Pathological disruption of CELF2 shuttling causes neuronal hyperactivity, learning deficits, and seizures.

Fiche publication

Date publication

juin 2026

Journal

The Journal of clinical investigation

Auteurs

Membres identifiés du Cancéropôle Est :
Pr PHILIPPE Christophe

Tous les auteurs :
Hua M, Aghanoori MR, MacPherson MJ, Ren Y, Siripala SV, Yang Y, Or YYY, Nguyen M, Duba-Kiss R, Feng D, Williams L, Gafuik CJ, Wang G, Quelin C, Keren B, Schuhmann S, Vasileiou G, Bourgois A, Vitobello A, Philippe C, Stark Z, Leventer RJ, McGillivray G, Tran Mau-Them F, Tessarech M, Prouteau C, Lakeman P, Motazacker MM, Latner DR, Caylor RC, van Ierland Y, Prijoles E, Lichty A, Theodorou E, Sweetser DA, Steel E, Cobben J, Dasouki MJ, Calame DG, Isidor B, Cogné B, Kesler M, Rackel B, Clark I, Kurrasch DM, Teskey GC, Ellis J, He G, Ryan SD, Mahoney DJ, Innes AM, Epp JR, Yang G

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/42275152

Résumé

De novo heterozygous variants in CELF2 have recently been associated with a rare neurodevelopmental disorder, yet the mechanisms linking specific variants to distinct clinical phenotypes remain poorly understood. Here, we reported a cohort of 18 individuals and provided evidence that variants causing CELF2 mislocalization, but not protein-null variants, were associated with seizures. Using proband-derived human cortical neurons and transgenic mouse models, we demonstrated that CELF2 underwent activity-dependent nucleocytoplasmic shuttling in excitatory neurons and that its cytoplasmic retention caused neuronal hyperactivity, elevated seizure susceptibility, and learning and memory deficits. We further found that cytoplasmic CELF2 regulated mRNAs critical for synaptic function and neuronal excitability and implicated in epileptic seizures and intellectual disability. Drug screening further identified AKT signaling as a key regulator of CELF2 nucleocytoplasmic shuttling and a candidate target for reversing neuronal hyperactivity. Together, our findings expand the clinical and genetic spectrum of CELF2-related neurodevelopmental disorders and establish a variant-specific mechanism that links CELF2 mislocalization to neuronal hyperactivity, seizures, and cognitive impairment.