Mice with mono-allelic p.R37H Dhdds variant show aberrant glycosylation and interneuron deficits
Year: 2025
Type: preprint
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, Dhdds R37H+/- strain, heterozygous for the human recurrent de novo c.110G>A:p.R37H pathogenic variant. Dhdds R37H+/- 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 Dhdds R37H+/- 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.
Authors: Afitz Da Silva, Merrick S. Fallah, Samuel Boris Tene Tadoum, Mehrnaz Fazeli, Irena J.J. Muffels, Siyan Wang, Francois 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, Tamas Kozicz, Pierre Thibault, Domenico Garozzo, Akilesh Pandey, Eva Morava, Elsa Rossignol, Alexey V. Pshezhetsky
Institutions: Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Icahn School of Medicine at Mount Sinai, McGill University, Tel Aviv University, Tel Aviv Sourasky Medical Center, Institute for Research in Immunology and Cancer, Alfred I. duPont Hospital for Children, University of Oxford, Mayo Clinic
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Award: G8409787642
OpenAlex ID: W4413390030