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Published on: August 10, 2018
GATA6 mutations cause human cardiac outflow tract defects by disrupting semaphorin-plexin signaling
Kazuki Kodo1, Tsutomu Nishizawa, Michiko Furutani
1Department of Pediatrics, Division of Pediatric Cardiology, Keio University School of Medicine, 35 Shinanomachi, Shinjyuku-ku, Tokyo 160-8582, Japan.
Insights
Mutations in the GATA6 gene cause congenital heart defects (CHD), specifically persistent truncus arteriosus (PTA). This occurs due to GATA6
Area of Science:
- Genetics
- Developmental Biology
- Cardiology
Background:
- Congenital heart diseases (CHD) affect nearly 1% of live births, leading to significant infant mortality and morbidity.
- The genetic basis for most CHDs remains largely unknown, hindering insights into their pathobiology.
Purpose of the Study:
- To investigate the genetic etiology of congenital heart defects (CHD), focusing on persistent truncus arteriosus (PTA).
- To identify specific genes and molecular pathways involved in cardiac outflow tract (OFT) development.
Main Methods:
- Systematic genetic analysis of DNA from patients diagnosed with PTA.
- Identification and characterization of mutations in the GATA6 gene.
- Transgenic analysis to assess the role of GATA6 in regulating downstream genes like SEMA3C and PLXNA2 during heart development.
Main Results:
- Identified two distinct GATA6 mutations in patients with PTA.
- Demonstrated that GATA6 directly regulates semaphorin 3C (SEMA3C) and plexin A2 (PLXNA2) gene expression.
- Showed that GATA6 mutant proteins are deficient in transactivating SEMA3C and PLXNA2, impacting OFT development.
Conclusions:
- Mutations in the GATA6 gene are a direct cause of CHD, particularly PTA, by disrupting OFT development.
- GATA6 plays a critical role in regulating semaphorin-plexin signaling essential for cardiac neural crest and OFT development.
Abstract:
Congenital heart diseases (CHD) occur in nearly 1% of all live births and are the major cause of infant mortality and morbidity. Although an improved understanding of the genetic causes of CHD would provide insight into the underlying pathobiology, the genetic etiology of most CHD remains unknown. Here we show that mutations in the gene encoding the transcription factor GATA6 cause CHD characteristic of a severe form of cardiac outflow tract (OFT) defect, namely persistent truncus arteriosus (PTA). Two different GATA6 mutations were identified by systematic genetic analysis using DNA from patients with PTA. Genes encoding the neurovascular guiding molecule semaphorin 3C (SEMA3C) and its receptor plexin A2 (PLXNA2) appear to be regulated directly by GATA6, and both GATA6 mutant proteins failed to transactivate these genes. Transgenic analysis further suggests that, in the developing heart, the expression of SEMA3C in the OFT/subpulmonary myocardium and PLXNA2 in the cardiac neural crest contributing to the OFT is dependent on GATA transcription factors. Together, our data implicate mutations in GATA6 as genetic causes of CHD involving OFT development, as a result of the disruption of the direct regulation of semaphorin-plexin signaling.
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