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.
Afitz Da Silva, Merrick S. Fallah, Samuel Boris Tene Tadoum et al.· Brain : a journal of neurolo...· 0 citations
Mucopolysaccharidosis IVA (MPS IVA) is a lysosomal storage disorder caused by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS), leading to progressive accumulation of keratan sulfate (KS) and chondroitin-6-sulfate (C6S) and resulting in systemic skeletal dysplasia. Severe, early-onset disease is frequently associated with destabilizing structural missense variants, including p.R386C. To model a loss-of-function missense variant associated with severe MPS IVA, we generated a GalnsR384C knock-in mouse, the murine ortholog of the most common human variant, p.R386C. Biochemical, histological, and skeletal phenotypes were evaluated across multiple tissues, and bone microarchitecture was assessed using microcomputed tomography (micro-CT). Genomic and biochemical assays were performed to assess allelic integrity, and principal component analysis (PCA) was used to integrate biochemical and structural parameters. GalnsR384C mice exhibited significantly reduced GALNS activity and elevated KS levels across various tissues. Histological examination revealed considerable vacuolization in cartilage and cardiac valves, while micro-CT illustrated altered bone microarchitecture consistent with disrupted endochondral ossification. During allele validation, a secondary missense variant (p.R384Y) was identified and characterized as a comparative model that led to defective GALNS activity, substrate accumulation, and analogous skeletal and cardiovascular pathology. PCA demonstrated clear differentiation between WT and mutant groups, with considerable multivariate overlap observed between GalnsR384C and GalnsR384Y mice. In conclusion, GalnsR384C and GalnsR384Y mice recapitulate key biochemical, skeletal, and histopathological features of MPS IVA and provide well-characterized murine models of severe GALNS loss-of-function resulting from clinically relevant missense variants. Rigorous genomic validation underscores the importance of careful allele-level characterization during genome-editing-based model generation.
Dione A Holder, B. Çelik, Sampurna Saikia et al.· Journal of Human Genetics· 0 citations
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