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

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 electroretinograms, 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.eye ͉ genetics ͉ morphology ͉ nanophthalmos

A genome-wide linkage scan in Tunisian families identifies a novel locus for non-syndromic posterior microphthalmia to chromosome 2q37.1

“…High hyperopia and an elevated papillomacular retinal fold are the main findings in such patients (Spitznas et al 1983;Goldblum and Mojon 1999;Khairallah et al 2002;Kim et al 2004). Although most of the instances are sporadic, some families from different genetic backgrounds affected with PM, segregating with an autosomal recessive inheritance, have been identified (Spitznas et al 1983;Khairallah et al 2002;Sundin et al 2005). Mutations in the MFRP gene have been involved in autosomal recessive, non-syndromic and syndromic forms of PM (Sundin et al 2005;AyalaRamirez et al 2006;Crespí et al 2008).…”

The genetic mechanisms of primary angle closure glaucoma

“…72,77 Mutations in MFRP to cause autosomal recessive nanophthalmos, which is characterized by short axial length, a high degree of hyperopia, a high lens-to-eye-volume ratio, as well as a small corneal diameter. 78,79 One function of MTHFR appears to be the remodeling of connective tissue and the extracellular matrix (ECM) of the anterior segment. 76 On the other hand, the combined genotype of two MTHFR polymorphisms (C677T and A1298C) was associated with PACG, but also correlated with high homocysteine serum levels in patients in a Punjabi study.…”

Clinical utility gene card for: Non-Syndromic Microphthalmia Including Next-Generation Sequencing-Based Approaches

“…Autosomalrecessive nanophthalmos 2 (NNO2) has been associated with homozygosity for a nonsense (NM_031433.3: c.523C4T, (p.Gln175Ter)) or frameshift (NM_031433.3: c.1143insC (p. Gly383Ter)) variant, and compound heterozygosity for a frameshift (NM_031433.3: c.498delC (p.Asn167Thrfs)) or a missense (NM_031433.3: c.545 T4C (p.Ile182Thr)) variant in MFRP. 41 Additional complications can develop, including angle-closure glaucoma, cystic oedema and retinal detachment. More recently, two segregating missense variants (NM_015544.2: c.577G4C (p.Ala193Pro); c.587A4C (p.His196Pro)) and a 34 bp heterozygous deletion (NM_015544.2: c.236_263+6del34) in TMEM98 have been described in autosomal-dominant nanophthalmos (NNO4) pedigrees.…”