<i>De novo MAP2K4</i> variants cause a novel neurodevelopmental syndrome with impaired JNK signaling in iPSC-derived neurons

<i>MAP2K4</i> 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 ten individuals with <i>de novo</i> or presumed <i>de novo MAP2K4</i> variants who present with a novel 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 iPSC-derived neurons with MAP2K4 deficiency. These neurons showed reduced JNK pathway activation and abnormal differentiation, characterized by persistence of progenitor-like cells and disrupted neurite morphology. Our findings establish <i>MAP2K4</i> as a Mendelian neurodevelopmental disorder 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.

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Publication Details

Journal
medRxiv
Published
2025-12-27
DOI
https://doi.org/10.64898/2025.12.23.25342932
Primary Topic
Melanoma and MAPK Pathways
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Lydia von Wintzingerode, Lívia Sertori Finoti, Rajesh Angireddy, Amanda J. Peterson et al.
medRxiv
Melanoma and MAPK Pathways
article

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

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

Abstract

<i>MAP2K4</i> 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 ten individuals with <i>de novo</i> or presumed <i>de novo MAP2K4</i> variants who present with a novel 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 iPSC-derived neurons with MAP2K4 deficiency. These neurons showed reduced JNK pathway activation and abnormal differentiation, characterized by persistence of progenitor-like cells and disrupted neurite morphology. Our findings establish <i>MAP2K4</i> as a Mendelian neurodevelopmental disorder 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.

medRxiv
Hôpital Necker-Enfants Malades (FR), University of Udine (IT), Royal Children's Hospital (AU), Children's Hospital of Philadelphia (US), Children's National (US), Radboud University Nijmegen (NL), Oregon Health & Science University (US), Heidelberg University (DE), IRCCS Materno Infantile Burlo Garofolo (IT), University Hospital Heidelberg (DE), UNSW Sydney (AU), Seattle Children's Hospital (US), Ospedale Santa Maria della Misericordia di Udine (IT), Hôpital des Enfants (FR), University of Pennsylvania (US), Neuroscience Research Australia (AU), Heidelberg University (US), Vanderbilt University Medical Center (US), Leipzig University (DE)
National Institutes of Health
Openalex Percentile: Top 36%
Melanoma and MAPK Pathways
DOIOpen Access PDFOpenAlex
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