<i>HEG1 </i>mutation causes recessive craniosynostosis alleviated by SC43

Craniosynostosis, the premature fusion of skull sutures, is a devastating developmental disorder predominantly attributed to dominant mutations in growth factor signaling pathways. Here, we identified an autosomal recessive syndrome featuring craniosynostosis, congenital heart defects, and brain atrophy in a human pedigree, segregating with <i>HEG1</i>^L23LM/L23LM mutation. Recapitulating the mutation in zebrafish and mouse models induced craniosynostosis, cardiac defects, and cognitive deficits. Mechanistically, the HEG1^L23LM mutation impaired signal peptide cleavage, disrupting its function as an inhibitory receptor, and diminishing recruitment of the phosphatase PTPN6 via a variant ITIM motif. This dysregulation triggered STAT3 hyperphosphorylation, driving pathogenic FGF2/FGFR2 pathway overactivation. Guided by a Petri net-based mathematical model of this pathway, we administered SC43, a PTPN6 activator, rescued HEG1^L23LM induced FGF2/FGFR2 overexpression <i>in vitro </i>and<i> in vivo</i>. Crucially, SC43 treatment robustly ameliorated craniosynostosis, cardiac phenotypes, and behavioral deficits in <i>Heg1</i>^L23LM/L23LM mice and a <i>FGFR2</i>-gain-of-function mouse model <i>R26R</i>^FGFR2:^<em>Sp7</em>, and rescued abnormal bone development in the zebrafish model<i>.</i> Our findings establish pathogenic <i>HEG1</i> mutations and unveil a HEG1–STAT3–FGF2/FGFR2 axis central to craniosynostosis. The demonstration that SC43 therapeutically targets this pathway opens avenues for pharmacological intervention in craniosynostosis and related disorders.