Altered Ocular Fibrillin Microfibril Composition in Mice With a Glaucoma-Causing Mutation of Adamts10

PURPOSE. Previously, we identified a G661R mutation of ADAMTS10 (a disintegrin-like and metalloprotease with thrombospondin type 1 motif 10) as being disease causative in a colony of Beagles with inherited primary open-angle glaucoma (POAG). Mutations in ADAMTS10 are known to cause Weill-Marchesani syndrome (WMS), which is also caused by mutations in the fibrillin-1 gene (FBN1), suggesting functional linkage between ADAMTS10 and fibrillin-1, the principal component of microfibrils. Here, we established a mouse line with the G661R mutation of Adamts10 (Adamts10(G661R/G661R)) to determine if they develop features of WMS and alterations of ocular fibrillin microfibrils. METHODS. Intraocular pressure (IOP) was measured using a TonoLab rebound tonometer. Central cornea thickness (CCT), anterior chamber depth (ACD) and axial length (AL) of the eye were examined by spectral-domain optical coherence tomography. Sagittal eye sections from mice at postnatal day 10 (P10) and at 3 and 24 months of age were stained with antibodies against fibrillin-1, fibrillin-2, and ADAMTS10. RESULTS. IOP was not elevated in Adamts10(G661R/G661R) mice. Adamts10(G661R/G661R) mice had smaller bodies, thicker CCT, and shallower ACD compared to wild-type mice but normal AL. Adamts10(G661R/G661R) mice displayed persistent fibrillin-2 and enhanced fibrillin-1 immunofluorescence in the lens zonules and in the hyaloid vasculature and its remnants in the vitreous. CONCLUSIONS. Adamts10(G661R/G661R) mice recapitulate the short stature and ocular phenotypes of WMS. The altered fibrillin-1 and fibrillin-2 immunoactivity in Adamts10(G661R/G661R) mice suggests that the G661R mutation of Adamts10 perturbs regulation of the fibrillin isotype composition of microfibrils in the mouse eye.

Automated summary

The study demonstrated that Adamts10(G661R/G661R) mice recapitulate the short stature and ocular phenotypes of WMS. The altered fibrillin-1 and fibrillin-2 immunoactivity in the mutant mice suggests that the G661R mutation of Adamts10 perturbs regulation of the fibrillin isotype composition of microfibrils in the mouse eye.