Hypo- and Hypermorphic FOXC1 Mutations in Dominant Glaucoma: Transactivation and Phenotypic Variability

Medina-Trillo, Cristina; Sánchez-Sánchez, Francisco; Aroca-Aguilar, José-Daniel; Ferre-Fernández, Jesús-José; Morales, Laura; Méndez-Hernández, Carmen-Dora; Blanco‐Kelly, Fiona; Ayuso, Carmen; García‐Feijoó, Julián; Escribano, Julio

doi:10.1371/journal.pone.0119272

Cited by 29 publications

(29 citation statements)

References 44 publications

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“…In addition, approximately 5% of the patients in these cohorts carried GPATCH3 rare variants in the heterozygous state. Segregation analysis of these variants failed to reveal a monogenic inheritance, but their elevated frequency among patients and the predicted functional impact for most of them suggest that they are disease-causing variants that may be involved in non-monogenic congenital glaucoma in accordance with our previous findings671219. Also in accordance with this hypothesis, a recent study reported that 10 of 189 unrelated PCG families carried heterozygous rare variants in the TEK gene with dominant transmission and highly variable expressivity, which was explained by stochastic developmental events or oligogenic/digenic inheritance24.…”

Section: Discussionsupporting

confidence: 89%

Whole-Exome Sequencing of Congenital Glaucoma Patients Reveals Hypermorphic Variants in GPATCH3, a New Gene Involved in Ocular and Craniofacial Development

Ferre-Fernández

Aroca-Aguilar

Medina-Trillo

et al. 2017

Sci Rep

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Congenital glaucoma (CG) is a heterogeneous, inherited and severe optical neuropathy that originates from maldevelopment of the anterior segment of the eye. To identify new disease genes, we performed whole-exome sequencing of 26 unrelated CG patients. In one patient we identified two rare, recessive and hypermorphic coding variants in GPATCH3, a gene of unidentified function, and 5% of a second group of 170 unrelated CG patients carried rare variants in this gene. The recombinant GPATCH3 protein activated in vitro the proximal promoter of CXCR4, a gene involved in embryo neural crest cell migration. The GPATCH3 protein was detected in human tissues relevant to glaucoma (e.g., ciliary body). This gene was expressed in the dermis, skeletal muscles, periocular mesenchymal-like cells and corneal endothelium of early zebrafish embryos. Morpholino-mediated knockdown and transient overexpression of gpatch3 led to varying degrees of goniodysgenesis and ocular and craniofacial abnormalities, recapitulating some of the features of zebrafish embryos deficient in the glaucoma-related genes pitx2 and foxc1. In conclusion, our data suggest the existence of high genetic heterogeneity in CG and provide evidence for the role of GPATCH3 in this disease. We also show that GPATCH3 is a new gene involved in ocular and craniofacial development.

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Section: Discussionsupporting

confidence: 89%

Whole-Exome Sequencing of Congenital Glaucoma Patients Reveals Hypermorphic Variants in GPATCH3, a New Gene Involved in Ocular and Craniofacial Development

Ferre-Fernández

Aroca-Aguilar

Medina-Trillo

et al. 2017

Sci Rep

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“…Two of the four FOXC1 carriers had hearing loss and the other two PITX2 carriers had dental and/or umbilical anomalies, none of which had been recorded before the molecular diagnosis. Individuals with variants in FOXC1 or PITX2 but without ocular features of ARS have been reported before, 15,27,28 and in some individuals ARM can be so mild that it results in a clinical diagnosis of PCG or POAG. The variable expressivity associated with FOXC1 and PITX2 variants can make clinical diagnosis of ARS challenging, especially in the absence of ARM.…”

Section: Discussionmentioning

confidence: 88%

Erratum: Glaucoma spectrum and age-related prevalence of individuals with FOXC1 and PITX2 variants

Souzeau¹,

Siggs²,

Zhou³

et al. 2017

Eur J Hum Genet

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Variation in FOXC1 and PITX2 is associated with Axenfeld-Rieger syndrome, characterised by structural defects of the anterior chamber of the eye and a range of systemic features. Approximately half of all affected individuals will develop glaucoma, but the age at diagnosis and the phenotypic spectrum have not been well defined. As phenotypic heterogeneity is common, we aimed to delineate the age-related penetrance and the full phenotypic spectrum of glaucoma in FOXC1 or PITX2 carriers recruited through a national disease registry. All coding exons of FOXC1 and PITX2 were directly sequenced and multiplex ligation-dependent probe amplification was performed to detect copy number variation. The cohort included 53 individuals from 24 families with disease-associated FOXC1 or PITX2 variants, including one individual diagnosed with primary congenital glaucoma and five with primary open-angle glaucoma. The overall prevalence of glaucoma was 58.5% and was similar for both genes (53.3% for FOXC1 vs 60.9% for PITX2, P = 0.59), however, the median age at glaucoma diagnosis was significantly lower in FOXC1 (6.0 ± 13.0 years) compared with PITX2 carriers (18.0 ± 10.6 years, P = 0.04). The penetrance at 10 years old was significantly lower in PITX2 than FOXC1 carriers (13.0% vs 42.9%, P = 0.03) but became comparable at 25 years old (71.4% vs 57.7%, P = 0.38). These findings have important implications for the genetic counselling of families affected by AxenfeldRieger syndrome, and also suggest that FOXC1 and PITX2 contribute to the genetic architecture of primary glaucoma subtypes.

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“…Interestingly, this variant was present in two patients who also had two other hypermorphic variants (c.-429C4G and p.(G380Rfs*144) in families PCG-96 and PCG-54, respectively) (Figure 1b and d), contributing to the overall increase in FOXC1 activity associated with these genotypes. Moreover, we have reported that the p.(G456dup) variant coinherited in one patient along with another hypermorphic FOXC1 variant (p.(Y47*)) seems to anticipate the glaucoma onset, 21 Figure 3 Altered transactivation activity of the FOXC1 variants identified in PCG patients. (a) A scheme of the cDNA construct containing the FOXC1-binding element present in the CXCR4 promoter, fused to luciferase and cloned into the PGL3 basic vector.…”

Section: Discussionmentioning

confidence: 99%

Rare FOXC1 variants in congenital glaucoma: identification of translation regulatory sequences

et al. 2015

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Primary congenital glaucoma (PCG) is the cause of a significant proportion of inherited visual loss in children, but the underlying mechanism is poorly understood. In this study, we assessed the relationship between PCG and FOXC1 variants by Sanger sequencing the proximal promoter and transcribed sequence of FOXC1 from a cohort of 133 PCG families with no known CYP1B1 or MYOC mutations. The pathogenicity of the identified variants was evaluated by functional analyses. Ten patients (7.5%) with no family history of glaucoma carried five different rare heterozygous FOXC1 variants with both increased (rs77888940:C4G, c.-429C4G, rs730882054:c.1134_144del(CGGCGGCGCGG), p.(G380Rfs*144) and rs35717904:A4T, c.*734A4T) and decreased (rs185790394: C4T, c.-244C4T and rs79691946:C4T, p.(P297S)) transactivation, ranging from 50 to 180% of the wild-type activity. The five variants did not show monogenic segregation, and four of them were absent in a control group (n = 233). To the best of our knowledge, one of these variants (p.(G380Rfs*144)) has not previously been described. One of the FOXC1 variant carriers (p.(P297S)) also coinherited a functionally altered rare PITX2 heterozygous variant (rs6533526:C4T, c.*454C4T). Bioinformatics and functional analyses provided novel information on three of these variants. c.-429C4G potentially disrupts a consensus sequence for a terminal oligopyrimidine tract, whereas c.-244C4T may alter the RNA secondary structure in the 5′-untranslated region (UTR) that affects mRNA translation. In addition, p.(G380Rfs*144) led to increased protein stability. In summary, these data reveal the presence of translation regulatory sequences in the UTRs of FOXC1 and provide evidence for a possible role of rare FOXC1 variants as modifying factors of goniodysgenesis in PCG.

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Hypo- and Hypermorphic FOXC1 Mutations in Dominant Glaucoma: Transactivation and Phenotypic Variability

Cited by 29 publications

References 44 publications

Whole-Exome Sequencing of Congenital Glaucoma Patients Reveals Hypermorphic Variants in GPATCH3, a New Gene Involved in Ocular and Craniofacial Development

Whole-Exome Sequencing of Congenital Glaucoma Patients Reveals Hypermorphic Variants in GPATCH3, a New Gene Involved in Ocular and Craniofacial Development

Erratum: Glaucoma spectrum and age-related prevalence of individuals with FOXC1 and PITX2 variants

Rare FOXC1 variants in congenital glaucoma: identification of translation regulatory sequences

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