Figure 2.

Schematic of proposed molecular mechanism of craniosynostosis and ectopia lentis phenotypes associated with ADAMTSL4, FBN1, and the TGFb pathway. (a) ADAMTSL4 is present and FBN1 is intact, TGFb ligand is tethered to fibrillin microfibrils, and the TGFb pathway is inactive. This does not cause a dysmorphic phenotype. (b) ADAMTSL4 is absent, fibrillin microfibrils are disintegrated leading to ectopia lentis, TGFb ligand is inappropriately released from extracellular matrix and binds TGFb receptors, and the TGFb pathway is aberrantly activated resulting in craniosynostosis. (c) ADAMTSL4 is present, but FBN1 is mutated, fibrillin microfibrils are disintegrated, TGFb ligand is inappropriately released from extracellular matrix and binds TGFb receptors, and the TGFb pathway is aberrantly activated resulting in Marfan syndrome with ectopia lentis. (d) ADAMTSL4 is present and fibrillin microfibrils are intact. Activating mutations in TGFb receptors and downstream modulators of the TGFb pathway cause aberrant signaling resulting in syndromic craniosynostosis (LDS/SGS) without ectopia lentis. (created with biorender.com).