Genetic Basis of Extreme Hyperopia

Abstract

Purpose: : Nanophthalmos is a rare inherited disorder characterized by extreme axial hyperopia. We have recently identified null mutations in the Membrane–type Frizzled–Related Protein gene (MFRP) at 11q23.3 as the cause of classic non–syndromic nanophthalmos in a large Amish–Mennonite kindred (PNAS 2005; vol 102: 9553–8). Adults with these mutations typically have visual acuity from 20/30 to 20/60, but are at high risk of developing angle closure glaucoma and exudative retinal detachment. Currently, we need to understand when and where human MFRP protein is expressed, and how this is related to the phenotype of nanophthalmos.

Methods: : Standard immunocytochemistry, ultrasound and ocular coherence tomography.

Results: : MFRP protein appears to be abundant on the apical surface of the adult retinal pigment epithelium (RPE) and in underlying vesicles, but absent from the basal surface and from Bruch's membrane. It is also detected in the pigmented layer of the ciliary body, but at much lower levels. It is not significantly expressed outside of the eye. In 14–week human embryos, intense signal for MFRP was observed only in RPE of the posterior third of the globe. We can infer that MFRP expression begins after melanin pigmentation appears, but well before outer segments are produced by the adjacent retinal photoreceptors. We are currently exploring the possibility that MFRP participates in endocytosis.

Conclusions: : The early onset of high level expression suggests a role for MFRP during the eye's embryonic and fetal growth, and is consistent with evidence that the eyes of MFRP–null patients are already very small at birth, and remain so throughout life. Initial results also indicate that MFRP is a membrane–bound protein, and not secreted into the interphotoreceptor matrix. Pronounced localization to the apical face of the RPE suggests that it is involved in interactions between RPE and retina, and argues against a role that requires its contact with components of the basement membrane.

Keywords: genetics • hyperopia • development