# Homeotic hotspot in the human genome for eye and brain disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2023 · $439,496

## Abstract

PROJECT SUMMARY
Classical homeotic mutations (e.g. Drosophila Ubx) disrupt embryonic development,
transforming one tissue type into another. We have discovered the molecular basis of
four human X-linked disorders affecting the eye or brain – BASR syndrome, foveal
dysgenesis, retinitis pigmentosa and spinocerebellar ataxia, which have a homeotic or
degenerative basis. Each disorder is caused by insertion of a large autosomal DNA
segment at the same Xq27 palindromic site near SOX3, which encodes a potent trans-
cription factor homologous to SRY (testis determinant). The Xq insertions are predicted
to disrupt chromatin architecture, activating SOX3 ectopically in tissues defined by newly
juxtaposed enhancers, and altering cell fate (homeosis) via a gain-of-function (GOF). We
propose that SOX3 changes retinal pigment epithelia (RPE) into neuroretina in BASR,
reprograms cerebellar Purkinje cells in SCAX5, and triggers photoreceptor degeneration
in RP24. Using a novel palinsert PCR assay, we defined the breakpoints and candidate
enhancers for each insertion. We also identified >10 further Xq27 disorders affecting the
eye, brain or other organs – including unsolved cases with a likely similar mechanism.
We will define new Xq27 palindrome insertions and test our hypothesis for disease
pathogenesis at chromatin and developmental levels, using [1] patient-derived iPSCs,
3D chromatin interaction assays (Hi-C), in vitro differentiation, serial scRNA-seq profiles;
and [2]
(homol
informative mouse transgenes, including the binary CRISPR/Cas9 Hprt HoP-In
ogy promoted integration) GOF system we pioneered – with Sox3HA expression
activated in RPE, rods, Purkinje cells, or other tissues via established Cre drivers, in a
constitutional (XY) or mosaic (XX) pattern, and in a sustained or Dox-inducible manner.

## Key facts

- **NIH application ID:** 10666455
- **Project number:** 5R01EY033742-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Thomas M. Glaser
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $439,496
- **Award type:** 5
- **Project period:** 2022-08-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10666455

## Citation

> US National Institutes of Health, RePORTER application 10666455, Homeotic hotspot in the human genome for eye and brain disease (5R01EY033742-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10666455. Licensed CC0.

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