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

ABSTRACT: 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:C>G, c.-429C>G, rs730882054:c.1134_144del(CGGCGGCGCGG), p.(G380Rfs*144) and rs35717904:A>T, c.*734A>T) and decreased (rs185790394: C>T, c.-244C>T and rs79691946:C>T, 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:C>T, c.*454C>T). Bioinformatics and functional analyses provided novel information on three of these variants. c.-429C>G potentially disrupts a consensus sequence for a terminal oligopyrimidine tract, whereas c.-244C>T 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.

SUBMITTER: Medina-Trillo C

PROVIDER: S-EPMC4930079 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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

Medina-Trillo Cristina C Aroca-Aguilar José-Daniel JD Méndez-Hernández Carmen-Dora CD Morales Laura L García-Antón Maite M García-Feijoo Julián J Escribano Julio J

European journal of human genetics : EJHG 20150729 5

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 ...[more]

PMID: 26220699

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Project description:ImportanceBoth primary and secondary forms of childhood glaucoma have many distinct causative mechanisms, and in many cases a cause is not immediately clear. The broad phenotypic spectrum of secondary glaucoma, particularly in individuals with variants in FOXC1 or PITX2 genes associated with Axenfeld-Rieger syndrome, makes it more difficult to diagnose patients with milder phenotypes. These cases are occasionally classified and managed as primary congenital glaucoma.ObjectiveTo investigate the prevalence of FOXC1 variants in participants with a suspected diagnosis of primary congenital glaucoma.Design, setting, and participantsAustralian and Italian cohorts were recruited from January 1, 2007, through March 1, 2016. Australian individuals were recruited through the Australian and New Zealand Registry of Advanced Glaucoma and Italian individuals through the Genetic and Ophthalmology Unit of l'Azienda Socio-Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda in Milan, Italy. We performed exome sequencing, in combination with Sanger sequencing and multiplex ligation-dependent probe amplification, to detect variants of FOXC1 in individuals with a suspected diagnosis of primary congenital glaucoma established by their treating specialist. Data analysis was completed from June 2015 to November 2017.Main outcome and measuresIdentification of single-nucleotide and copy number variants in FOXC1, along with phenotypic characterization of the individuals who carried them.ResultsA total of 131 individuals with a suspected diagnosis of primary congenital glaucoma were included. The mean (SD) age at recruitment in the Australian cohort was 24.3 (18.1) years; 37 of 84 Australian participants (44.0%) were female, and 71 of 84 (84.5%) were of European ancestry. The mean (SD) age at recruitment was 22.5 (18.4) years in the Italian cohort; 21 of 47 Italian participants (44.7%) were female, and 45 of 47 (95.7%) were of European ancestry. We observed rare, predicted deleterious FOXC1 variants in 8 of 131 participants (6.1%), or 8 of 166 participants (4.8%) when including those explained by variants in CYP1B1. On reexamination or reinvestigation, all of these individuals had at least 1 detectable ocular and/or systemic feature associated with Axenfeld-Rieger syndrome.Conclusions and relevanceThese data highlight the genetic and phenotypic heterogeneity of childhood glaucoma and support the use of gene panels incorporating FOXC1 as a diagnostic aid, especially because clinical features of Axenfeld-Rieger syndrome can be subtle. Further replication of these results will be needed to support the future use of such panels.

Project description:Congenital glaucoma (CG) is a severe and inherited childhood optical neuropathy that leads to irreversible visual loss and blindness in children. CG pathogenesis remains largely unexplained in most patients. Herein we have extended our previous studies to evaluate the role of FOXC2 and PITX2 variants in CG. Variants of the proximal promoter and transcribed sequence of these two genes were analyzed by Sanger sequencing in a cohort of 133 CG families. To investigate possible oligogenic inheritance involving FOXC2 or PITX2 and CYP1B1, we also analyzed FOXC2 and PITX2 variants in a group of 25 CG cases who were known to carry CYP1B1 glaucoma-associated genotypes. The functional effect of three identified variants was assessed by transactivation luciferase reporter assays, protein stability and subcellular localization analyses. We found eight probands (6.0%) who carried four rare FOXC2 variants in the heterozygous state. In addition, we found an elevated frequency (8%) of heterozygous and rare PITX2 variants in the group of CG cases who were known to carry CYP1B1 glaucoma-associated genotypes, and one of these PITX2 variants arose de novo. To the best of our knowledge, two of the identified variants (FOXC2: c.1183C>A, p.(H395N); and PITX2: c.535C>A, p.(P179T)) have not been previously identified. Examination of the genotype-phenotype correlation in this group suggests that the presence of the infrequent PITX2 variants increase the severity of the phenotype. Transactivation reporter analyses showed partial functional alteration of three identified amino acid substitutions (FOXC2: p.(C498R) and p.(H395N); PITX2: p.(P179T)). In summary, the increased frequency in PCG patients of rare FOXC2 and PITX2 variants with mild functional alterations, suggests they play a role as putative modifier factors in this disease further supporting that CG is not a simple monogenic disease and provides novel insights into the complex pathological mechanisms that underlie CG.

Dataset Information

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

Publications

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

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