In ectopia lentis observed in MFS, the fibers of the ciliary zonule appeared stretched or ruptured, consistent with a pathogenesis from haploinsufficiency, but in WMS, the problem appears to be aberrant formation of the zonule and the lens.
11,12 Therefore, insights on the composition and formation of the zonule are especially valuable in the context of microfibril disorders. FBN1, FBN2, and FBN3 can form homo- or heterotypic microfibrils.
13–15 Previous studies have indicated that in general, FBN2 and FBN3 are predominantly expressed during embryogenesis, whereas FBN1 dominates in mature tissues.
16–18 In the adult human eye, fibrillin-1 was found in the zonule, ciliary body, the lens capsule and iris, and in both basement membranes of the cornea (i.e., the epithelial Bowman's membrane and endothelial Descemet membrane).
2 Mass spectrometry identified only fibrillin-1 and microfibril-associated glycoprotein 1 (MAGP1) in isolated human and bovine ciliary zonules.
19 Fibrillin-1 and -2 were previously localized in Bowman's membrane of the adult cornea.
20 In rodents, fibrillin-2, MAGP1, ADAMTS10, and latent-transforming growth factor-β binding protein 2 (LTBP2) are present in the ciliary zonule.
13,21,22 Interestingly, mutations in
ADAMTS10 or
LTBP2, both found in association with microfibrils, and
ADAMTS17, cause recessive WMS 1 (OMIM #277600), WMS 3/primary congenital glaucoma (OMIM #613086, #251750, #614819), and Weill-Marchesani-like syndrome (OMIM #613195), respectively.
23–26 In these eyes, ectopia lentis, microspherophakia, and, in the case of mutations in
LTBP2, megalocornea, are present.
23,25,26 Mutations affecting an ADAMTS-like protein, ADAMTSL4, lead to recessive isolated ectopia lentis and ectopia lentis et pupillae (OMIM #225200, #225100).
27–29 Recent analysis of mouse ocular development identified strong developmental expression of
Fbn2 and showed that
Fbn1 knockout mice had a ciliary zonule composed of fibrillin-2 microfibrils.
13,21 Although the role of LTBP2 in the eye is not known, ablation of
Ltbp2 caused a loss of the ciliary zonules in mice.
13,22