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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:Background:Fibroblast growth factor 10 (FGF10) is implicated in the growth and development of the eye. Four singles nucleotide polymorphisms (SNPs) in the FGF10 gene (including rs1384449, rs339501, rs12517396 and rs10462070) were found to be associated with extreme myopia (EM, refractive error???-?10.0 diopters) in Japanese and Chinese Taiwan population. This case-control association study was conducted to explore the relationship between these four SNPs and high myopia in a western Chinese population. Methods:A total of 869 high myopia patients (HM, including 485 EM patients) and 899 healthy controls were recruited. These four SNPs were genotyped using the ABI SNaPshot method. Five genetic models (allelic, homozygous, heterozygous, dominant, and recessive) were applied to further evaluate the possible correlation between the SNPs and high myopia. The linkage-disequilibrium block (LD) structure was tested by Haploview Software. Results:In our study, no statistically significant differences were found between HM/EM patients and controls after Bonferroni multiple-correction (P?>?0.05) in the allele frequencies of these four SNPs in the FGF10 gene. We further found that rs12517396AA and rs10462070GG carriers showed a decreased risk of HM/EM compared with rs12517396AC?+?CC and rs10462070GA?+?AA carriers (P?=?0.045, OR?=?0.366; P?=?0.021, OR?=?0.131; P?=?0.03, OR?=?0.341; P?=?0.015, OR?=?0.122; respectively). Additionally, rs12517396AA and rs10462070GG carriers showed the same decreased risk of HM/EM compared with rs12517396CC and rs10462070AA carriers (P?=?0.048, OR?=?0.370; P?=?0.023, OR?=?0.133; P?=?0.032, OR?=?0.346; P?=?0.017, OR?=?0.126). However, these significant associations between rs12517396/rs10462070 and HM/EM disappeared after Bonferroni multiple-correction (P?>?0.05). Conclusion:Our findings indicate that rs12517396 and rs10462070 had marginal association with HM and EM. The other two common polymorphisms in FGF10 unlikely have significant effects in the genetic predisposition to HM/EM in western Chinese population. Further replication studies are needed to validate our findings in both animal models and human genetic epidemiologic studies.

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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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