Extreme hyperopia is the result of null mutations in MFRP , which encodes a Frizzled-related protein

doi:10.1073/pnas.0501451102

Extreme hyperopia is the result of null mutations in MFRP, which encodes a Frizzled-related protein

^aLaboratory of Developmental Genetics, ^eJohns Hopkins Clinic for Hereditary Eye Diseases, ^jKrieger Center for Pediatric Ophthalmology, ^mOcular Imaging and Low Vision Clinics, Wilmer Eye Institute, ^bDepartment of Molecular Biology and Genetics, School of Medicine, and ^lDepartment of Biostatistics, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD 21287; ^fDepartment of Ophthalmology, University of Coimbra, 3000-033 Coimbra, Portugal; ⁱInstituto de Oftalmologia Dr. Gama Pinto, 1169-019 Lisbon, Portugal; and ^kCole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH 44195

Edited by Jeremy Nathans, The Johns Hopkins University School of Medicine, Baltimore, MD (received for review February 21, 2005)

Abstract

Nanophthalmos is a rare disorder of eye development characterized by extreme hyperopia (farsightedness), with refractive error in the range of +8.00 to +25.00 diopters. Because the cornea and lens are normal in size and shape, hyperopia occurs because insufficient growth along the visual axis places these lensing components too close to the retina. Nanophthalmic eyes show considerable thickening of both the choroidal vascular bed and scleral coat, which provide nutritive and structural support for the retina. Thickening of these tissues is a general feature of axial hyperopia, whereas the opposite occurs in myopia. We have mapped recessive nanophthalmos to a unique locus at 11q23.3 and identified four independent mutations in MFRP, a gene that is selectively expressed in the eye and encodes a protein with homology to Tolloid proteases and the Wnt-binding domain of the Frizzled transmembrane receptors. This gene is not critical for retinal function, as patients entirely lacking MFRP can still have good refraction-corrected vision, produce clinically normal electro-retinograms, and show only modest anomalies in the dark adaptation of photoreceptors. MFRP appears primarily devoted to regulating axial length of the eye. It remains to be determined whether natural variation in its activity plays a role in common refractive errors.

Footnotes

↵ c To whom correspondence should be addressed. E-mail: osundin{at}jhmi.edu.
↵ d Present address: National Institutes of Health/Foundation for Advanced Education in the Sciences, Bethesda, MD 20814.
↵ g Present address: National Institutes of Health/National Cancer Institute, Bethesda, MD 20892.
↵ h Present address: Massachusetts Eye and Ear Infirmary, Boston, MA 02114.
↵ n Present address: Department of Ophthalmology, Greater Baltimore Medical Center, Towson, MD 21204.
↵ o Present address: Food and Drug Administration, Rockville, MD 20857.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: RPE, retinal pigment epithelium; ERG, electroretinography; MFRP, membrane-type Frizzled-related protein; CRD, cysteine-rich domain; Mb, megabase; RE, right eye.