Mutations of P4HA2 encoding prolyl 4-hydroxylase 2 are associated with nonsyndromic high myopia

Guo, Hui; Tong, Ping; Liu, Yanling; Lu, Xia; Wang, Tianyun; Tian, Qi; Liu, Ying; Hu, Yuantai; Zheng, Yu; Jin, Xuemin; Li, Yunping; Wang, Xiong; Tang, Beisha; Feng, Yong; Li, Jia‐Da; Pan, Qian; Hu, Zhengmao; Xia, Kun

doi:10.1038/gim.2015.28

Cited by 65 publications

(58 citation statements)

References 24 publications

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“…Interestingly, HM occurs concomitantly in IRD patients with GRM6 or CACNA1F mutations (32,62). Our findings are consistent with a previous study showing that 23.8% (71/298) of patients with EOHM actually harbor mutations in IRD genes (38).…”

Section: Discussionsupporting

confidence: 82%

“…Population-based epidemiological investigations found that the disease is associated with environmental risk factors, such as a close reading distance and less outdoor activity (8,9). With the advent of nextgeneration sequencing, a few of disease genes have been discovered in recent years (18)(19)(20)(21)(22)(23)(24). Because myopia is dependent on both genetics and lifestyle and preschool children have less exposure to environmental risks, we designed this study using a special cohort with EOHM.…”

Section: Discussionmentioning

confidence: 99%

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Trio-based exome sequencing arrests de novo mutations in early-onset high myopia

Jin

Huang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The etiology of the highly myopic condition has been unclear for decades. We investigated the genetic contributions to early-onset high myopia (EOHM), which is defined as having a refraction of less than or equal to −6 diopters before the age of 6, when children are less likely to be exposed to high educational pressures. Trios (two nonmyopic parents and one child) were examined to uncover pathogenic mutations using whole-exome sequencing. We identified parent-transmitted biallelic mutations or de novo mutations in asyet-unknown or reported genes in 16 probands. Interestingly, an increased rate of de novo mutations was identified in the EOHM patients. Among the newly identified candidate genes, a BSG mutation was identified in one EOHM proband. Expanded screening of 1,040 patients found an additional four mutations in the same gene. Then, we generated Bsg mutant mice to further elucidate the functional impact of this gene and observed typical myopic phenotypes, including an elongated axial length. Using a trio-based exonic screening study in EOHM, we deciphered a prominent role for de novo mutations in EOHM patients without myopic parents. The discovery of a disease gene, BSG, provides insights into myopic development and its etiology, which expands our current understanding of high myopia and might be useful for future treatment and prevention.early-onset high myopia | de novo mutations | BSG | rare inherited mutations

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Trio-based exome sequencing arrests de novo mutations in early-onset high myopia

Jin

Huang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…10,11 In humans, a deficiency of ascorbate leads to scurvy, 12,13 a disease caused by collagen instability. 14 Moreover, nonsyndromic high myopia (which is a leading cause of blindness 15 ) and certain neurological processes 16 could arise in part from low CP4H activity. The complete loss of CP4H activity is lethal to Caenorhabditis elegans 17,18 and mice.…”

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confidence: 99%

Human Collagen Prolyl 4-Hydroxylase Is Activated by Ligands for Its Iron Center

Vasta

Raines

2016

Biochemistry

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Collagen is the most abundant protein in animals. The posttranslational hydroxylation of proline residues in collagen contributes greatly to its conformational stability. Deficient hydroxylation is associated with a variety of disease states, including scurvy. The hydroxylation of proline residues in collagen is catalyzed by an Fe(II)- and α-ketoglutarate-dependent dioxygenase, collagen prolyl 4-hydroxylase (CP4H). CP4H has long been known to suffer oxidative inactivation during catalysis, and the cofactor ascorbate (vitamin C) is required to reactivate the enzyme by reducing its iron center from Fe(III) to Fe(II). Herein, we report on the discovery of the first synthetic activators of CP4H. Specifically, we find that 2,2′-bipyridine-4 carboxylate and 2,2′-bipyridine-5-carboxylate serve as ligands for the iron center in human CP4H that enhance the rate of ascorbate-dependent reactivation. This new mode of CP4H activation is available to other biheteroaryl compounds but does not necessarily extend to other prolyl 4 hydroxylases. As collagen is weakened in many indications, analogous activators of CP4H could have therapeutic benefit.

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“…14,15 Further studies analyzing nonpathogenic myopia (MSE < −1.00 D) in highly aggregated families identified genomic regions likely to be harboring high-risk genetic variants. 16–20 Although several chromosomal regions have been identified in families with strong linkage evidence for causal variants with a large effect on myopia risk, the specific causal genes and specific risk variants have not been identified.…”

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confidence: 99%

Caucasian Families Exhibit Significant Linkage of Myopia to Chromosome 11p

Musolf

Simpson

Moiz

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PurposeMyopia is a common visual disorder caused by eye overgrowth, resulting in blurry vision. It affects one in four Americans, and its prevalence is increasing. The genetic mechanisms that underpin myopia are not completely understood. Here, we use genotype data and linkage analyses to identify high-risk genetic loci that are significantly linked to myopia.MethodsIndividuals from 56 Caucasian families with a history of myopia were genotyped on an exome-based array, and the single nucleotide polymorphism (SNP) data were merged with microsatellite genotype data. Refractive error measures on the samples were converted into binary phenotypes consisting of affected, unaffected, or unknown myopia status. Parametric linkage analyses assuming an autosomal dominant model with 90% penetrance and 10% phenocopy rate were performed.ResultsSingle variant two-point analyses yielded three significantly linked SNPs at 11p14.1 and 11p11.2; a further 45 SNPs at 11p were found to be suggestive. No other chromosome had any significant SNPs or more than seven suggestive linkages. Two of the significant SNPs were located in BBOX1-AS1 and one in the intergenic region between ORA47 and TRIM49B. Collapsed haplotype pattern two-point analysis and multipoint analyses also yielded multiple suggestively linked genes at 11p. Multipoint analysis also identified suggestive evidence of linkage on 20q13.ConclusionsWe identified three genome-wide significant linked variants on 11p for myopia in Caucasians. Although the novel specific signals still need to be replicated, 11p is a promising region that has been identified by other linkage studies with a number of potentially interesting candidate genes. We hope that the identification of these regions on 11p as potential causal regions for myopia will lead to more focus on these regions and maybe possible replication of our specific linkage peaks in other studies. We further plan targeted sequencing on 11p for our most highly linked families to more clearly understand the source of the linkage in this region.

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Mutations of P4HA2 encoding prolyl 4-hydroxylase 2 are associated with nonsyndromic high myopia

Abstract: Conclusion:P4HA2 was identified as a novel causative gene for nonsyndromic high myopia. This study also indicated that the disruption of posttranslational modifications of collagen is an important factor in the pathogenesis of high myopia.

Cited by 65 publications

References 24 publications

Trio-based exome sequencing arrests de novo mutations in early-onset high myopia

Trio-based exome sequencing arrests de novo mutations in early-onset high myopia

Human Collagen Prolyl 4-Hydroxylase Is Activated by Ligands for Its Iron Center

Caucasian Families Exhibit Significant Linkage of Myopia to Chromosome 11p

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