# Genetic studies of a pleiotropic transmembrane protease: insight from color variation in non-model organisms

> **NIH NIH R01** · STANFORD UNIVERSITY · 2024 · $665,448

## Abstract

Project Summary/Abstract
Mendelian variation in pigmentation is a rich genetic resource to identify and study signaling pathways relevant
to human biology, but the repertoire of mutations that affect pigmentation in mice and in humans coat color has
become saturated. Advances in genome sequencing technology now extend the reach of forward genetics
beyond humans and model organisms to domestic and wild animals, for which there are many pigmentary
phenotypes likely to represent conserved signaling pathways but whose molecular basis is unknown.
Using pigmentary variation in domestic cats, our research group discovered a striking connection between a
novel transmembrane protease encoded by Transmembrane aminopeptidase Q (Taqpep) and a secreted Wnt
inhibitor encoded by Dickkopf 4 (Dkk4). Initial studies of Taqpep knockout mice reveal a role in multiple cell
types and tissues including hair, the enteric nervous system, and the palate. In a different non-model organism,
the plains zebra, Taqpep is a candidate gene for aberrant striping in an isolated population in Rwanda.
Our results point to a central role for Taqpep in pathways and tissues that are directly relevant to human
biology and disease, but a molecular understanding of those pathways is most effectively approached by
combining forward genetics for gene discovery in non-model mammalian organisms with experimental genetics
in laboratory mice and studies in cultured mammalian cells. We propose to:
(1) Identify additional components of Taqpep action by forward genetics in Bengal cats and by analysis of fetal
 cat skin
(2) Expand initial genetic studies of color pattern variation in zebras
(3) Determine the mechanism of Taqpep action using experimental mouse genetics and proteomics

## Key facts

- **NIH application ID:** 10899629
- **Project number:** 5R01AR082708-03
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Gregory Stefan Barsh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $665,448
- **Award type:** 5
- **Project period:** 2024-01-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10899629

## Citation

> US National Institutes of Health, RePORTER application 10899629, Genetic studies of a pleiotropic transmembrane protease: insight from color variation in non-model organisms (5R01AR082708-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10899629. Licensed CC0.

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