De novo monoallelic Reelin missense variants cause dominant neuronal migration disorders via a dominant-negative mechanism.
J Clin Invest
; 134(16)2024 Jul 09.
Article
in En
| MEDLINE
| ID: mdl-38980724
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Serine Endopeptidases
/
Cell Adhesion Molecules, Neuronal
/
Cell Movement
/
Extracellular Matrix Proteins
/
Mutation, Missense
/
Reelin Protein
/
Nerve Tissue Proteins
Limits:
Animals
/
Female
/
Humans
/
Male
Language:
En
Journal:
J Clin Invest
Year:
2024
Document type:
Article
Country of publication:
United States