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Evaluation of MFRP as a candidate gene for high hyperopia.

ABSTRACT: PURPOSE: Mutations in the membrane-type frizzled-related protein (MFRP) gene have been identified in patients with pathologic high hyperopia associated with nanophthalmos or microphthalmia. This study is to test if a mutation in MFRP is responsible for physiologic high hyperopia. METHODS: DNA was prepared from venous leukocytes of 51 patients with physiologic high hyperopia (refraction of spherical equivalent > or = +5.00 [diopters] D) and 96 controls (refraction of spherical equivalent between -0.50 D and +1.00 D). The coding regions and adjacent intronic sequence of MFRP were amplified by polymerase chain reaction (PCR) and were then analyzed by cycle sequencing. Variations detected were further evaluated in normal controls and available family members by heteroduplex- single-strand conformation polymorphism (SSCP) analysis or sequencing. RESULTS: The average spherical refractive error of patients was +8.41 D in the right eye (from +6.00 D to +16.5 D) and was +8.76 D in the left eye (from +6.00 D to +16.5 D). Five novel heterozygous variations in MFRP, c.55-14_55-13insGTAT, c.496C>G, c.664C>A, c.669G>A, and c.770G>A, were identified. Of these, c.664C>A (p.Pro222Thr) and c.669G>A (p.=) were not observed in the 96 normal controls. In addition, one known c.192C>G substitution and five single nucleotide polymorphisms (SNPs; rs883247, rs3814762, rs36015759, rs2510143, and rs35885438) were detected. CONCLUSIONS: Several novel variations in MFRP were detected in Chinese. Our results imply that MFRP is less likely to play a major role in physiologic high hyperopia.

SUBMITTER: Wang P

PROVIDER: S-EPMC2629737 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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Evaluation of MFRP as a candidate gene for high hyperopia.

Wang Panfeng P Yang Zhikuan Z Li Shiqiang S Xiao Xueshan X Guo Xiangming X Zhang Qingjiong Q

Molecular vision 20090123

<h4>Purpose</h4>Mutations in the membrane-type frizzled-related protein (MFRP) gene have been identified in patients with pathologic high hyperopia associated with nanophthalmos or microphthalmia. This study is to test if a mutation in MFRP is responsible for physiologic high hyperopia.<h4>Methods</h4>DNA was prepared from venous leukocytes of 51 patients with physiologic high hyperopia (refraction of spherical equivalent > or = +5.00 [diopters] D) and 96 controls (refraction of spherical equiva ...[more]

PMID: 19169412

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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.

Project description:ImportanceUncertainty currently exists about whether the same genetic variants are associated with susceptibility to low myopia (LM) and high myopia (HM) and to myopia and hyperopia. Addressing this question is fundamental to understanding the genetics of refractive error and has clinical relevance for genotype-based prediction of children at risk for HM and for identification of new therapeutic targets.ObjectiveTo assess whether a common set of genetic variants are associated with susceptibility to HM, LM, and hyperopia.Design, setting, and participantsThis genetic association study assessed unrelated UK Biobank participants 40 to 69 years of age of European and Asian ancestry. Participants 40 to 69 years of age living in the United Kingdom were recruited from January 1, 2006, to October 31, 2010. Of the total sample of 502 682 participants, 117 279 (23.3%) underwent an ophthalmic assessment. Data analysis was performed from December 12, 2019, to June 23, 2020.ExposuresFour refractive error groups were defined: HM, -6.00 diopters (D) or less; LM, -3.00 to -1.00 D; hyperopia, +2.00 D or greater; and emmetropia, 0.00 to +1.00 D. Four genome-wide association study (GWAS) analyses were performed in participants of European ancestry: (1) HM vs emmetropia, (2) LM vs emmetropia, (3) hyperopia vs emmetropia, and (4) LM vs hyperopia. Polygenic risk scores were generated from GWAS summary statistics, yielding 4 sets of polygenic risk scores. Performance was assessed in independent replication samples of European and Asian ancestry.Main outcomes and measuresOdds ratios (ORs) of polygenic risk scores in replication samples.ResultsA total of 51 841 unrelated individuals of European ancestry and 2165 unrelated individuals of Asian ancestry were assigned to a specific refractive error group and included in our analyses. Polygenic risk scores derived from all 4 GWAS analyses were predictive of all categories of refractive error in both European and Asian replication samples. For example, the polygenic risk score derived from the HM vs emmetropia GWAS was predictive in the European sample of HM vs emmetropia (OR, 1.58; 95% CI, 1.41-1.77; P = 1.54 × 10-15) as well as LM vs emmetropia (OR, 1.15; 95% CI, 1.07-1.23; P = 8.14 × 10-5), hyperopia vs emmetropia (OR, 0.83; 95% CI, 0.77-0.89; P = 4.18 × 10-7), and LM vs hyperopia (OR, 1.45; 95% CI, 1.33-1.59; P = 1.43 × 10-16).Conclusions and relevanceGenetic risk variants were shared across HM, LM, and hyperopia and across European and Asian samples. Individuals with HM inherited a higher number of variants from among the same set of myopia-predisposing alleles and not different risk alleles compared with individuals with LM. These findings suggest that treatment interventions targeting common genetic risk variants associated with refractive error could be effective against both LM and HM.

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Evaluation of MFRP as a candidate gene for high hyperopia.

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Evaluation of MFRP as a candidate gene for high hyperopia.

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