HEG1 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 HEG1L23LM/L23LM mutation. Recapitulating the mutation in zebrafish and mouse models induced craniosynostosis, cardiac defects, and cognitive deficits. Mechanistically, the HEG1L23LM 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 HEG1L23LM induced FGF2/FGFR2 overexpression in vitro and in vivo. Crucially, SC43 treatment robustly ameliorated craniosynostosis, cardiac phenotypes, and behavioral deficits in Heg1L23LM/L23LM mice and a FGFR2-gain-of-function mouse model R26RFGFR2:Sp7, and rescued abnormal bone development in the zebrafish model. Our findings establish pathogenic HEG1 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.