# Molecular Genetics of BBS

> **NIH NIH R01** · LURIE CHILDREN'S HOSPITAL OF CHICAGO · 2022 · $427,811

## Abstract

The generation of 1000s of patient exomes and genomes, while accelerating diagnoses, has also highlighted
the complexity of previously-considered “simple” traits. Numerous examples are now reported of patients with
deleterious alleles in multiple genes. In some, the phenotype reflects an amalgam of two disorders; in others, it
is the product of genetic interactions. Moreover, recent exome- or panel-based resequencing of groups of
genes known to cause a host of dominant or recessive disorders are beginning to report an enrichment of rare
variants in patients, highlighting the concept of mutational burden. Bardet-Biedl syndrome (BBS), a founding
ciliopathy, has been a model for studying these phenomena and for beginning to understand the contribution of
such alleles to non-penetrance and variable expressivity. This is because: (a) the majority of the recessive
burden in BBS is now known, with ~80% of BBS patients harboring recessive mutations in 22 genes; (b) most
BBS proteins are necessary for cilia structure/function and assemble into defined complexes; and (c) we and
others have developed quantitative in vitro and in vivo tools to assess the total functional output of the cilium;
to establish the effect of variants; and to measure genetic interactions. This Renewal focuses on three themes.
First, we will capitalize on extensive genetic and functional data from previous cycles to build a comprehensive
map of mutational distribution in a biological module. Through the rigorous analysis of two independent BBS
patient cohorts, we have observed a 2.5-fold increase of rare variants in known BBS genes beyond the
recessive driver. This variation is not distributed randomly but intimates an interaction between mutations that
map to different macromolecular complexes. Using established, mouse models of BBS, we will ask how these
interactions might potentiate or exacerbate discrete BBS endophenotypes. Second, we will take advantage of
recent observations in humans and mouse models of ciliopathies to dissect the role of cis- and -trans acting
genetic modifiers. Focusing on TTC21B/IFT139, a gene that contributes causal and modifying mutations
across the ciliopathy disease spectrum, we will test the hypothesis that mutations in that locus contribute to the
development of renal disease in BBS, by leveraging extensive data from zebrafish models and testing the
paradigm in the mouse. In parallel, using a combination of computational and biological tools, will ask whether
discrete point mutations in that locus can account for the variable activity of the disease-causing allele
p.P209L, a hypomorph in human but a null allele in the mouse. Finally, grounded on recent observations
derived from a genome-wide genetic suppressor screen that augmentation of the proteasome ameliorates BBS
in vitro and in vivo, we will employ our recently-developed proteasome sensor screening paradigm to perform a
small molecule screen for new therapeutic leads. These studies will provide...

## Key facts

- **NIH application ID:** 10475603
- **Project number:** 5R01HD042601-20
- **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:** 2022
- **Award amount:** $427,811
- **Award type:** 5
- **Project period:** 2003-06-05 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10475603

## Citation

> US National Institutes of Health, RePORTER application 10475603, Molecular Genetics of BBS (5R01HD042601-20). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10475603. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*