GATA6 mutations cause human cardiac outflow tract defects by disrupting semaphorin-plexin signaling.
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.
Kodo
Kazuki
K
Department of Pediatrics, Division of Pediatric Cardiology, Keio University School of Medicine, 35 Shinanomachi, Shinjyuku-ku, Tokyo 160-8582, Japan.
Nishizawa
Tsutomu
T
Furutani
Michiko
M
Arai
Shoichi
S
Yamamura
Eiji
E
Joo
Kunitaka
K
Takahashi
Takao
T
Matsuoka
Rumiko
R
Yamagishi
Hiroyuki
H
D000818:Animals; D001483:Base Sequence; D005260:Female; D050993:GATA6 Transcription Factor / Q000235:genetics* / Q000502:physiology; D006321:Heart / Q000502:physiology; D006330:Heart Defects, Congenital / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D039961:Semaphorins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction
D050993:GATA6 Transcription Factor; C494759:GATA6 protein, human; C494760:Gata6 protein, mouse; D009419:Nerve Tissue Proteins; C515995:PLXNA2 protein, human; C492113:Plxna2 protein, mouse; D011956:Receptors, Cell Surface; C543908:Sema3C protein, human; D039961:Semaphorins; C510203:semaphorin 3C protein, mouse