shunji Tomatsu, Yoni Haitin, Tamás Kozicz, Pierre Thibault, Domenico Garozzo, Akhilesh Pandey, Éva Morava, Elsa Rossignol, Alexey V. Pshezhetsky
Are you one of these authors? Claim your profile
Journal Brain research
Year 2026
DOI
10.1093/brain/awag304
URL
https://doi.org/10.1093/brain/awag304
Keywords Keywords not found

Citations

No citations found. To add a citation, contact the admin at info@scimatic.org

Comments

No comments yet. Be the first to comment on this article.