# The role of planar cell polarity signaling in outflow tract malformation in 22q11.2 deletion syndrome

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $652,745

## Abstract

Malformation of the outflow tract (OFT) is one of the most common congenital heart defects (CHD) in humans
and a leading cause of childhood lethality. Their etiology, however, is largely unknown as most CHDs are
thought to be complex genetic disorders arising from mutations in multiple genes. The long-term objectives of
this project are to define how different pathways interact to regulate OFT morphogenesis, to identify the
genetic mutations/ variants altering these pathways in humans, and to elucidate how the mutations/ variants
interact to modify OFT malformations. The knowledge will guide us to design diagnostic and therapeutic
approaches. In humans with 22q11.2 Deletion Syndrome (DS), heterozygous loss of TBX1, a T-box
transcription factor, predisposes them to CHDs at a high rate of 65%. The highly variable clinical manifestation
of OFT defects in 22q11.2DS individuals with the identical deletion has led to the hypothesis that genetic
variants, residing outside the deletion and affecting TBX1-networks, may interact with TBX1 haploinsufficiency
to modify the clinical presentation of OFT malformation. The objective of the current proposal is to understand
how alteration of planar cell polarity (PCP) signaling, an evolutionarily conserved signaling mechanism that
regulates tissue morphogenesis, may contribute to OFT malformation in 22q11.2DS patients. The objective will
be achieved by specifically testing 1) how Tbx1 may regulate morphogenesis in cardiac progenitors in the
second heart field (SHF) through PCP signaling to promote OFT formation in mice; 2) how 3 functionally
validated PCP genes variants identified in 22q11.2DS patients may modify the OFT defects in Tbx1 mutant
mice, and 3) how additional predicted risk and protective PCP gene variants found in 22q11.2DS patients may
alter PCP signaling activity. Building upon our preliminary studies that PCP regulates cell polarity and polarized
cell behavior to promote SHF morphogenesis and SHF cell deployment to the OFT, we will first determine how
Tbx1 mutants may phenocopy the morphogenetic defects in PCP mutants, and whether constitutively
activating PCP in the SHF may rescue SHF morphogenesis and OFT defects in Tbx1 mutants. Secondly, we
will use CRISPR/Cas9 to create mouse models for three human PCP variants that we already discovered from
22q11.2DS patients and functionally validated in Xenopus, and test how variants dampening or enhancing
PCP activity may impact OFT malformations in Tbx1 mutant mice. Finally, using a quantitative assay we
established in Xenopus, we will systematically analyze a large number of rare predicted PCP gene variants
associated specifically with 22q11.2DS individual either with or without OFT defects, and perform cellular and
molecular studies to determine mechanistically how these variant alter PCP signaling. These studies will
elucidate whether perturbation of PCP signaling is a key pathogenic mechanism of OFT malformation in
22q11.2DS, and how PCP gene varian...

## Key facts

- **NIH application ID:** 9985632
- **Project number:** 5R01HL138470-04
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** CHENBEI CHANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $652,745
- **Award type:** 5
- **Project period:** 2017-07-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9985632

## Citation

> US National Institutes of Health, RePORTER application 9985632, The role of planar cell polarity signaling in outflow tract malformation in 22q11.2 deletion syndrome (5R01HL138470-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9985632. Licensed CC0.

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