De novo MAP2K4 variants cause a neurodevelopmental syndrome and impaired JNK signaling in iPSC-derived neurons.

Authors

Tomoki T Nomakuchi, Alyssa L Rippert, Sabrina A Santos De León, Elizabeth M Gonzalez, Dong Li, Rajesh Angireddy, Livia Sertori Finoti, Flavio Faletra, Luciana Musante, Rinne Tuula, David J Amor, Lydia von Wintzingerode, Rami Abou Jamra, Samantha R Stover, Jillian G Buchan, Jennifer Hayek, Eyby Leon, Tania Attie-Bitach, Marlene Rio, Genevieve Baujat, Elisabeth Wallach, Amandine Smail, Kerith-Rae Dias, Ulrich Pfeifer, Amanda Peterson, Rebecca C Ahrens-Nicklas, Elizabeth J K Bhoj

Published in

American journal of human genetics. Oct 13, 2026. Epub Oct 13, 2026.

Abstract

MAP2K4 encodes a kinase that activates the c-Jun N-terminal kinase (JNK) pathway, which is essential for human neurodevelopment. While somatic MAP2K4 loss has been observed in cancer, germline variants have not previously been linked to human disease. We describe nine individuals with de novo MAP2K4 variants and one individual with a MAP2K4 variant of unknown inheritance who present with a syndromic neurodevelopmental disorder. Shared features include developmental delay or intellectual disability, epilepsy, and variable congenital malformations, most commonly affecting the genitourinary system. To define the mechanism, we generated CRISPR-edited induced pluripotent stem cell (iPSC)-derived neurons with MAP2K4 deficiency. These neurons showed reduced JNK pathway activation and impaired maturation in the neurogenin 2 (NGN2) system, characterized by persistence of progenitor-like cells and disrupted neurite morphology. Our findings establish MAP2K4 as a Mendelian neurodevelopmental disorder-associated gene and identify impaired JNK signaling as the underlying mechanism. More broadly, this work expands the spectrum of JNK pathway disorders and underscores the critical role of JNK signaling in human brain development.

PMID:
42869028
Bibliographic data and abstract were imported from PubMed on 14 Oct 2026.

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