Mechanism of Disease: Recessive ADAMTSL4 Mutations and Craniosynostosis with Ectopia Lentis

Abstract

Craniosynostosis, the premature fusion of the calvarial bones, has numerous etiologies. Among them, several involve mutations in genes related to the TGFb signaling pathway, a critical molecular mediator of human development. These TGFb pathway-associated craniosynostosis syndromes include Loeys-Dietz syndrome (LDS) and Shprintzen-Goldberg syndrome (SGS). LDS and SGS have many similarities common to fibrillinopathies, specifically Marfan syndrome (MFS), which is caused by mutations in FBN1. Historically discriminating features of MFS from LDS and SGS are (1) the presence of ectopia lentis (the subluxation/dislocation of the ocular lens) and (2) the absence of craniosynostosis. Curiously, several instances of a seemingly novel syndrome involving only craniosynostosis and ectopia lentis have recently been reported to be caused by recessive mutations in ADAMTSL4, a poorly characterized gene as of yet. Here, we report on two new cases of craniosynostosis with ectopia lentis, each harboring recessive mutations in ADAMTSL4. We also discuss a proposed mechanism for the relationship between ADAMTSL4, FBN1, and TGFb pathway-related syndromes.

Figure 1

Patient 1. (a) Chromatograms (top: paternally inherited c.767_786del, bottom: maternally inherited c.2177 + 3_2177+6delGAGT). Pedigree (blue: c.767_786del, orange: c.2177 + 3_2177 + 6delGAGT, solid star: ectopia lentis with craniosynostosis). Patient 2. (b) Chromatogram (recessively inherited c.767_786del). Pedigree (blue: c.767_786del, solid triangle: ectopia lentis et pupillae with craniosynostosis, open triangle: isolated ectopia lentis et pupillae).

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).