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

De novo MAP2K4 variants are linked to a neurodevelopmental syndrome with impaired JNK signaling in iPSC-derived neurons, affecting nine individuals with developmental delays.

• Why it matters: Understanding the genetic basis of neurodevelopmental disorders is crucial, especially for genes like MAP2K4 that activate the JNK pathway, which is vital for brain development. This work addresses the gap in knowledge about germline MAP2K4 variants and their role in human disease.
• What they did: Researchers generated CRISPR-edited iPSC-derived neurons with MAP2K4 deficiency and observed reduced JNK pathway activation, impaired neuronal maturation, persistent progenitor-like cells, and disrupted neurite morphology.
• The result: Findings establish MAP2K4 as a gene associated with a Mendelian neurodevelopmental disorder and highlight impaired JNK signaling as the underlying mechanism, expanding the spectrum of JNK pathway disorders.