Nanophthalmos is a rare genetic disorder in which both eyes are well formed, but have unusually short axial lengths. Extreme hyperopia, from +8 to +25 diopters, occurs because the image-forming cornea and lens are too close to the retina. As adults, nanophthalmos patients often develop major secondary complications, including angle closure glaucoma, macular edema and exudative retinal detachment. During the first funding period of EY013610 we discovered the novel NN02 locus at 11q23.3, and identified null mutations in MFRP as the cause of nanophthalmos (OMIM 609549). MFRP encodes an integral membrane protein expressed at significant levels only in the ciliary body and retinal pigment epithelium (RPE). It is a protein of unknown function that includes four globular domains with homology to non-catalytic elements of the Tolloid proteases, and a single domain homologous to the Wnt-binding portion of the Frizzled receptor. Patients completely lacking MFRP function have axial lengths ranging from 15.4 to 16.3 mm, relative to the population average of 23.5 mm. Lens-corrected visual acuity varies from 20/20 to 20/200, and physiological tests demonstrate that this gene is not essential for the basic function of rods and cones. No neurological or other anomalies are apparent, indicating that the required functions of MFRP are highly eye-specific. The gene does not appear to play the same role in ocular development of the mouse. A mutation in mouse Mfrp causes postnatal photoreceptor degeneration but does not affect ocular size. Out of 28 families, we have identified MFRP null mutations in all 4 recessive families. No mutations were identified in the one family exhibiting dominant inheritance, or in the 23 sporadic patients. For the second funding period we propose to identify severe and hypomorphic mutant alleles of MFRP that exist in the population and to determine their phenotypic effect. We will determine whether common genetic variation in MFRP acts as a quantitative trait in the families of sporadic nanophthalmos patients. We will also determine whether genetic variation in MFRP has the potential to govern axial length and anterior chamber depth in the general population. If we can establish that such genetic variation contributes to human ocular biometry, this would provide an essential basis and rationale for any therapeutic interventions involving the function of this gene.
Nanophthalmos is a rare, inherited form of extreme farsightedness that often progresses to angle closure glaucoma, retinal detachment and blindness. It is one of the best Mendelian models for primary angle closure glaucoma, a major cause of severe visual disability, especially in populations of Indian or Asian descent. The identification of common gene variants of MFRP that alter ocular shape and predispose the eye to angle closure glaucoma promises to further our understanding of the origins of this widespread disease, and to provide a foundation for developing more effective treatment.
