# Transcriptional and Developmental Basis of the Human X-linked Homeotic Hotspot

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2024 · $41,972

## Abstract

Abstract
Human eye development is an exquisitely balanced crosstalk of numerous signaling pathways that iteratively
dictate the ebb and flow of this complex and highly physiologically active organ. Amongst the plethora of genetic
mutations that can derail this sensitive programming, larger scale ocular malformations are encapsulated under
a spectrum known as Microphthalmia (small eye globes), Anophthalmia (missing eye globes), and Coloboma
(failed closure of the choroid fissure), collectively referred as MAC syndrome that affects approximately 1:10,000
live births. The following proposal highlights an anomalous index case of human bilateral anophthalmia and XX
sex-reversal (BASR) syndrome. This anatomically male child was born with bilateral anophthalmia, a left cystic
orbital mass, focal brain lesions, and is genetically female (XX). Their disease is the result of a de novo mutation
on the long arm of their paternal X chromosome (Xq27). This region contains an extra copy of a large fragment
(640k base pairs) from the long arm of chromosome 9 (9q21) which translocated during paternal meiosis I. The
translocated fragment contained regulatory elements of an ion channel gene, TRPM3. Most fascinatingly, the
exact point in which the translocation happened was at a 180 base pair palindrome on Xq27 that has been the
causal site of mutation for a staggering number of other congenital disorders that affect, not just the eye, but
numerous other tissue compartments or organ systems. These disorders involve the translocation of different
autosomal fragments that land at this locus. To address BASR etiology, as well as molecularly unify all the
disorders that map back to this translocation hotspot, we hypothesize that SOX3, a neighboring transcription
factor, is ectopically activated within tissue domains that correspond to the translocated fragments. Additionally,
we hypothesize that SOX3 in BASR was activated in the pigmented monolayer of cells in the back of the retina
(retinal pigment epithelium; RPE) that is essential for photoreceptor health and ocular genesis. The following
training plan seeks to test this hypothesized SOX3 etiology through both in vitro and in vivo modalities. By utilizing
immortalized blood cells from the BASR patient, I aim to characterize the misfolded higher-order genetic
landscape that comprises the Xq27 mutation through sequencing of closely associated regions (Hi-C).
Additionally, induced pluripotent stem cells from the BASR patient will be induced to become RPE, during which
I will gather and conduct serial analysis of the genetic expression of this process within a BASR context via
single-cell sequencing. I aim to complement these efforts with characterization of a BASR mouse model, in which
partially formed eye rudiments within these newly generated transgenic mice that ectopically express Sox3 will
be immuno-detected and qualitatively assessed for any potential transdifferentiation.

## Key facts

- **NIH application ID:** 10998027
- **Project number:** 1F31EY036742-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Joseph Rosas
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $41,972
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10998027

## Citation

> US National Institutes of Health, RePORTER application 10998027, Transcriptional and Developmental Basis of the Human X-linked Homeotic Hotspot (1F31EY036742-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10998027. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*