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1.
Adv Exp Med Biol ; 1441: 481-493, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38884727

RESUMO

The relative simplicity of the clinical presentation and management of an atrial septal defect belies the complexity of the developmental pathogenesis. Here, we describe the anatomic development of the atrial septum and the venous return to the atrial chambers. Experimental models suggest how mutations and naturally occurring genetic variation could affect developmental steps to cause a defect within the oval fossa, the so-called secundum defect, or other interatrial communications, such as the sinus venosus defect or ostium primum defect.


Assuntos
Modelos Animais de Doenças , Comunicação Interatrial , Comunicação Interatrial/genética , Comunicação Interatrial/patologia , Comunicação Interatrial/fisiopatologia , Animais , Humanos , Mutação , Septo Interatrial/patologia , Transdução de Sinais/genética
2.
Nature ; 520(7546): 230-3, 2015 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-25830876

RESUMO

Maternal age is a risk factor for congenital heart disease even in the absence of any chromosomal abnormality in the newborn. Whether the basis of this risk resides with the mother or oocyte is unknown. The impact of maternal age on congenital heart disease can be modelled in mouse pups that harbour a mutation of the cardiac transcription factor gene Nkx2-5 (ref. 8). Here, reciprocal ovarian transplants between young and old mothers establish a maternal basis for the age-associated risk in mice. A high-fat diet does not accelerate the effect of maternal ageing, so hyperglycaemia and obesity do not simply explain the mechanism. The age-associated risk varies with the mother's strain background, making it a quantitative genetic trait. Most remarkably, voluntary exercise, whether begun by mothers at a young age or later in life, can mitigate the risk when they are older. Thus, even when the offspring carry a causal mutation, an intervention aimed at the mother can meaningfully reduce their risk of congenital heart disease.


Assuntos
Envelhecimento/fisiologia , Cardiopatias/congênito , Cardiopatias/prevenção & controle , Idade Materna , Condicionamento Físico Animal/fisiologia , Prenhez/fisiologia , Idade de Início , Envelhecimento/genética , Animais , Animais Recém-Nascidos , Dieta Hiperlipídica , Feminino , Predisposição Genética para Doença , Coração/fisiologia , Coração/fisiopatologia , Cardiopatias/etiologia , Cardiopatias/genética , Proteína Homeobox Nkx-2.5 , Proteínas de Homeodomínio/genética , Hiperglicemia , Camundongos , Obesidade , Ovário/transplante , Fenótipo , Gravidez , Prenhez/genética , Locos de Características Quantitativas/genética , Risco , Fatores de Transcrição/genética
3.
Genes (Basel) ; 12(9)2021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34573350

RESUMO

In newborns, severe congenital heart defects are rarer than mild ones. This epidemiological relationship between heart defect severity and incidence lacks explanation. Here, an analysis of ~10,000 Nkx2-5+/- mice from two inbred strain crosses illustrates the fundamental role of epistasis. Modifier genes raise or lower the risk of specific defects via pairwise (G×GNkx) and higher-order (G×G×GNkx) interactions with Nkx2-5. Their effect sizes correlate with the severity of a defect. The risk loci for mild, atrial septal defects exert predominantly small G×GNkx effects, while the loci for severe, atrioventricular septal defects exert large G×GNkx and G×G×GNkx effects. The loci for moderately severe ventricular septal defects have intermediate effects. Interestingly, G×G×GNkx effects are three times more likely to suppress risk when the genotypes at the first two loci are from the same rather than different parental inbred strains. This suggests the genetic coadaptation of interacting G×G×GNkx loci, a phenomenon that Dobzhansky first described in Drosophila. Thus, epistasis plays dual roles in the pathogenesis of congenital heart disease and the robustness of cardiac development. The empirical results suggest a relationship between the fitness cost and genetic architecture of a disease phenotype and a means for phenotypic robustness to have evolved.


Assuntos
Aptidão Genética , Comunicação Interatrial/genética , Comunicação Interventricular/genética , Defeitos dos Septos Cardíacos/genética , Proteína Homeobox Nkx-2.5/genética , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Feminino , Loci Gênicos , Defeitos dos Septos Cardíacos/diagnóstico , Comunicação Interatrial/diagnóstico , Comunicação Interventricular/diagnóstico , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Índice de Gravidade de Doença
4.
Mol Cell Endocrinol ; 435: 94-102, 2016 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-27555292

RESUMO

Despite decades of progress, congenital heart disease remains a major cause of mortality and suffering in children and young adults. Prevention would be ideal, but formidable biological and technical hurdles face any intervention that seeks to target the main causes, genetic mutations in the embryo. Other factors, however, significantly modify the total risk in individuals who carry mutations. Investigation of these factors could lead to an alternative approach to prevention. To define the risk modifiers, our group has taken an "experimental epidemiologic" approach via inbred mouse strain crosses. The original intent was to map genes that modify an individual's risk of heart defects caused by an Nkx2-5 mutation. During the analysis of >2000 Nkx2-5(+/-) offspring from one cross we serendipitously discovered a maternal-age associated risk, which also exists in humans. Reciprocal ovarian transplants between young and old mothers indicate that the incidence of heart defects correlates with the age of the mother and not the oocyte, which implicates a maternal pathway as the basis of the risk. The quantitative risk varies between strain backgrounds, so maternal genetic polymorphisms determine the activity of a factor or factors in the pathway. Most strikingly, voluntary exercise by the mother mitigates the risk. Therefore, congenital heart disease can in principle be prevented by targeting a maternal pathway even if the embryo carries a causative mutation. Further mechanistic insight is necessary to develop an intervention that could be implemented on a broad scale, but the physiology of maternal-fetal interactions, aging, and exercise are notoriously complex and undefined. This suggests that an unbiased genetic approach would most efficiently lead to the relevant pathway. A genetic foundation would lay the groundwork for human studies and clinical trials.


Assuntos
Modelos Animais de Doenças , Predisposição Genética para Doença , Cardiopatias Congênitas/etiologia , Cardiopatias Congênitas/prevenção & controle , Idade Materna , Polimorfismo de Nucleotídeo Único , Complicações na Gravidez/genética , Animais , Exercício Físico , Feminino , Cardiopatias Congênitas/genética , Humanos , Camundongos , Gravidez , Fatores de Risco
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