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Disruption of foxc1 genes in zebrafish results in dosage-dependent phenotypes overlapping Axenfeld-Rieger syndrome.

ABSTRACT: The Forkhead Box C1 (FOXC1) gene encodes a forkhead/winged helix transcription factor involved in embryonic development. Mutations in this gene cause dysgenesis of the anterior segment of the eye, most commonly Axenfeld-Rieger syndrome (ARS), often with other systemic features. The developmental mechanisms and pathways regulated by FOXC1 remain largely unknown. There are two conserved orthologs of FOXC1 in zebrafish, foxc1a and foxc1b. To further examine the role of FOXC1 in vertebrates, we generated foxc1a and foxc1b single knockout zebrafish lines and bred them to obtain various allelic combinations. Three genotypes demonstrated visible phenotypes: foxc1a-/- single homozygous and foxc1-/- double knockout homozygous embryos presented with similar characteristics comprised of severe global vascular defects and early lethality, as well as microphthalmia, periocular edema and absence of the anterior chamber of the eye; additionally, fish with heterozygous loss of foxc1a combined with homozygosity for foxc1b (foxc1a+/-;foxc1b-/-) demonstrated craniofacial defects, heart anomalies and scoliosis. All other single and combined genotypes appeared normal. Analysis of foxc1 expression detected a significant increase in foxc1a levels in homozygous and heterozygous mutant eyes, suggesting a mechanism for foxc1a upregulation when its function is compromised; interestingly, the expression of another ARS-associated gene, pitx2, was responsive to the estimated level of wild-type Foxc1a, indicating a possible role for this protein in the regulation of pitx2 expression. Altogether, our results support a conserved role for foxc1 in the formation of many organs, consistent with the features observed in human patients, and highlight the importance of correct FOXC1/foxc1 dosage for vertebrate development.

SUBMITTER: Ferre-Fernandez JJ

PROVIDER: S-EPMC7530528 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:The surgical management of glaucoma associated with Axenfeld-Rieger Syndrome (ARS) is poorly described in the literature. The goal of this study is to compare the effectiveness of various glaucoma surgeries on intraocular pressure (IOP) management in ARS. METHODS:Retrospective cohort study at a university hospital-based practice of patients diagnosed with ARS between 1973 and 2018. Exclusion criterion was follow-up less than 1?year. The number of eyes with glaucoma (IOP???21?mmHg with corneal edema, Haabs striae, optic nerve cupping or buphthalmos) requiring surgery was determined. The success and survival rates of goniotomy, trabeculotomy±trabeculectomy (no antifibrotics), cycloablation, trabeculectomy with anti-fibrotics, and glaucoma drainage device placement were assessed. Success was defined as IOP of 5-20?mmHg and no additional IOP-lowering surgery or visually devastating complications. Kaplan-Meier survival curves and the Wilcoxon test were used for statistical analysis. RESULTS:In 32 patients identified with ARS (median age at presentation 6.9?years, 0-58.7?years; median follow-up 5.4?years, 1.1-43.7?years), 23 (71.9%) patients were diagnosed with glaucoma at median age 6.3?years (0-57.9?years). In glaucomatous eyes (46 eyes), mean IOP at presentation was 21.8?±?9.3?mmHg (median 20?mmHg, 4-45?mmHg) on 1.0?±?1.6 glaucoma medications. Thirty-one eyes of 18 patients required glaucoma surgery with 2.2?±?1.2 IOP-lowering surgeries per eye. Goniotomy (6 eyes) showed 43% success with 4.3?±?3.9?years of IOP control. Trabeculotomy±trabeculectomy (6 eyes) had 17% success rate with 14.8?±?12.7?years of IOP control. Trabeculectomy with anti-fibrotics (14 eyes) showed 57% success with 16.5?±?13.5?years of IOP control. Ahmed© (FP7 or FP8) valve placement (8 eyes) had 25% success rate with 1.7?±?1.9?years of IOP control. Baerveldt© (250 or 350) device placement (8 eyes) showed 70% success with 1.9?±?2.3?years of IOP control. Cycloablation (4 eyes) had 33% success rate with 2.7?±?3.5?years of IOP control. At final follow-up, mean IOP (12.6?±?3.8?mmHg, median 11.8?mmHg, 7-19?mmHg) in glaucomatous eyes was significantly decreased (p?<?0.0001), but there was no difference in number of glaucoma medications (1.6?±?1.5, p?=?0.1). CONCLUSIONS:In our series, greater than 70% of patients with ARS have secondary glaucoma that often requires multiple surgeries. Trabeculectomy with anti-fibrotics and Baerveldt glaucoma drainage devices showed the greatest success in obtaining IOP control.

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Disruption of foxc1 genes in zebrafish results in dosage-dependent phenotypes overlapping Axenfeld-Rieger syndrome.

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