# Genetic and Functional Studies of Human Ciliary Syndromes

> **NIH NIH R01** · LURIE CHILDREN'S HOSPITAL OF CHICAGO · 2020 · $441,234

## Abstract

The ciliopathies are a group of >100 genetic disorders unified by overlapping structural and/or functional
defects of the cilium and the basal body. The study of these disorders has highlighted fundamental
developmental and homeostatic mechanisms, while offering the opportunity to develop computational and
functional tools to discover new causal genes; to expand the phenotypic spectrum of known genes; and to
design rational therapeutic paradigms. In the backdrop of striking progress during the past two decades, major
challenges and opportunities remain. Specifically, despite a diagnostic rate that for some ciliopathies
approaches 90%, the predictive power of the genotype at the primary recessive locus remains insufficient to
inform clinical manifestation. This is in part because our understanding of the pathomechanisms of pleiotropy
and variable expressivity remain poorly understood. Moreover, almost all ciliopathy discovery work to date has:
(a) focused on coding mutations and genomic rearrangements; and (b) assumed that the pathogenicity of
alleles is constant in all cellular contexts. In this Renewal, we aspire to improve upon these knowledge gaps.
First, we will take advantage of a genome-wide siRNA screen on cells ablated for BBS4 that report on aberrant
Wnt signaling. This experiment harvested 81 genes that, when suppressed, exacerbate ciliary cellular
phenotypes and therefore represent de facto candidates for harboring either causal or epistatic mutations in
patients with ciliary disease. We will test this hypothesis by sequencing our phenotypically diverse patient
cohort and testing functionally resultant candidate genes and alleles using state-of-the-art in vivo tools.
Critically, the majority of these 81 genes are not components of the ciliary apparatus, offering the opportunity to
forge new biological links between ciliary dysfunction and other cellular processes. In parallel, we will pursue
studies that will explore a new phenomenon of allele pathogenicity, in which bona fide pathogenic missense
variants behave as deleterious to protein function in some splice isoforms but benign in others. Using a
combination of in vivo complementation testing and in vitro biochemical studies, we will ask how common
these phenomena are and whether subcellular localization or stability might represent informative biochemical
drivers of these phenomena. Finally, through a genome-wide screen for miRNAs that regulate ciliogenesis, we
discovered let-7b as a regulator of ciliary length. Subsequent transcriptomic analysis identified 42 ciliary genes
with differential expression correlated to let-7b dosage, and which harbor predicted let-7b sites in their 3’ UTR.
We will use this rich dataset to ask whether such miRNA binding sites in 3’ UTRs of known ciliopathy genes
contribute to causality and modification in this group of disorders. Together, our studies will inform the genetic
architecture of the ciliopathy disease entity by discovering sites that likely...

## Key facts

- **NIH application ID:** 10017953
- **Project number:** 5R01DK072301-16
- **Recipient organization:** LURIE CHILDREN'S HOSPITAL OF CHICAGO
- **Principal Investigator:** Erica Ellen Davis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $441,234
- **Award type:** 5
- **Project period:** 2019-09-14 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10017953

## Citation

> US National Institutes of Health, RePORTER application 10017953, Genetic and Functional Studies of Human Ciliary Syndromes (5R01DK072301-16). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10017953. Licensed CC0.

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