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

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Publication Details

Journal
Brain
Published
2026-09-11
DOI
https://doi.org/10.1093/brain/awag304
Primary Topic
Plant biochemistry and biosynthesis
Type
article
Field-Weighted Citation Impact
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article

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

Merrick S. Fallah, Angela Messina, Mahsa Taherzadeh, Rohit Budhraja et al.
Brain
Plant biochemistry and biosynthesis
article

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

Merrick S. Fallah, Angela Messina, Mahsa Taherzadeh, Rohit Budhraja, Akhilesh Pandey, Afitz Da Silva, Domenico Garozzo, François Grenier, Alexey V. Pshezhetsky, Elsa Rossignol, Éric Bonneil, Yojiro Yamanaka, Yoni Haitin, Luisa Sturiale, Tamás Kozicz, Éva Morava, Frances M. Platt, Samuel Boris Tene Tadoum, Siyan Wang, Fadi F. Hamdan, Shaukat Khan, Danielle te Vruchte, Mehrnaz Fazeli, Irena J J Muffels, Shunji Tomatsu, Moshe Giladi, Pierre Thibault, Graziella Di Cristo
article en

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.

Brain
Alfred I. duPont Hospital for Children (US), Mayo Clinic (US), Tel Aviv University (IL), Medical University of Graz (AT), Tel Aviv Sourasky Medical Center (IL), Centre Hospitalier Universitaire Sainte-Justine (CA), University of Oxford (GB), Institute for Research in Immunology and Cancer (CA), McGill Genome Centre (CA), Mayo Clinic in Arizona (US), Mayo Clinic in Florida (US), Institute of Polymers, Composites and Biomaterials (IT), McGill University (CA), Université de Montréal (CA), Icahn School of Medicine at Mount Sinai (US)
Good health and well-being
Openalex Percentile: Top 18%
Plant biochemistry and biosynthesis
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