# Molecular mechanisms of anterior segment disorders

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2020 · $385,000

## Abstract

PROJECT SUMMARY
Anterior segment dysgenesis (ASD) phenotypes comprise a group of disorders characterized by structural
abnormalities involving the iris, cornea, iridocorneal angle, and lens, and associated with a high risk of visual
impairment through glaucoma, corneal opacification and other complications. This group of conditions includes
Axenfeld-Rieger anomaly (ARA) and syndrome (ARS), aniridia, Peters anomaly/corneal opacities, and
pediatric glaucoma (even in the absence of visible ASD, believed to be associated with abnormal development
of the outflow tract). We identified mutations in PITX2 as the cause of ARS and then expanded associated
phenotypes to other ASDs; the second ARS gene, FOXC1, was also subsequently shown to explain diverse
ASD phenotypes and a recent study implicates it in POAG in multiple populations. PITX2 and FOXC1 play a
major role in ASD, explaining 40-60% of ARA/ARS with the majority of negative cases remaining unexplained.
For the broader ASD spectrum, the success rate for identifying a genetic diagnosis varies in populations but,
likewise, continues to be incomplete (less than 50%) necessitating the identification of novel mechanisms. The
overall goal of this project is to uncover mechanisms of ASD and associated glaucoma/visual impairment by
investigating diverse aspects of this disease: human phenotype, mechanisms associated with PITX2/FOXC1,
and novel gene discovery through exome/genome human studies and CRISPR-Cas9 editing in zebrafish.
Specifically, we aim: 1) To reveal the full range of ocular anomalies in ‘anterior segment dysgenesis’
disorders. High-resolution imaging in individuals with ASD will investigate the possibility of posterior segment
defects and their contribution to vision loss. This aim will provide new insight into human disease as suggested
by our initial data which identified novel features in two (out of two) ARS patients; 2) To define developmental
roles and pathways of FOXC1 and PITX2 and explore their contribution to human disease. This aim will
identify targets of foxc1 in zebrafish using recently developed lines and explore regulatory elements of this
gene. Our preliminary results from one of the foxc1 regulatory deletion mutants show a strong glaucoma
phenotype, different from the loss-of-function line, and is likely to become the first zebrafish embryonic
glaucoma mutant. The obtained results will be analyzed together with the previously generated pitx2 data to
reveal common pathways. Since our earlier data indicate dysregulation of the WNT pathway as a major
outcome of pitx2 deficiency, its role in the eye phenotype will be further examined; and finally, 3) To discover
novel factors with a role in anterior segment dysgenesis by utilizing exome/genome data from families
affected with ASD and genome editing-based modeling in zebrafish. The identified factors will be evaluated for
their position in known pathways using our previously developed resources. The strength of our application i...

## Key facts

- **NIH application ID:** 9971807
- **Project number:** 2R01EY015518-10A1
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Elena V Semina
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $385,000
- **Award type:** 2
- **Project period:** 2004-12-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9971807

## Citation

> US National Institutes of Health, RePORTER application 9971807, Molecular mechanisms of anterior segment disorders (2R01EY015518-10A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9971807. Licensed CC0.

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