Kazuki Kodo

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.

Mechanisms underlying early development of pulmonary vascular obstructive disease in Down syndrome: An imbalance in biosynthesis of thromboxane A2 and prostacyclin.

Patients with Down syndrome (DS) and a left‐to‐right shunt often develop early severe pulmonary hypertension (PH) and pulmonary vascular obstructive disease (PVOD); the pathophysiological mechanisms underlying the development of these complications are yet to be determined. To investigate the mechanisms, we evaluated the biosynthesis of thromboxane (TX) A2 and prostacyclin (PGI2) in four groups of infants, cross‐classified as shown below, by measuring the urinary excretion levels of 11‐dehydro‐TXB2 and 2,3‐dinor‐6‐keto‐PGF1α: DS infants with a left‐to‐right shunt and PH (D‐PH, n = 18), DS infants without congenital heart defect (D‐C, n = 8), non‐DS infants with a left‐to‐right shunt and PH (ND‐PH, n = 12), and non‐DS infants without congenital heart defect (ND‐C, n = 22). The urinary excretion ratios of 11‐dehydro‐TXB2 to 2,3‐dinor‐6‐keto‐PGF1α in the D‐PH, D‐C, ND‐PH, and ND‐C groups were 7.69, 4.71, 2.10, and 2.27, respectively. The ratio of 11‐dehydro‐TXB2 to 2,3‐dinor‐6‐keto‐PGF1α was higher in the presence of DS (P < 0.001), independently of the presence of PH (P = 0.297). The predominant biosynthesis of TXA2 over PGI2, leading to vasoconstriction, was observed in DS infants, irrespective of the presence/absence of PH. This imbalance in the biosynthesis of vasoactive eicosanoids may account for the rapid progression of PVOD in DS infants with a left‐to‐right shunt.

Inositol 1,4,5-trisphosphate receptors are essential for the development of the second heart field

Congenital heart defects (CHDs) occur in 0.5-1% of live births, yet the underlying genetic etiology remains mostly unknown. Recently, a new source of myocardial cells, namely the second heart field (SHF), was discovered in the splanchnic mesoderm. Abnormal development of the SHF leads to a spectrum of outflow tract defects, such as persistent truncus arteriosus and tetralogy of Fallot. Intracellular Ca(2+) signaling is known to be essential for many aspects of heart biology including heart development, but its role in the SHF is uncertain. Here, we analyzed mice deficient for genes encoding inositol 1,4,5-trisphosphate receptors (IP(3)Rs), which are intracellular Ca(2+) release channels on the endo/sarcoplasmic reticulum that mediate Ca(2+) mobilization. Mouse embryos that are double mutant for IP(3)R type 1 and type 3 (IP(3)R1(-/-)IP(3)R3(-/-)) show hypoplasia of the outflow tract and the right ventricle, reduced expression of specific molecular markers and enhanced apoptosis of mesodermal cells in the SHF. Gene expression analyses suggest that IP(3)R-mediated Ca(2+) signaling may involve, at least in part, the Mef2C-Smyd1 pathway, a transcriptional cascade essential for the SHF. These data reveal that IP(3)R type 1 and type 3 may play a redundant role in the development of the SHF.

Vasculitis associated with septicemia: case report and review of the literature.

Abstract. We report an unusual case in which infectious endocarditis presented systemic vasculitis and glomerulonephritis as the initial manifestation of the disease. The patient was a 16-year-old girl with congenital cyanotic heart disease who presented with skin purpura, proteinuria, and hematuria. She had hypergammaglobulinemia, cryoglobulinemia, and positive circulating immune complexes. Renal biopsy revealed crescentic glomerulonephritis. Her serum C3 level, which was initially normal, became decreased, and prednisolone and azathioprine were administered with a tentative diagnosis of systemic lupus erythematosus (SLE). Soon after, she developed fever and renal failure. Blood culture grew Streptococcus pyogenes, and the diagnosis of infectious endocarditis was made. Eight cases of systemic vasculitis and glomerulonephritis associated with infectious endocarditis have been described in the literature. Infectious endocarditis should be included in the differential diagnosis of systemic vasculitis and glomerulonephritis.

GATA transcription factors in congenital heart defects: A Commentary on a novel GATA6 mutation in patients with tetralogy of Fallot or atrial septal defect

GATA transcription factors in congenital heart defects: A Commentary on a novel GATA6 mutation in patients with tetralogy of Fallot or atrial septal defect

Molecular embryology for an understanding of congenital heart diseases

Congenital heart diseases (CHD) result from abnormal morphogenesis of the embryonic cardiovascular system and usually involve defects in specific structural components of the developing heart and vessels. Therefore, an understanding of “Molecular Embryology”, with specific focus on the individual modular steps involved in cardiovascular morphogenesis, is particularly relevant to those wishing to have a better insight into the origin of CHD. Recent advances in molecular embryology suggest that the cardiovascular system arises from multiple distinct embryonic origins, and a population of myocardial precursor cells in the pharyngeal mesoderm anterior to the early heart tube, denoted the “second heart field”, has been identified. Discovery of the second heart field has important implications for the interpretation of cardiac outflow tract development and provides new insights into the morphogenesis of CHD.

Hyponatremia, hypophosphatemia, and hypouricemia in a girl with macrophage activation syndrome

Macrophage activation syndrome, a life-threatening complication of rheumatic disorders, is accompanied by the overproduction of cytokines. We describe a girl with macrophage activation syndrome complicating systemic-onset juvenile arthritis who developed hyponatremia, hypophosphatemia, and hypouricemia associated with a high level of serum tumor necrosis factor α. Renal proximal tubule dysfunction was considered to be the cause, which may be attributable to tumor necrosis factor α.

Regulation of Sema3c and the Interaction between Cardiac Neural Crest and Second Heart Field during Outflow Tract Development

The cardiac neural crest cells (cNCCs) and the second heart field (SHF) play key roles in development of the cardiac outflow tract (OFT) for establishment of completely separated pulmonary and systemic circulations in vertebrates. A neurovascular guiding factor, Semaphorin 3c (Sema3c), is required for the development of the OFT, however, its regulation of the interaction between cNCCs and SHF remains to be determined. Here, we show that a Sema3c is a candidate that mediates interaction between cNCCs and the SHF during development of the OFT. Foxc1/c2 directly activates the transcription of Sema3c in the OFT, whereas, a hypomorph of Tbx1, a key SHF transcription factor, resulted in the ectopic expression of Sema3c in the pharyngeal arch region. Fgf8, a downstream secreted factor of Tbx1, inhibited the expression of Sema3c in cNCCs via activation of ERK1/2 signaling. Blocking of FGF8 caused ectopic expression of SEMA3C and a migration defect of cNCCs, resulting in abnormal chick pharyngeal arch development. These results suggest that proper spatio-temporal expression of Sema3c, regulated positively by Foxc1/c2 and negatively by the Tbx1-Fgf8 cascade, respectively, is essential for the interaction between cNCCs and the SHF that correctly navigates cNCCs towards the OFT, composed of SHF-derived cells.

A History and Interaction of Outflow Progenitor Cells Implicated in “Takao Syndrome”

Progenitor cells, derived from the cardiac neural crest (CNC) and the second heart field (SHF), play key roles in development of the cardiac outflow tract (OFT), and their interaction is essential for establishment of the separate pulmonary and systemic circulation in vertebrates. 22q11.2 deletion syndrome (22q11DS) or Takao syndrome is the most common human chromosomal deletion syndrome that is highly associated with OFT defects. Historically, based on the observations in animal models, OFT defects implicated in the 22q11/Takao syndrome are believed to result primarily from abnormal development of CNC that populate into the conotruncal region of the heart. In the twenty-first century, elegant efforts to model 22q11/Takao syndrome in mice succeeded in the identification of T-box-containing transcription factor, Tbx1, as an etiology of OFT defects in this syndrome. Subsequent investigations of the Tbx1 expression pattern revealed that Tbx1 was surprisingly not detectable in CNC but was expressed in the SHF and provided a new concept of molecular and cellular basis for OFT defects associated with 22q11/Takao syndrome. More recently, it was reported that mutations in the gene encoding the transcription factor GATA6 caused CHD characteristic of OFT defects. Genes encoding the neurovascular guiding molecule semaphorin 3C (SEMA3C) and its receptor plexin A2 (PLXNA2) appear to be regulated directly by GATA6. Elucidation of molecular mechanism involving GATA6, SEMA3C, PLXNA2, and TBX1 in the interaction between the CNC and the SHF would provide new insights into the OFT development.