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Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ellis van Creveld syndrome (EVC) is an autosomal recessive disorder which has previously been mapped to human chromosome 4p16.1. This disorder is characterized by disproportionate dwarfism, polydactyly, cleft palate, natal teeth, and congenital heart disease. The MSX1 homeobox gene also maps to the 4p16.1 region. Msx gene transcripts in the mouse embryo are known to be involved in pattern formation of the developing limb bud and craniofacial bones. Thus, on the basis of both map location and known gene function, MSX1 was an excellent candidate as the causative gene for EVC. Nonetheless, direct DNA sequencing of both exons of the MSX1 gene in five affected individuals segregating with the EVC phenotype, as well as those of two obligate carriers, revealed no mutations in the coding region of the gene.
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PMID:Exclusion of the MSX1 homeobox gene as the gene for the Ellis van Creveld syndrome in the Amish. 888 77

Congenital heart disease (CHD), cardiomyopathy, and vasculopathies are common causes of mortality and morbidity in pediatrics, including the perinatal period. This article reviews evidence that single gene defects cause many of the pediatric heart diseases. Vasculopathies discussed include Marfan's syndrome, supravalvar aortic stenosis and Williams' syndrome, Alagille's syndrome, and hereditary telangiectasia, the Osler-Weber-Rendu syndrome. Genetic causes of hypertrophic cardiomyopathy caused by sarcomeric protein mutations (beta-cardiac myosin heavy chain) and of dilated cardiomyopathy secondary to structural protein deficiencies (dystrophin) are presented. Defects in proteins essential for myocardial energy production such as oxidative phosphorylation proteins and fatty acid oxidation genes that cause cardiomyopathy or sudden death are described. Gene ablation models in mice, such as RXR alpha and homeobox gene knockouts, which result in cardiac phenotypes resembling human congenital heart disease, are described. Familial types of human CHD which are being investigated for genetic causes by positional cloning methods and known cytogenetic causes of CHD, including the CATCH-22 syndrome and monosomy at 22q11, are presented. General lessons and principles derived from these new and exciting discoveries in human cardiovascular development are surmised.
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PMID:The genetic basis of pediatric cardiovascular disease. 909 Jul 81

Csx/Nkx2.5 is a vertebrate homeobox gene with a sequence homology to the Drosophila tinman, which is required for the dorsal mesoderm specification. Recently, heterozygous mutations of this gene were found to cause human congenital heart disease (Schott, J.-J., Benson, D. W., Basson, C. T., Pease, W., Silberbach, G. M., Moak, J. P., Maron, B. J., Seidman, C. E. and Seidman, J. G. (1998) Science 281, 108-111). To investigate the functions of Csx/Nkx2.5 in cardiac and extracardiac development in the vertebrate, we have generated and analyzed mutant mice completely null for Csx/Nkx2.5. Homozygous null embryos showed arrest of cardiac development after looping and poor development of blood vessels. Moreover, there were severe defects in vascular formation and hematopoiesis in the mutant yolk sac. Interestingly, TUNEL staining and PCNA staining showed neither enhanced apoptosis nor reduced cell proliferation in the mutant myocardium. In situ hybridization studies demonstrated that, among 20 candidate genes examined, expression of ANF, BNP, MLC2V, N-myc, MEF2C, HAND1 and Msx2 was disturbed in the mutant heart. Moreover, in the heart of adult chimeric mice generated from Csx/Nkx2.5 null ES cells, there were almost no ES cell-derived cardiac myocytes, while there were substantial contributions of Csx /Nkx2.5-deficient cells in other organs. Whole-mount &bgr;-gal staining of chimeric embryos showed that more than 20% contribution of Csx/Nkx2. 5-deficient cells in the heart arrested cardiac development. These results indicate that (1) the complete null mutation of Csx/Nkx2.5 did not abolish initial heart looping, (2) there was no enhanced apoptosis or defective cell cycle entry in Csx/Nkx2.5 null cardiac myocytes, (3) Csx/Nkx2.5 regulates expression of several essential transcription factors in the developing heart, (4) Csx/Nkx2.5 is required for later differentiation of cardiac myocytes, (5) Csx/Nkx2. 5 null cells exert dominant interfering effects on cardiac development, and (6) there were severe defects in yolk sac angiogenesis and hematopoiesis in the Csx/Nkx2.5 null embryos.
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PMID:The cardiac homeobox gene Csx/Nkx2.5 lies genetically upstream of multiple genes essential for heart development. 1002 45

The murine homeobox gene Csx/Nkx2.5 is an evolutionarily highly conserved gene related to the Drosophila tinman gene, which specifies cardiac and visceral mesoderm. Since Csx/Nkx2.5 plays an essential role in heart development, studying its regulation is essential for the better understanding of molecular mechanisms of cardiogenesis and the pathogenesis of congenital heart disease in humans. In this study, we characterized the murine Csx/Nkx2.5 gene and identified two novel untranslated exons, 1a, and 1b, resulting in three different Csx/Nkx2.5 transcripts. To examine the tissue-specific transcriptional regulation in vivo, we analyzed a total of 23 kb of Csx/Nkx2.5 upstream and downstream sequences by generating transgenic embryos carrying lacZ reporter constructs containing various lengths of flanking sequence. With 14 kb of 5' flanking sequence, lacZ expression was observed in the cardiac crescent at E7.5, and in the outflow tract, the interatrial groove, the atrioventricular canal and right and left ventricles, as well as in pharyngeal floor, thyroid primordia, and stomach at E10.5. In adult animals, lacZ expression of the transgene was limited to the atrioventricular junction and the subendocardium of the ventricular septum. Reducing the size of flanking sequence to 3.3 kb of intron 2 restricted lacZ expression to the outflow tract and the basal part of the right ventricle in E10.5 embryos. In contrast, the addition of 6 kb of 3' flanking sequence caused strong expression of the reporter gene in the entire right ventricle. Interestingly, Csx/Nkx2. 5 seems to be negatively regulated by its own gene product, because when lacZ was "knocked-in" to replace the entire coding exons, lacZ expression was much higher in the heart of homozygous embryos than that in the heterozygote. These results indicate that the transcriptional regulatory elements of Csx/Nkx 2.5 seems unexpectedly highly modular, and is temporally regulated in a dynamic manner by different enhancer regions. Since Csx/Nkx2.5-like genes are expressed in all species having a heart, their complex modular organization with multiple enhancers probably reflects progressive addition of regulatory elements during the evolution from a simple heart tube to a complex four-chambered organ.
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PMID:Complex modular cis-acting elements regulate expression of the cardiac specifying homeobox gene Csx/Nkx2.5. 1006 37

The Tbx family of transcription factors are prominently expressed in the early cardiac primordium throughout the animal kingdom. Mutations in Tbx genes result invariably in defective formation and function of the heart, including congenital heart disease in humans. Similar to their vertebrate counterpart, the Drosophila Tbx20 gene pair, neuromancer1 (nmr1, FlyBase:H15) and neuromancer2 (nmr2, Flybase:mid), exhibits a dynamic expression pattern, including in all contractile myocardial cells. Deletion mutants of nmr1 combined with mesoderm-specific knock-down of nmr2 exhibit phenotypes that suggest nmr is critical for correct specification of the cardiac progenitor populations as well as for morphogenesis and assembly of the contractile heart tube. Loss-of-nmr-function causes a switch in cell fates in the cardiogenic region, in that the progenitors expressing the homeobox gene even skipped (eve) are expanded accompanied by a corresponding reduction of the progenitors expressing the homeobox gene ladybird (lbe). As a result, the number of differentiating myocardial cells is severely reduced whereas pericardial cell populations are expanded. Conversely, pan-mesodermal expression of nmr represses eve, while causing an expansion of cardiac lbe expression, as well as ectopic mesodermal expression of the homeobox gene tinman. In addition, nmr mutants with less severe penetrance exhibit cell alignment defects of the myocardium at the dorsal midline, suggesting nmr is also required for cell polarity acquisition of the heart tube. In exploring the regulation of nmr, we find that the GATA factor Pannier is essential for cardiac expression, and acts synergistically with Tinman in promoting nmr expression. Moreover, reducing nmr function in the absence of pannier further aggravates the deficit in cardiac mesoderm specification. Taken together, the data suggest that nmr acts both in concert with and subsequent to pannier and tinman in cardiac specification and differentiation. We propose that nmr is another determinant of cardiogenesis, along with tinman and pannier.
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PMID:Neuromancer Tbx20-related genes (H15/midline) promote cell fate specification and morphogenesis of the Drosophila heart. 1573 76

The ventricular septal defect (VSD) is the most common type of congenital heart disease (CHD). The morbidity and mortality of CHD patients are significantly higher due to late cardiac complications, likely caused by genetic defects. Mutations in cardiac transcription factor genes such as GATA-4, TBX5, and NKX2-5 have been implicated in CHD cases. The NKX2-5 gene, a homeobox gene, is expressed in the developing heart and the adult heart. Because NKX2-5 is a dosage-sensitive regulator during embryonic development, the authors hypothesized that the expression levels of the NKX2-5 gene rather than the mutant protein may play important roles in CHD. In this study, the promoter regions and exon regions of the NKX2-5 gene were bidirectionally sequenced in large cohorts of VSD patients and healthy control subjects. The results showed that a novel sequence variant (g.4574c>deletion), found only in one VSD patient, and a single nucleotide polymorphism (rs118026695), the frequency of which was significantly higher in VSD patients, were identified within the promoter region. Functional analysis confirmed that these sequence variants significantly enhanced the transcriptional activities of the NKX2-5 gene promoter, altering the expression of the NKX2-5 gene and the cardiac gene regulatory network. In addition, a synonymous mutation in the second exon of the NKX2-5 gene was identified in one VSD patient, which may affect the translation process. Therefore, the authors' data provide supportive evidence that mutations in the coding region of the NKX2-5 gene and sequence variants within its promoter region may be among the contributors to the CHD etiology.
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PMID:Genetic and functional analysis of the NKX2-5 gene promoter in patients with ventricular septal defects. 2257 68

The cardiac homeobox gene Nkx2.5 plays a key and dosage-sensitive role in the differentiation of outflow tract and right ventricle from progenitors of the second heart field (SHF) and Nkx2.5 mutation is strongly associated with human outflow tract congenital heart disease (OFT CHD). Therefore defining the regulatory mechanisms controlling Nkx2.5 expression in SHF populations serves an important function in understanding the etiology of complex CHD. Through a comparative analysis of regulatory elements controlling SHF expression of Nkx2.5 in the chicken and mouse, we have found evidence that Nkx2.5 autoregulation is important for maintaining Nkx2.5 expression during SHF differentiation in both species. However the mechanism of Nkx2.5 maintenance differs between placental mammals and non-mammalian vertebrates: in chick Nkx2.5 binds directly to a genomic enhancer element that is required to maintain Nkx2.5 expression in the SHF. In addition, it is likely that this is true in other non-mammalian vertebrates given that they possess a similar genomic organization. By contrast, in placental mammals, Nkx2.5 autoregulation in the SHF functions indirectly through Mef2c. These data underscore a tight relationship in mammals between Nkx2.5 and Mef2c in SHF transcriptional regulation, and highlight the potential for evolutionary cis-regulatory analysis to identify core, conserved components of the gene networks controlling heart development.
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PMID:Evolutionary conservation of Nkx2.5 autoregulation in the second heart field. 2316 93

Axenfeld-Rieger syndrome (ARS) is an autosomal dominant condition characterized by ophthalmologic anterior segment abnormalities and extraocular findings including dental anomalies and redundant periumbilical skin. Intragenic mutations in the homeobox gene PITX2 or the transcription factor encoding FOXC1 were identified, and genomic rearrangements encompassing either gene also cause ARS. A molecular etiology is identified in 40-60%. Extraocular anomalies occur more often with intragenic PITX2 than FOXC1 mutations. We report on a patient with infantile glaucoma presenting at age 21 months with congestive heart failure due to a dysplastic arcade mitral valve necessitating valve replacement, and mildly hypoplastic left ventricular outflow tract and aortic arch. Family history included early onset glaucoma in four relatives; congenital hip dysplasia requiring surgery in three; and an atrial septal defect in the affected maternal grandmother. Despite the absence of dental or umbilical abnormalities, anterior chamber abnormalities consistent with ARS were present in affected individuals. Molecular testing revealed a novel FOXC1 mutation (c.508C>T; p.Arg170Trp) in the proband and his affected mother; other family members were unavailable. A literature review revealed four reports of congenital heart disease associated with intragenic FOXC1 mutations, and none with intragenic PITX2 mutations. Previously, mouse studies showed Foxc1 (Mf1) expression in the developing valves and atrial septum, supporting a causal relationship of FOXC1 mutations for valvar anomalies and ASD. Hip dysplasia in three family members suggests a role for FOXC1 in the femoral head dysplasia of de Hauwere syndrome with 6p25 deletions. Further reports of clinical and molecular diagnoses will clarify genotype-phenotype correlation.
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PMID:Cardiac anomalies in Axenfeld-Rieger syndrome due to a novel FOXC1 mutation. 2323 55

The ventricular conduction system (VCS) orchestrates the harmonious contraction in every heartbeat. Defects in the VCS are often associated with life-threatening arrhythmias and also promote adverse remodeling in heart disease. We have previously established that the Irx3 homeobox gene regulates rapid electrical propagation in the VCS by modulating the transcription of gap junction proteins Cx40 and Cx43. However, it is unknown whether other factors contribute to the conduction defects observed in Irx3 knockout (Irx3(-/-)) mice. In this study, we show that during the early postnatal period, Irx3(-/-) mice develop morphological defects in the VCS which are temporally dissociated from changes in gap junction expression. These morphological defects were accompanied with progressive changes in the cardiac electrocardiogram including right bundle branch block. Hypoplastic VCS was not associated with increased apoptosis of VCS cardiomyocytes but with a lack of recruitment and maturation of ventricular cardiomyocytes into the VCS. Computational analysis followed by functional verification revealed that Irx3 promotes VCS-enriched transcripts targeted by Nkx2.5 and/or Tbx5. Altogether, these results indicate that, in addition to ensuring the appropriate expression of gap junctional channels in the VCS, Irx3 is necessary for the postnatal maturation of the VCS, possibly via its interactions with Tbx5 and Nkx2.5.
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PMID:Irx3 is required for postnatal maturation of the mouse ventricular conduction system. 2678 75