RESUMEN
BACKGROUND: Serious congenital heart defects occur as a result of improper atrioventricular septum (AVS) development during embryogenesis. Despite extensive knowledge of the genetic control of AVS development, few genetic lesions have been identified that are responsible for AVS-associated congenital heart defects. METHODS AND RESULTS: We sequenced 32 genes known to be important in AVS development in patients with AVS defects and identified 11 novel coding single-nucleotide polymorphisms that are predicted to impair protein function. We focused on variants identified in the bone morphogenetic protein receptor, ALK2, and subjected 2 identified variants to functional analysis. The coding single-nucleotide polymorphisms R307L and L343P are heterozygous missense substitutions and were each identified in single individuals. The L343P allele had impaired functional activity as measured by in vitro kinase and bone morphogenetic protein-specific transcriptional response assays and dominant-interfering activity in vivo. In vivo analysis of zebrafish embryos injected with ALK2 L343P RNA revealed improper atrioventricular canal formation. CONCLUSIONS: These data identify the dominant-negative allele ALK2 L343P in a patient with AVS defects.
Asunto(s)
Receptores de Activinas Tipo I/metabolismo , Alelos , Genes Dominantes , Defectos de los Tabiques Cardíacos/metabolismo , Polimorfismo de Nucleótido Simple , Receptores de Activinas Tipo I/genética , Sustitución de Aminoácidos , Animales , Células COS , Bovinos , Chlorocebus aethiops , Femenino , Corazón/embriología , Corazón/fisiopatología , Defectos de los Tabiques Cardíacos/genética , Defectos de los Tabiques Cardíacos/fisiopatología , Humanos , Masculino , Mutación Missense , Miocardio/metabolismo , Países Bajos , Pez Cebra/embriología , Pez Cebra/genéticaRESUMEN
INTRODUCTION: In patients after ST-elevation myocardial infarction (STEMI), antiplatelet therapy reduces subsequent cardiac events, which are often attributed to recurrent thrombosis with (sub)total occlusion in the infarct-related artery. Whether antiplatelet therapy influences the often subclinical process of coronary disease progression in noninfarct arteries has not been reported. METHODS: Quantitative coronary angiography of noninfarct arteries was performed on paired cine-angiograms of 149 patients from fibrinolytic trials who had a patent infarct-related artery 3 to 4 weeks following STEMI and who were randomized to either continue the daily combination of 50-mg aspirin and 400-mg dipyridamole or to matching placebo. Follow-up angiography was scheduled at 1 year. RESULTS: On a per-patient basis, the change in minimal luminal diameter (MLD) was 0.00 mm in the aspirin/dipyridamole group (n = 76) and was 0.01 mm in the placebo group (n = 73). There was no difference between these groups in the changes in MLD (-0.02 mm; 95% CI -0.09 to 0.05), neither were there significant differences in mean luminal diameter and diameter stenosis. Progression (1 segment/patient with > or = 0.40 mm decrease in MLD) was seen in two thirds of patients and did not independently predict long-term death and/or reinfarction. CONCLUSION: In this placebo-controlled trial after STEMI, the combination of aspirin and dipyridamole did not affect noninfarct artery disease progression. Progression did not predict long-term clinical outcome.
Asunto(s)
Aspirina/uso terapéutico , Enfermedad Coronaria/prevención & control , Dipiridamol/uso terapéutico , Infarto del Miocardio/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Angiografía Coronaria , Enfermedad Coronaria/mortalidad , Progresión de la Enfermedad , Quimioterapia Combinada , Humanos , Pronóstico , Modelos de Riesgos Proporcionales , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Down's syndrome (DS), resulting from an additional copy of chromosome 21 (trisomy 21), is frequently associated with congenital heart defects (CHDs). Although the increased dosage of chromosome 21 sequences is likely to be part of the etiology of cardiac defects, only a proportion of DS patients exhibit a congenital heart defect (birth prevalence 40-60%). Through a large-candidate gene-sequencing screen in patients with atrioventricular septal defects, substitutions were identified in bone morphogenetic protein (BMP) type I receptor ALK2 and two other genes in a patient with DS and a primum-type atrial septal defect. Structural modeling of the cytoplasmic domain of the ALK2 receptor suggests that H286 is in close proximity to the nucleotide-binding site of the kinase domain. We investigated whether this p.His286Asp substitution altered ALK2 function by using both in vitro as well as in vivo assays. The p.His286Asp variant demonstrated impaired functional activity as measured by BMP-specific transcriptional response assays. Furthermore, mild dominant-interfering activity was observed in vivo compared with wild-type ALK2 as determined by RNA injection into zebrafish embryos. These data indicate that in the context of a DS background, ALK2-mediated reduction of BMP signaling may contribute to CHDs.
Asunto(s)
Receptores de Activinas Tipo I/genética , Síndrome de Down/genética , Cardiopatías Congénitas/etiología , Cardiopatías Congénitas/genética , Mutación/genética , Receptores de Activinas Tipo I/química , Receptores de Activinas Tipo I/metabolismo , Animales , Proteína Morfogenética Ósea 1/metabolismo , Bovinos , Síndrome de Down/complicaciones , Femenino , Cardiopatías Congénitas/diagnóstico , Defectos del Tabique Interatrial/genética , Defectos del Tabique Interatrial/patología , Humanos , Masculino , Conformación Proteica , Pez Cebra/genéticaRESUMEN
Through the use of animal studies, many candidate genes (mainly encoding transcriptional factors and receptors) have been implicated in the development of congenital heart disease. Thus far, only a minority of these genes have been shown to carry mutations associated with congenital disease in humans, e.g., GATA 4, TBX-5, NOTCH1 and NKX2-5. Mutations in these genes can cause a variety of cardiac defects even within the same family. Conversely, similar phenotypes are observed for different gene mutations suggesting a common pathway. Multiple genes and genetic pathways have been related to atrioventricular valve formation, although most of these genes have not yet been demonstrated as causative in human atrioventricular valve defects. Key pathways include the epidermal growth factor receptor pathway and related interacting pathways, most importantly the pathway of UDP-glucose dehydrogenase, resulting ultimately in activation of Ras. Other examples of interacting pathways include that of Nodal/Cited2/Pitx2, Wnt, Notch and ECE. Further studies are needed to investigate the pathways which are crucial for atrioventricular valve formation in humans. Understanding the underlying molecular process of abnormal atrioventricular valve formation in patients with congenital heart disease may provide important insight, in the etiology and possibly into preventive or treatment regimes.