# Genetic Analysis of Organ Patterning Defects in Ciliopathies

> **NIH NIH R01** · YALE UNIVERSITY · 2022 · $383,357

## Abstract

Abstract:
Ciliopathies are an expanding group of human disorders whose cellular basis can be traced to defects in the
formation or function of small, cellular organelles called cilia. Cilia are found on almost every cell type in the
vertebrate body and thus ciliopathies can encompass defects in multiple organs and tissues. Strikingly,
ciliopathies span a spectrum, ranging from infertility to neonatal lethality but the genetics underlying these
divergent phenotypes are poorly understood. Defining the genes and genetic interactions that regulate cilia
function is essential to understanding the etiology of these diseases as well as for developing future therapies.
 We have developed mice carrying a spontaneous mutation (hop) in the Ift56 gene into a new model for
defining the genetic control of ciliopathy severity. Ift56 is a highly conserved cilia-localized protein that is
required for cilia function in several model organisms. We recently discovered that while the Ift56hop
phenotype is viable and mild on the Balb mouse background, it is lethal on the B6 background. The phenotype
of the hop-B6 mutant models VACTERL Association in humans and overlaps with the Ift27 mutant ciliopathy
phenotype. Our objectives are to 1) utilize the hop-B6 mutant as a means to understand VACTERL disorders,
2) define the function of Ift56 in mammalian cilia, and 3) isolate genetic loci that interact with the Ift56 mutation
in order to elucidate the genetic landscape underlying ciliopathies.
 Our First Aim focuses on analyzing the tissue defects in Ift56-B6 mutants. Histological approaches coupled
with gene expression analysis and microCT imaging will provide key insight into signaling and developmental
patterning events controlled by Ift56 and the VACTERL-associated defects in hop-B6 mutants
 Aim2 explores the ciliary roles of Ift56, and how these are altered in the B6 and Balb backgrounds. Using
candidate and proteomic approaches, we will determine the set of proteins that require Ift56 function for their
localization and trafficking within cilia. Finally, we test the requirement of Ift56 for IFTB complex integrity.
 In our Third Aim we map, isolate and validate modifiers of the hop phenotype in the B6 and Balb
backgrounds. We will also examine genetic interactions between Ift27 and hop mutants as well as the effects
of the Balb modifier background on the Ift27 phenotype. These experiments will identify key genetic modifiers
of ciliopathy severity and provide new targets for resequencing in ciliopathy patients.
 Together, the proposed studies will uncover the conserved functions of Ift56, a key cilia protein, by defining
how Ift56 regulates cilia and organogenesis. More broadly, these studies have the opportunity to uncover
unique insights into how genetic variants across the genome modify ciliopathy severity. Results from this study
will shed key and novel insights into cilia biology and ciliopathies, and lay the groundwork for future diagnostic
and therapeutic strate...

## Key facts

- **NIH application ID:** 10477030
- **Project number:** 5R01HD093608-05
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** ZHAOXIA SUN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $383,357
- **Award type:** 5
- **Project period:** 2018-09-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10477030

## Citation

> US National Institutes of Health, RePORTER application 10477030, Genetic Analysis of Organ Patterning Defects in Ciliopathies (5R01HD093608-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10477030. Licensed CC0.

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