# Microphthalmia, anophthalmia and coloboma (MAC) and retinoic acid pathway genes

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2024 · $401,250

## Abstract

SUMMARY
Microphthalmia, anophthalmia and coloboma (MAC) are a group of clinically and genetically related eye defects
that cause significant visual impairment. MAC can be caused by pathogenic variants in transcription factors and
other genes involved in eye development and by environmental factors such as maternal vitamin A deficiency
(VAD). Vitamin A is critical for retinoic acid (RA) synthesis and pathogenic variants causing loss or gain of function
for the genes in the RA pathway, such as STRA6, can result in severe MAC. We hypothesize that genetic variation
in the RA pathway genes and genes involved in retinol metabolism can result in a predisposition, or lower
threshold, for the deleterious effects of VAD on eye development that contributes to the phenotypic severity of
MAC. This gene-environment interaction is highly relevant for countries where VAD is common and remains a
public health concern, such as India. In addition, the downstream genes that are dysregulated by lack of vitamin
A are poorly understood and are amenable to study in animal models. To identify the full spectrum of genetic
variation in the RA pathway and other genes in patients with MAC, our first Aim will recruit patients with MAC
and perform detailed phenotyping, environmental screening, and imaging so that we can generate accurate
phenotype genotype correlations. We will generate, analyze and compare whole genome sequencing (GS) data
from our collaborators, Dr. Tibrewal and Dr. Kumar, in patients of Asian ancestry with our studies using GS in
patients with MAC of predominantly European ancestry. We will also prospectively recruit patients with MAC
diagnosed in the newborn period from centers in the USA, so that we can obtain retinol levels from umbilical cord
blood in babies with MAC and retinol levels in maternal plasma around the time of delivery. With this data, we
will compare the severity of MAC with sequence variants that we observe in the RA pathway genes and in other
eye developmental genes, for patients of different ancestries, with and without evidence of VAD from symptoms
or from low levels of retinol. In our second Aim, we will use gene-editing with Clustered Regularly Interspaced
Short Palindromic Repeats/Cas9 to determine the effects of altered function for stra6 and other genes in the RA
pathway on ocular morphogenesis in zebrafish. All crispants will have detailed phenotyping at different timepoints
during eye development, including gene expression studies with single cell RNA-Seq, to determine the
downstream genes that are regulated by RA. We will also investigate if we can rescue, or partially rescue, the
deleterious effects of genetic variants in stra6 and other genes causing MAC on eye morphogenesis by titrating
levels of RA and retinol during periods of ocular development in Danio rerio. With this Aim, we will use an animal
model to generate data regarding downstream genes, tissues and developmental timepoints that are affected by
deficiencies of RA...

## Key facts

- **NIH application ID:** 10918222
- **Project number:** 5R01EY035500-02
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Anne M Slavotinek
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $401,250
- **Award type:** 5
- **Project period:** 2023-09-30 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10918222

## Citation

> US National Institutes of Health, RePORTER application 10918222, Microphthalmia, anophthalmia and coloboma (MAC) and retinoic acid pathway genes (5R01EY035500-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10918222. Licensed CC0.

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