ArticleThe Journal of clinical investigation2024
De novo monoallelic Reelin missense variants cause dominant neuronal migration disorders via a dominant-negative mechanism.
Article in The Journal of clinical investigation, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- Serum soluble PD-L1 predicts hepatocellular carcinoma development across distinct virological cohorts of chronic hepatitis C.Hepatology international · 2026Article
- Multi-omics profiling reveals MAGEL2-driven defects in human corticogenesis shared across Prader-Willi and Schaaf-Yang syndromes.bioRxiv : the preprint server for biology · 2026Article
- Zygosity-Dependent Phenotypic Spectrum ofHuman mutation · 2026Article
- Shared Disease Mechanisms in Neurodevelopmental Disorders: A Cellular and Molecular Biology Perspective.Brain sciences · 2025Review
- Altered Short Non-Coding RNA Landscape in the Hippocampus of a Mouse Model of CDKL5 Deficiency Disorder.Biomolecules · 2025Article
- Regulatory mechanism of Reelin activity: a platform for exploiting Reelin as a therapeutic agent.Frontiers in molecular neuroscience · 2025Review
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Authors and funding
24 authors.
Funding
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Abstract
Reelin (RELN) is a secreted glycoprotein essential for cerebral cortex development. In humans, recessive RELN variants cause cortical and cerebellar malformations, while heterozygous variants were associated with epilepsy, autism, and mild cortical abnormalities. However, the functional effects of RELN variants remain unknown. We identified inherited and de novo RELN missense variants in heterozygous patients with neuronal migration disorders (NMDs) as diverse as pachygyria and polymicrogyria. We investigated in culture and in the developing mouse cerebral cortex how different variants impacted RELN function. Polymicrogyria-associated variants behaved as gain-of-function, showing an enhanced ability to induce neuronal aggregation, while those linked to pachygyria behaved as loss-of-function, leading to defective neuronal aggregation/migration. The pachygyria-associated de novo heterozygous RELN variants acted as dominant-negative by preventing WT RELN secretion in culture, animal models, and patients, thereby causing dominant NMDs. We demonstrated how mutant RELN proteins in vitro and in vivo predict cortical malformation phenotypes, providing valuable insights into the pathogenesis of such disorders.
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