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Heart malformation

About: Heart malformation is a research topic. Over the lifetime, 2295 publications have been published within this topic receiving 51040 citations.


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Journal ArticleDOI
TL;DR: The spectrum and distribution of PTPN11 mutations in a large, well-characterized cohort with NS revealed that pulmonic stenosis was more prevalent among the group of subjects with NS who had PTP N11 mutations than it was in the group without them, andotype-phenotype analysis revealed that hypertrophic cardiomyopathy was less prevalent among those with PTPn11 mutations.
Abstract: Noonan syndrome (NS) is a developmental disorder characterized by facial dysmorphia, short stature, cardiac defects, and skeletal malformations. We recently demonstrated that mutations in PTPN11, the gene encoding the non-receptor-type protein tyrosine phosphatase SHP-2 (src homology region 2-domain phosphatase-2), cause NS, accounting for approximately 50% of cases of this genetically heterogeneous disorder in a small cohort. All mutations were missense changes and clustered at the interacting portions of the amino-terminal src-homology 2 (N-SH2) and protein tyrosine phosphatase (PTP) domains. A gain of function was postulated as a mechanism for the disease. Here, we report the spectrum and distribution of PTPN11 mutations in a large, well-characterized cohort with NS. Mutations were found in 54 of 119 (45%) unrelated individuals with sporadic or familial NS. There was a significantly higher prevalence of mutations among familial cases than among sporadic ones. All defects were missense, and several were recurrent. The vast majority of mutations altered amino acid residues located in or around the interacting surfaces of the N-SH2 and PTP domains, but defects also affected residues in the C-SH2 domain, as well as in the peptide linking the N-SH2 and C-SH2 domains. Genotype-phenotype analysis revealed that pulmonic stenosis was more prevalent among the group of subjects with NS who had PTPN11 mutations than it was in the group without them (70.6% vs. 46.2%; P<.01), whereas hypertrophic cardiomyopathy was less prevalent among those with PTPN11 mutations (5.9% vs. 26.2%; P<.005). The prevalence of other congenital heart malformations, short stature, pectus deformity, cryptorchidism, and developmental delay did not differ between the two groups. A PTPN11 mutation was identified in a family inheriting Noonan-like/multiple giant-cell lesion syndrome, extending the phenotypic range of disease associated with this gene.

702 citations

Journal ArticleDOI
01 Apr 2006-Heart
TL;DR: The curvature of the ventricular septum places the right ventricular outflow tract antero-cephalad to that of the left ventricle’s resulting in a characteristic “cross over” relationship.
Abstract: Often overlooked, and considered the poor relation of the left ventricle, there is increasing interest in the right ventricle particularly with regard to right ventricular failure. Right ventricular function may be impaired as a result of pressure or volume overload, often secondary to right heart valve or muscle pathology. Coronary artery disease may also lead to right ventricular dysfunction when the right coronary artery is occluded. In congenital heart malformations the right ventricle may also be affected, particularly in conditions that have the right ventricle supporting the systemic circulation or it becomes the sole pumping chamber following univentricular repair at surgery. Finally, right-to-left shunting may lead to right ventricular dilatation. Imaging the right ventricle by echocardiography is challenging because of the very particular crescentic shape of the right ventricle wrapping around the left ventricle, but it is important and ought to be part of the standard echocardiographic examination of the heart. To help understand cross sectional imaging of the right ventricle, we first review its location and its component parts, including the tricuspid and pulmonary valves, before discussing echo-anatomic correlations. The right ventricle in the normal heart is the most anteriorly situated cardiac chamber since it is located immediately behind the sternum. It also marks the inferior border of the cardiac silhouette. In contrast to the near conical shape of the left ventricle, the right ventricle is more triangular in shape when viewed from the front and it curves over the left ventricle. When seen from the apex, the right edge of the right ventricle is sharp, forming the acute margin of the heart. In cross section the cavity appears like a crescent. Thus, the curvature of the ventricular septum places the right ventricular outflow tract antero-cephalad to that of the left ventricle’s resulting in a characteristic “cross over” relationship …

508 citations

Journal ArticleDOI
TL;DR: It is demonstrated that DSCR1, the product of a chromosome 21 gene highly expressed in brain, heart and skeletal muscle, is overexpressed in the brain of Down syndrome fetuses, and interacts physically and functionally with calcineurin A, the catalytic subunit of the Ca(2+)/calmodulin-dependent protein phosphatase PP2B.
Abstract: Down syndrome is one of the major causes of mental retardation and congenital heart malformations. Other common clinical features of Down syndrome include gastrointestinal anomalies, immune system defects and Alzheimer's disease pathological and neurochemical changes. The most likely consequence of the presence of three copies of chromosome 21 is the overexpression of its resident genes, a fact which must underlie the pathogenesis of the abnormalities that occur in Down syndrome. Here we show that DSCR1, the product of a chromosome 21 gene highly expressed in brain, heart and skeletal muscle, is overexpressed in the brain of Down syndrome fetuses, and interacts physically and functionally with calcineurin A, the catalytic subunit of the Ca(2+)/calmodulin-dependent protein phosphatase PP2B. The DSCR1 binding region in calcineurin A is located in the linker region between the calcineurin A catalytic domain and the calcineurin B binding domain, outside of other functional domains previously defined in calcineurin A. DSCR1 belongs to a family of evolutionarily conserved proteins with three members in humans: DSCR1, ZAKI-4 and DSCR1L2. We further demonstrate that overexpression of DSCR1 and ZAKI-4 inhibits calcineurin-dependent gene transcription through the inhibition of NF-AT translocation to the nucleus. Together, these results suggest that members of this newly described family of human proteins are endogenous regulators of calcineurin-mediated signaling pathways and as such, they may be involved in many physiological processes.

453 citations


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Performance
Metrics
No. of papers in the topic in previous years
YearPapers
20224
202196
202097
2019101
2018114
201768