Severe retinopathy of prematurity associated with<i>FZD4</i>mutations

Ells, Anna L.; Guernsey, Duane L.; Wallace, Karin; Zheng, Binyou; Vincer, Michael; Allen, Alexander C.; Ingram, April; daSilva, Orlando; Siebert, Lee; Sheidow, Tom G.; Beis, Jill; Robitaille, Johane

doi:10.3109/13816810903479834

Cited by 51 publications

(35 citation statements)

References 31 publications

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“…NDP, FZD4, and LRP5 genetic variants have all been identified in patients with ROP. 98,[99][100][101] These findings suggest that FEVR genes may be implicated in ROP disease; however, several small gene association studies have been carried out which have not supported this hypothesis. [102][103][104][105] Further larger studies are required before any definitive conclusions can be made regarding the association of specific genetic variants and severity of ROP.…”

Section: Retinopathy Of Prematuritymentioning

confidence: 99%

Familial exudative vitreoretinopathy and related retinopathies

Gilmour

2014

Eye

221

175

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Familial exudative vitreoretinopathy (FEVR) is a rare inherited disorder of retinal angiogenesis. Cases can be autosomal dominant, autosomal recessive, or X-linked. FEVR patients have an avascular peripheral retina which, depending on the degree of ischaemia, causes the secondary complications of the disease. Expressivity may be asymmetric and is highly variable. Five genes have been identified that when mutated, cause FEVR; NDP (X-linked), FZD4 (autosomal dominant and recessive), LRP5 (autosomal dominant and recessive), TSPAN12 (autosomal dominant and recessive), and ZNF408 (autosomal dominant). Four of these genes have been shown to have a central role in Norrin/Frizzled4 signalling, suggesting a critical role for this pathway in retinal angiogenesis. In addition to the ocular features, LRP5 mutations can cause osteopenia and osteoporosis. All FEVR patients in whom molecular testing is not easily accessible should have dual energy X-ray absorptiometry (DEXA) scans to assess bone mineral density, as treatment can be initiated to reduce the risk of bone fractures.

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Section: Retinopathy Of Prematuritymentioning

confidence: 99%

Familial exudative vitreoretinopathy and related retinopathies

Gilmour

2014

Eye

221

175

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“…Therefore, the attributes of our population and analyses may have allowed us to better discriminate between risk of severe ROP and that of prematurity compared to previous candidate gene studies. [13][14][15][16][17] Retinopathy of prematurity is included among rare diseases even though it is one of the most common pediatric retinal conditions. Retinopathy of prematurity also has different phenotypes based on resources for prenatal and perinatal care.…”

Section: Discussionmentioning

confidence: 99%

“…Another strength was the inclusion of candidate genes chosen for involvement in the pathomechanisms of biologic features of ROP or with conditions in prematurity associated with ROP, or ones that had been reported in previous candidate gene studies. [11][12][13][14][15][16][17][18][19][20][21] Generally the pathways involved inflammation, oxidation, angiogenesis, and development. Additionally, TagSNPs were chosen to represent the entire variation within a gene and to limit testing of repetitive signals by SNPs in high linkage disequilibrium.…”

Section: Discussionmentioning

confidence: 99%

“…1,2 Retinopathy of prematurity has been associated with environmental factors, including high supplemental oxygen at birth, 3 fluctuations in oxygenation, 4 oxidative stress, 5 and more recently with genetic predisposition based on racial and regional risk profiles [6][7][8][9] and a heritability estimate of 70%. 10 Candidate gene analyses reported ROP associated with gene variants in the WNT signaling pathway (e.g., NDP, FZD4, LRP5), [11][12][13][14][15][16][17] which is important in development; in EPAS1blindness from scarring or retinal detachment if not treated, whereas most ROP is nonsevere and resolves without treatment. In addition, previous candidate gene studies enrolled infants from a broad range of birth weights and gestational ages.…”

Section: Purposementioning

confidence: 99%

“…Previously reported candidate genes [11][12][13][14][15][16][17][18][19][20][21] and additional ones involving pathways in neurodevelopment, inflammation, angiogenesis, or oxidation were included. Tagging single nucleotide polymorphisms (TagSNPs) were chosen for genotyping using HapMap (provided in the public domain at http:// www.hapmap.org/) and the following criteria: minor allele frequency greater than 10%, r 2 value of at least 0.8, and TagSNP tagged for at least six other SNPs.…”

Section: Discovery Cohortmentioning

confidence: 99%

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Genetic Variants Associated With Severe Retinopathy of Prematurity in Extremely Low Birth Weight Infants

Hartnett

Morrison

Smith

et al. 2014

Invest. Ophthalmol. Vis. Sci.

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Citation: Hartnett ME, Morrison MA, Smith S, et al. Genetic variants associated with severe retinopathy of prematurity in extremely low birth weight infants. Invest Ophthalmol Vis Sci. 2014;55:6194-6203. DOI: 10.1167/iovs.14-14841 PURPOSE. To determine genetic variants associated with severe retinopathy of prematurity (ROP) in a candidate gene cohort study of US preterm infants.METHODS. Preterm infants in the discovery cohort were enrolled through the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network, and those in the replication cohort were from the University of Iowa. All infants were phenotyped for ROP severity. Because of differences in the durations of enrollment between cohorts, severe ROP was defined as threshold disease in the discovery cohort and as threshold disease or type 1 ROP in the replication cohort. Whole genome amplified DNA from stored blood spot samples from the Neonatal Research Network biorepository was genotyped using an Illumina GoldenGate platform for candidate gene single nucleotide polymorphisms (SNPs) involving angiogenic, developmental, inflammatory, and oxidative pathways. Three analyses were performed to determine significant epidemiologic variables and SNPs associated with levels of ROP severity. Analyses controlled for multiple comparisons, ancestral eigenvalues, family relatedness, and significant epidemiologic variables. Single nucleotide polymorphisms significantly associated with ROP severity from the discovery cohort were analyzed in the replication cohort and in meta-analysis.RESULTS. Eight hundred seventeen infants in the discovery cohort and 543 in the replication cohort were analyzed. Severe ROP occurred in 126 infants in the discovery and in 14 in the replication cohort. In both cohorts, ventilation days and seizure occurrence were associated with severe ROP. After controlling for significant factors and multiple comparisons, two intronic SNPs in the gene BDNF (rs7934165 and rs2049046, P < 3.1 3 10 À5 ) were associated with severe ROP in the discovery cohort and were not associated with severe ROP in the replication cohort. However, when the cohorts were analyzed together in an exploratory meta-analysis, rs7934165 increased in associated significance with severe ROP (P ¼ 2.9 3 10 À7 ).CONCLUSIONS. Variants in BDNF encoding brain-derived neurotrophic factor were associated with severe ROP in a large candidate gene study of infants with threshold ROP.

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Overview of the mutation spectrum in familial exudative vitreoretinopathy and Norrie disease with identification of 21 novel variants in FZD4, LRP5, and NDP

et al. 2010

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Wnt signaling is a crucial component of the cell machinery orchestrating a series of physiological processes such as cell survival, proliferation, and migration. Among the plethora of roles that Wnt signaling plays, its canonical branch regulates eye organogenesis and angiogenesis. Mutations in the genes encoding the low density lipoprotein receptor protein 5 (LRP5) and frizzled 4 (FZD4), acting as coreceptors for Wnt ligands, cause familial exudative vitreoretinopathy (FEVR). Moreover, mutations in the gene encoding NDP, a ligand for these Wnt receptors, cause Norrie disease and FEVR. Both FEVR and Norrie disease share similar phenotypic characteristics, including abnormal vascularization of the peripheral retina and formation of fibrovascular masses in the eye that can lead to blindness. In this mutation update, we report 21 novel variants for FZD4, LRP5, and NDP, and discuss the putative functional consequences of missense mutations. In addition, we provide a comprehensive overview of all previously published variants in the aforementioned genes and summarize the phenotypic characteristics in mouse models carrying mutations in the orthologous genes. The increasing molecular understanding of Wnt signaling, related to ocular development and blood supply, offers more tools for accurate disease diagnosis that may be important in the development of therapeutic interventions.

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Severe retinopathy of prematurity associated withFZD4mutations

Abstract: Mutations in the FZD4 gene in this group of premature infants supports a role for the FZD4 pathway in the development of severe ROP and accounts for approximately 3% of severe ROP in Caucasian premature infants.

Cited by 51 publications

References 31 publications

Familial exudative vitreoretinopathy and related retinopathies

Familial exudative vitreoretinopathy and related retinopathies

Genetic Variants Associated With Severe Retinopathy of Prematurity in Extremely Low Birth Weight Infants

Overview of the mutation spectrum in familial exudative vitreoretinopathy and Norrie disease with identification of 21 novel variants in FZD4, LRP5, and NDP

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