# The role of continuous phenotypic variation in structural defects of the face

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $560,183

## Abstract

Summary
Despite tremendous progress in clinical genomics, nearly half of children with genetic disease never receive a
diagnosis. One reason is that patients are initially diagnosed based on symptoms and physical manifestations
but for many genetic conditions, those symptoms can vary dramatically even for patients with the same
mutation. When patients with the same mutation have different phenotypes, that also has implications for
treatment and prognosis, even when a molecular diagnosis is secured. The long-term goal of our research
program is to understand how genotype is translated to variation in phenotype using a variety of model
systems. In our previous funding cycle, we used an allelic series of Fibroblast growth factor 8 (Fgf8) mice and
showed that levels of Fgf8 gene expression and downstream signalling factors were non-linearly related to the
phenotype. Little change in phenotype occurs until Fgf8 drops below 50% compared to the wildtype, and then
below that level small changes in Fgf8 produce large changes in the mean phenotype and its variance. The
next step in our research advances this concept and helps generate a more mechanistic understanding of
variable penetrance and robustness. Specifically, we propose two conceptually related aims that address
distinct concepts in understanding the central question of how mutations perturb development to generate
varied phenotypic outcomes. In specific Aim 1, we test mechanisms by which gene interactions within a
pathway generate variable penetrance and expressivity. Our previous research has identified epistatic
interactions that may modulate FGF8, and in this Aim, we test these interactions directly. In Specific Aim 2, we
test how a mutation that affects a specific but ubiquitous process generates a multi-modal range of
phenotypes. This is important because genetic diseases often involve disruptions to mechanisms that operate
across diverse tissues and at many points in development and yet result in highly specific birth defects such as
holoprosencephaly or cleft lip and palate. As a model for this general phenomenon, we investigate the effects
of a null mutation in Nitric Oxide Synthase Interacting Protein (Nosip) in mice. NOSIP is an E3-monoubiquitin
ligase that modifies activity of target proteins with diverse developmental roles. In both aims, we employ a
highly innovative combination of imaging, morphometric, transcriptomic and experimental approaches to
integrate multiple levels of input (genetic, molecular, cellular) to understand how the effects of a mutation
cascade across levels from gene expression to cellular dynamics to influence organismal form.

## Key facts

- **NIH application ID:** 10746763
- **Project number:** 5R01DE019638-13
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Benedikt Hallgrimsson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $560,183
- **Award type:** 5
- **Project period:** 2010-07-23 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10746763

## Citation

> US National Institutes of Health, RePORTER application 10746763, The role of continuous phenotypic variation in structural defects of the face (5R01DE019638-13). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10746763. Licensed CC0.

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