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

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 GY, 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 (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Book Volume: 136

Journal Issue: 14

DOI: 10.1172/JCI199698

Abstract

De novo heterozygous variants in CUGBP Elav-like family member 2 (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.

Authors with CRIS profile

Involved external institutions

University of Alberta Canada (CA) University of Calgary Canada (CA) L'institut Du Thorax France (FR) University of Toronto Canada (CA) Chongqing Medical University China (CN) Centre hospitalier universitaire (CHU) d'Angers France (FR) Pitié-Salpêtrière University Hospital / Hôpital universitaire Pitié-Salpêtrière France (FR) CHU de Caen Normandie France (FR) Centre hospitalier universitaire (CHU) de Dijon Bourgogne France (FR) Le Centre Hospitalier Régional de Metz-Thionville France (FR) Murdoch Childrens Research Institute Australia (AU) University of Amsterdam Netherlands (NL) HudsonAlpha United States (USA) (US) Greenwood Genetic Center United States (USA) (US) Erasmus University Medical Center (MC) Netherlands (NL) Massachusetts General Hospital United States (USA) (US) Great Ormond Street Hospital (GOSH) United Kingdom (GB) Imperial College London / The Imperial College of Science, Technology and Medicine United Kingdom (GB)

How to cite

APA:

Hua, M., Aghanoori, M.R., MacPherson, M.J., Ren, Y., Siripala, S.V., Yang, Y.,... Yang, G. (2026). Pathological disruption of CELF2 shuttling causes neuronal hyperactivity, learning deficits, and seizures. Journal of Clinical Investigation, 136(14). https://doi.org/10.1172/JCI199698

MLA:

Hua, Michelle, et al. "Pathological disruption of CELF2 shuttling causes neuronal hyperactivity, learning deficits, and seizures." Journal of Clinical Investigation 136.14 (2026).

BibTeX: Download