# New Mechanisms of Heterotaxy and Congenital Heart Disease: Nucleoporins at Cilia

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $592,085

## Abstract

Project Summary
Congenital heart disease (CHD) is one of the major causes of infant mortality and morbidity in the US.
However, we know little about the genetic causes of this disease. Multiple studies have now identified
nucleoporins, the protein components that build nuclear pore complexes, as candidate genes for Heterotaxy, a
disorder of left-right patterning that can lead to a severe form of CHD. In our previous work, we proposed a
likely model for how nucleoporins could contribute to left-right patterning by establishing that Nup188 and its
binding partner Nup93 are essential for cardiac development, left-right patterning and cilia in a frog model.
Importantly, we discovered that both Nup188 and Nup93 are localized to the bases of cilia where they form
assemblies that are structurally distinct from nuclear pore complexes. Despite this progress, we do not yet
have a clear catalogue of the nucleoporins that localize to cilia bases, nor do we understand precisely how
they function. To meet these challenges, we intend to fully leverage the unique and complementary expertise
of our team that includes clinician scientists, developmental and cell biologists, including super-resolution
microscopists. We will thus take a multidisciplinary approach to: 1) Interrogate the function of emerging
nucleoporin variants linked to CHD in our rapid and efficient Xenopus CHD model; 2) Use proximity-detection
methods like BioID in cell culture to fully identify the nucleoporins that localize to cilium bases and their cilium-
specific binding partners; and 3) Use these data in concert with sophisticated pulse-chase analyses coupled to
next generation multi-color 3D super resolution imaging to fully define the mechanisms of nucleoporin
recruitment and their nanoscale distribution at the cilium base. Lastly, we will directly explore nucleoporin
function in building both primary and multi-cilia in cell culture and Xenopus models. Our results promise to
provide a framework to identify how emerging nucleoporin (and cilium base) gene variants underlie CHD while
also informing fundamental mechanisms that function at the cell and tissue-level.

## Key facts

- **NIH application ID:** 9971565
- **Project number:** 5R01HL124402-06
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Mustafa K Khokha
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $592,085
- **Award type:** 5
- **Project period:** 2015-04-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9971565

## Citation

> US National Institutes of Health, RePORTER application 9971565, New Mechanisms of Heterotaxy and Congenital Heart Disease: Nucleoporins at Cilia (5R01HL124402-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9971565. Licensed CC0.

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