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.congenital heart disease ͉ persistent truncus arteriosus ͉ cardiac neural crest C ongenital heart diseases (CHD) constitute a major percentage of clinically significant birth defects with an estimated prevalence of 4-10 per 1,000 live infants (1). Cardiac outflow tract (OFT) defects are estimated to account for approximately 30% of CHD (2) and usually require an intervention during the first year of life. A variety of OFT defects results from disturbance of the morphogenetic patterning of the anterior pole of the heart, which is essential for the establishment of separate systemic and pulmonary circulations in higher vertebrates. Persistent truncus arteriosus (PTA), which is attributed to missing septation of the OFT, is recognized as the most severe phenotype of OFT defect, and is often associated with an unfavorable prognosis because complete surgical repair is not always possible (3). Although an improved understanding of possible genetic causes would provide insight into the pathogenesis of CHD and allow for better assessment of disease risk, prenatal diagnosis, and critical information for disease prevention, the etiology of most CHD, including OFT defects, remains unknown because of the multifactorial nature of the diseases (4-6).Based on animal studies, it appears that abnormal development of cardiac neural crest (CNC) cells, an ectoderm-derived cell lineage, contributes significantly to the pathology of OFT defects (7-12). During early embryogenesis, CNC cells arise from the dorsal neural tube and migrate ventrally as mesenchymal cells to populate the OFT, where they coalesce to form the aorticopulmonary septum, which divides the single truncus arteriosus (embryonic OFT) into the aorta and pulmonary artery, resulting in the establishment of separate systemic and pulmonary c...

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We have obtained the 5820 nucleotide sequence encoding all 1939 amino acids of the human cardiac alpha-myosin heavy chain (alpha-MHC), as established by dideoxy sequencing of cloned cDNA, genomic DNA and polymerase chain reaction (PCR) amplification products. This sequence represents overlapping fragments of the entire coding sequence. Amino acid sequence comparison of the human cardiac alpha-MHC with the published human cardiac beta-MHC have demonstrated that there are, at least, 7 isoform-specific divergent regions, including functionally important binding protein-related sites such as ATP, actin and myosin light chain. It has been reported that in the rat, there are 8 isoform-specific divergent regions. The 7th divergent area (residue area 1633-1657, which is thought to mediate thick filament formation) in the light meromyosin region in the rat is not apparent in the human. The amino acid compositions of cardiac alpha- and beta-MHCs in the human and the rat, and human embryonic skeletal muscle and chicken gizzard smooth muscles were compared. Amino acid sequences in cardiac alpha- and beta-MHCs in the human and the rat are well conserved. In the head portion, the amino acid composition divergence of human cardiac alpha-MHC is ranked between rat cardiac alpha-MHC and human cardiac beta- or rat cardiac beta-MHC; human skeletal muscle MHC is the most divergent of the myosin isoform examined. These data predict that human cardiac alpha-MHC may have undergone evolutionary changes toward obtaining the biochemical and physiological properties of cardiac beta-MHC.

A method of preparation of a more palatable therapeutic formula for phenylketonuria (PKU), consisting of low-phenylalanine peptide (LPP), was reported. There were no adverse effects and, in fact, there was a reduced frequency of diarrhea in patients who received LPP formula for more than 6 months. The LPP formula can be used not only as a more palatable therapeutic milk for PKU, but also as an ingredient to make more palatable foods of low-phenylalanine content.

A proanthocyanidin-free (ant-free) barley with improved quality, Mokkei 92-130, was bred from the cross between Ant 13-347, an ant-free mutant and Haruna Nijo, a Japanese malting barley variety. The malting and brewing quality of the line are described in this paper, while its agronomic performance will be summarised elsewhere. Mokkei 92-130 achieved high levels in some malting quality character including hot water extract, diastatic power and apparent attenuation limit, which were significantly low in most of the ant-free lines and varieties previously reported. Cell wall degradation was also improved. Overall malting quality was found to be satisfactory in Mokkei 92-130. Pilot-scale brewing trials showed that Mokkei 92-130 had superior colloidal stability (less haze formed) in its final beer compared with the normal counterparts. Beer brewed with ant-free barley at a pilot-scale performed as well as the standard production in sensory evaluations soon after bottling, although it was rated poorer than the control after one month storage at ambient temperature.Key Words: Proanthocyanidin-free, malting quality, haze, colloidal stability, flavour, flavour stability. Proanthocyanidins present in the testa (seed coat) of were significantly lower levels of extract4 '7'10'11'19'22'27'28, barley kernel are considered to be the most potent of the diastatic power2-4'11'22-27-29 and apparent attenuation haze causing polyphenols2-814-15'20'23. There are two limit2-22-25'29 than current commercial varieties. In recent practical ways for brewers to achieve high physical or reports, however, acceptable levels of diastatic power colloidal stability of beer; one is pitching silica gel or have been achieved25-28. Incomplete cell wall degrading enzyme to remove or degrade proteins, the degradation was also observed; resulting in high extract other is to absorb polyphenols to difference2-4-7-10'11'27, low friability25-27, high polyvinylpolypyrolidons (PVPP)14-18'20. Alternatively viscosity25'27-29 and high wort beta-glucan4-22. The proanthocyanidin-free (ant-free) barley might be used as finished beer brewed from the malt of an ant-free line raw material. In such barley, the biosynthesis pathway was rated poorly in sensory evaluation22. However, no of proanthocyanidins is genetically blocked. Overall this detrimental effects were also reported on the final beer represents a more natural and potentially inexpensive from the other ant-free lines29, and acceptable flavour step forward in colloidal stability of beer22. and flavour stability was reported for another line13.Since the first report of an ant-free barley mutant in Because of these defects, no ant-free line or variety has 197616, many ant-free barley lines have been produced been widely grown even though it may contribute to through mutagenesis. As had been expected, beer brewed superior colloidal stability in beer. The genes coding antfrom the malt of these mutants and even of their free characteristics appear to have a negative effect on such progenies exhibited improve...