Dataset Information

Extreme hyperopia is the result of null mutations in MFRP, 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 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.

SUBMITTER: Sundin OH

PROVIDER: S-EPMC1172243 | biostudies-literature | 2005 Jul

REPOSITORIES: biostudies-literature

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

Sundin Olof H OH Leppert Gregory S GS Silva Eduardo D ED Yang Jun-Ming JM Dharmaraj Sharola S Maumenee Irene H IH Santos Luisa Coutinho LC Parsa Cameron F CF Traboulsi Elias I EI Broman Karl W KW Dibernardo Cathy C Sunness Janet S JS Toy Jeffrey J Weinberg Ethan M EM

Proceedings of the National Academy of Sciences of the United States of America 20050623 27

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 f ...[more]

PMID: 15976030

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Project description:PURPOSE: Primary angle closure (PAC) is the early stage of primary angle closure glaucoma (PACG). It is believed that the formation of PAC is regulated by a tissue remodeling pathway. This study investigated the association between gene variants in extracellular matrix metalloprotease-9 (MMP-9), methylenetetrahydrofolate reductase (MTHFR), frizzled-related protein (MFRP), heat shock protein 70 (HSP70), and PAC. METHODS: The study was part of the Jiangsu Eye Study. The sample consisted of 232 subjects with PAC and 306 controls obtained from a population-based prevalence survey conducted in Funing County in Jiangsu Province, China. The single nucleotide polymorphisms (SNPs) included rs17576 and rs3918249 in MMP-9, rs1801133 in MTHFR, rs3814762 in MFRP, and rs1043618 in HSP70. SNP genotyping was performed with a TaqMan MGB probe using the real-time PCR system. RESULTS: Among the five SNPs tested, only MFRP rs3814762 and HSP70 rs1043618 showed a nominal association with PAC. The frequency of the minor T allele of MFRP rs3814762 was higher in the control group than in the PAC group (uncorrected p=0.016 and p=0.027, for alleles and genotypes, respectively) and conferred an odds ratio (OR) of 0.67 in the allelic analysis, indicating a protective role of the SNP in developing PAC. In contrast, the frequency of the CC genotype of HSP70 rs1043618 was higher in the PAC group than in the control group (uncorrected p=0.048 and p=0.022 for the genotypes general model and recessive model, respectively) and conferred an OR of 1.79 in the recessive model, indicating a harmful role in developing PAC. However, the differences did not remain statistically significant after Bonferroni correction. The remaining three SNPs showed no differences in the distribution of the genotypes and allele frequencies between the two groups. CONCLUSIONS: Our study reveals a suggestive association of MFRP and HSP70 with PAC in a Han Chinese population. The results from this population-based survey will serve as the baseline for prospective observation of the role of tissue remodeling pathway in the development of PACG.

Project description:The membrane-type frizzled-related protein (MFRP) gene is selectively expressed in the retinal pigment epithelium and ciliary body, and mutations of this gene cause nanophthalmos. The MFRP gene may not be essential for retinal function but has been hypothesized to play a role in ocular axial length regulation. The involvement of the MFRP gene in moderate to high hyperopic, isolated microphthalmic/anophthalmic, and high myopic patients was tested in two phases: a mutation screening/sequence variant discovery phase and a genetic association study phase.Eleven hyperopic, ten microphthalmic/anophthalmic, and seven non-syndromic high-grade myopic patients of varying ages and 11 control subjects participated in the mutation screening phase. Sixteen primer pairs were designed to amplify the 13 exons of the MFRP gene including intron/exon boundaries. Polymerase chain reactions were performed, and amplified products were sequenced using standard techniques. Normal and affected individual DNA sequences were compared alongside the known reference sequence (UCSC genome browser) for the MFRP gene. The genetic association study included 146 multiplex non-syndromic high-grade myopia families. Seventeen intragenic and flanking single nucleotide polymorphisms (SNPs) were chosen for the MFRP gene and genotyped in the large data set using the Taqman allelic discrimination assay. The family-based association Pedigree Disequilibrium Test (PDT) and GenoPDT were performed.The average spherical refractive error of the hyperopic patient cohort was +4.21 diopters (D; range +2.00 to +9.25 D) and of the myopic patient cohort was -12.36 D (range -8.25 to -14.50 D). A total of 16 SNPs were identified by direct sequencing. No significant association was determined between the 16 MFRP gene SNPs and the moderate to high hyperopia, microphthalmia/anophthalmia affection status, and high myopia. Family based association analysis did not reveal any association between the 17 SNPs genotyped in the larger family data set for any refractive error type.Sequence variants of the MFRP gene do not appear to be associated with either the less severe forms of hyperopia, extreme forms of limited eye growth and development, or high myopia. These results indicate that the MFRP gene may not play a role in regulating ocular axial length in these phenotypes.

Dataset Information

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

Publications

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

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