# Diversity Supplement - Genetic Basis of Congenital Anophthalmia

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2020 · $78,469

## Abstract

PROJECT SUMMARY
Anophthalmia, microphthalmia and coloboma (MAC) are birth defects in which the eyes
are absent or very small, or where the choroid fissure fails to close in the optic cup. Most
cases are sporadic, but Mendelian pedigrees have been described, typically with low
penetrance. Few genes have been identified, encoding transcription and growth factors
(e.g. SOX2, BMP4) active during early eye development. Most cases are unexplained.
Maternal nutrition may contribute to the etiology. We found that mutations in 3 retinoid
(vitamin A) pathway genes (RBP4, STRA6, ALDH1A3) account for >5% of MAC cases,
including a new gain-of-function mechanism for this disease. The RBP4 alleles encode
dominant-negative serum retinol binding proteins, which bind retinol cargo poorly but
adhere to the STRA6 cell surface receptor too tightly (40-fold higher affinity) – so may
disrupt retinol transfer across the yolk sac and placenta, to the embryo. The dnRBP4
mutations define a new mode of maternal inheritance and illuminate a critical protein-
receptor interaction. In addition, clustered STRA6 point mutations suggest a new domain
function for this polytopic receptor. We will investigate the mechanism for increased RBP
affinity and critical features of the RBP-STRA6 interaction, and test the receptor comp-
etition model for MAC pathogenesis [
1
] in vitro and [
2
] in vivo, using a comprehensive
biochemical, cell-based, radioisotopic and histological approach, mouse models with
specific knock-out or genome-edited (CRISPR/Cas9) alleles, and dietary manipulation.
In addition, [ ] we will systematically screen a cohort of MAC patients using exome
3
sequencing (WES) and segmental dosage (SNP) analysis to find causative mutations in
new genes, and will explore the developmental basis in compelling cases. One example
is BASR (bilateral anophthalmia with sex reversal), arising from an X-autosome translo-
cation, with trans-fating of RPE to neural retina as a potential mechanism. We will test
this hypothesis in vitro (chromatin topology and iPSC differentiation assays) and in vivo
(specific transgenic mice).

## Key facts

- **NIH application ID:** 10155118
- **Project number:** 3R01EY019497-09S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Thomas M. Glaser
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $78,469
- **Award type:** 3
- **Project period:** 2009-04-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10155118

## Citation

> US National Institutes of Health, RePORTER application 10155118, Diversity Supplement - Genetic Basis of Congenital Anophthalmia (3R01EY019497-09S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10155118. Licensed CC0.

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