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.
Authors
Martina Riva, Sofia Ferreira, Kotaro Hayashi, Yoann Saillour, Vera P. Medvedeva, Takao Honda, Kanehiro Hayashi, Claire Altersitz, Shahad Albadri, Marion Rosello, Julie Dang, Malo Serafini, Frédéric Causeret, Olivia J. Henry, Charles-Joris Roux, Céline Bellesme, Elena Freri, Dragana Josifova, Elena Parrini, Renzo Guerrini, Filippo Del Bene, Kazunori Nakajima, Nadia Bahi-Buisson, Alessandra Pierani
Figure 7
Pachygyria-associated de novo variants dominantly suppress RELN secretion in animal models and patients.
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)