RESUMEN
Hypercholesterolemia has not traditionally been considered an important risk factor in the pathogenesis of stroke. However, recent studies show that statin therapy significantly reduces ischemic stroke for patients with established coronary artery disease. Statin therapy may reduce stroke through amelioration of precerebral atherosclerosis in the carotid artery and the aorta. Anti-atherosclerotic, anti-inflammatory, and antithrombotic actions of statins occur within the blood and in plaque. Statins may also protect against cerebral ischemia through beneficial modulation of the brain endothelial nitric oxide system. Ongoing studies are exploring the role of statin therapy in the primary prevention of stroke and in the prevention of cognitive decline and multi-infarct cerebrovascular disease.
Asunto(s)
Anticolesterolemiantes/uso terapéutico , Fibrinolíticos/uso terapéutico , Ácidos Heptanoicos/uso terapéutico , Lovastatina/uso terapéutico , Pirroles/uso terapéutico , Accidente Cerebrovascular/prevención & control , Antiinflamatorios/uso terapéutico , Anticolesterolemiantes/farmacología , Atorvastatina , Isquemia Encefálica/complicaciones , Encefalitis/prevención & control , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/enzimología , Fibrinolíticos/farmacología , Ácidos Heptanoicos/farmacología , Humanos , Lovastatina/farmacología , Óxido Nítrico Sintasa/metabolismo , Pirroles/farmacología , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/fisiopatologíaRESUMEN
An emerging body of evidence indicates that beta-hydroxy-beta-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or 'statins', provide neuroprotection in addition to reducing ischaemic stroke. Statins reduce the incidence of ischaemic stroke by stabilising atherosclerotic plaques in the precerebral vasculature and through antithrombotic actions, and the neuroprotective effects of statins may confer significant clinical benefit. Some of these neuroprotective effects are likely to be cholesterol independent and mediated by the interruption of isoprenoid biosynthesis. Therapy with statins may modulate endothelial function and preserve blood flow to regions exposed to an ischaemic insult. In particular, statin-mediated preservation of endothelial nitric oxide synthase activity in cerebral vasculature, especially in the ischaemic penumbra, may limit neurological deficit. Moreover, putative anti-inflammatory and antioxidant properties of statins may confer additional neuroprotection. Further large clinical trials are necessary to address the role of statin therapy in the primary prevention of stroke, small vessel cerebrovascular disease and vascular dementia.
Asunto(s)
Isquemia Encefálica/tratamiento farmacológico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Accidente Cerebrovascular/tratamiento farmacológico , Antioxidantes/farmacología , Citocinas/biosíntesis , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Antígeno de Macrófago-1/análisis , Óxido Nítrico Sintasa/fisiologíaAsunto(s)
Complejos Multienzimáticos/genética , Mutación Missense , Proteínas Serina-Treonina Quinasas/genética , Síndrome de Wolff-Parkinson-White/genética , Proteínas Quinasas Activadas por AMP , Cardiomiopatía Hipertrófica/genética , Cromosomas Humanos Par 7 , Electrocardiografía , Electrofisiología , Genes Dominantes , Humanos , Complejos Multienzimáticos/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Síndrome de Wolff-Parkinson-White/fisiopatologíaRESUMEN
BACKGROUND: Aortic aneurysms cause significant mortality, and >20% relate to hereditary disorders. Familial aortic aneurysm (FAA) has been described in such conditions as the Marfan and Ehlers-Danlos type IV syndromes, due to defects in the fibrillin-1 and type III procollagen genes, respectively. Other gene defects that cause isolated aneurysms, however, have not thus far been described. METHODS AND RESULTS: We studied 3 families affected by FAA. No family met the diagnostic criteria for either Marfan or Ehlers-Danlos syndrome. Echocardiography defined involvement of both the thoracic and abdominal aorta. In family ANA, candidate gene analysis excluded linkage to loci associated with aneurysm formation, including fibrillin-1, fibrillin-2, and type III procollagen, and chromosome 3p24.2-p25. Genome-wide linkage analysis identified a 2.3-cM FAA locus (FAA1) on chromosome 11q23.3-q24 with a maximum multipoint logarithm of the odds score of 4.4. In family ANB, FAA was linked to fibrillin-1. In family ANF, however, FAA was not linked to any locus previously associated with aneurysm formation, including fibrillin-1 and FAA1. CONCLUSIONS: FAA disease is genetically heterogeneous. We have identified a novel FAA locus at chromosome 11q23.3-q24, a critical step toward elucidating 1 gene defect responsible for aortic dilatation. Future characterization of the FAA1 gene will enhance our ability to achieve presymptomatic diagnosis of aortic aneurysms and will define molecular mechanisms to target therapeutics.
Asunto(s)
Aneurisma de la Aorta/genética , Cromosomas Humanos Par 11/genética , Adolescente , Adulto , Anciano , Aneurisma de la Aorta/patología , Niño , Preescolar , Bandeo Cromosómico , Mapeo Cromosómico , Salud de la Familia , Femenino , Heterogeneidad Genética , Predisposición Genética a la Enfermedad/genética , Humanos , Lactante , Escala de Lod , Masculino , Repeticiones de Microsatélite , Persona de Mediana Edad , LinajeRESUMEN
BACKGROUND: Aneurysms and dissections affecting the ascending aorta are associated primarily with degeneration of the aortic media, called medial necrosis. Families identified with dominant inheritance of thoracic aortic aneurysms and dissections (TAA/dissections) indicate that single gene mutations can cause medial necrosis in the absence of an associated syndrome. METHODS AND RESULTS: Fifteen families were identified with multiple members with TAAs/dissections. DNA from affected members from 2 of the families was used for a genome-wide search for the location of the defective gene by use of random polymorphic markers. The data were analyzed by the affected-pedigree-member method of linkage analysis. This analysis revealed 3 chromosomal loci with multiple markers demonstrating evidence of linkage to the phenotype. Linkage analysis using further markers in these regions and DNA from 15 families confirmed linkage of some of the families to 5q13-14. Genetic heterogeneity for the condition was confirmed by a heterogeneity test. Data from 9 families with the highest conditional probability of being linked to 5q were used to calculate the pairwise and multipoint logarithm of the odds (LOD) scores, with a maximum LOD of 4.74, with no recombination being obtained for the marker D5S2029. In 6 families, the phenotype was not linked to the 5q locus. CONCLUSIONS: A major locus for familial TAAs and dissections maps to 5q13-14, with the majority (9 of 15) of the families identified demonstrating evidence of linkage to this locus. The condition is genetically heterogeneous, with 6 families not demonstrating evidence of linkage to any loci previously associated with aneurysm formation.
Asunto(s)
Aneurisma de la Aorta Torácica/genética , Disección Aórtica/genética , Proteínas de la Matriz Extracelular , Proteoglicanos , Disección Aórtica/patología , Aneurisma de la Aorta Torácica/patología , Proteoglicanos Tipo Condroitín Sulfato/genética , Mapeo Cromosómico , Cromosomas Humanos Par 5/genética , Salud de la Familia , Femenino , Heterogeneidad Genética , Genoma Humano , Genotipo , Haplotipos , Humanos , Lectinas Tipo C , Escala de Lod , Masculino , Repeticiones de Microsatélite , Linaje , Polimorfismo de Nucleótido Simple , Proteínas/genética , Análisis de Secuencia de ADN , Trombospondinas/genética , VersicanosRESUMEN
Recent molecular genetic investigations of primary cardiac tumors (myxomas, lipomas, rhabdomyomas, and fibromas) have provided insight into fundamental mechanisms of cardiac cell growth. Myxomas are the most common adult cardiac tumor, and familial cardiac myxomas are now appreciated to be caused by mutations in the PRKAR1alpha gene that encodes a regulatory subunit of protein kinase A. Cytogenetic studies have targeted candidate chromosomal loci that may be perturbed during cardiac lipoma pathogenesis. Rhabdomyomas, the most common pediatric cardiac neoplasm, are frequently associated with tuberous sclerosis, caused by mutations in the TSC-1 and TSC-2 genes. The study of Gorlin syndrome has shed light on the etiology of cardiac fibromas. This disorder is caused by mutation of the PTC gene, which regulates cell growth, commitment and differentiation. In the future, manipulation of PRKAR1alpha-, TSC-, and PTC-dependent pathways may foster new strategies to regenerate myocardium in the ischemic or myopathic heart.
Asunto(s)
Neoplasias Cardíacas , Fibroma/genética , Neoplasias Cardíacas/genética , Humanos , Lipoma/genética , Biología Molecular/tendencias , Mixoma/genética , Rabdomioma/genéticaRESUMEN
Mutations in human TBX5, a member of the T-box transcription factor gene family, cause congenital cardiac septation defects and isomerism in autosomal dominant Holt-Oram syndrome. To determine the cellular function of TBX5 in cardiogenesis, we overexpressed wild-type and mutant human TBX5 isoforms in vitro and in vivo. TBX5 inhibited cell proliferation of D17 canine osteosarcoma cells and MEQC quail cardiomyocyte-like cells in vitro. Mutagenesis of the 5' end of the T-box but not the 3' end of the T-box abolished this effect. Overexpression of TBX5 in embryonic chick hearts showed that TBX5 inhibits myocardial growth and trabeculation. TBX5 effects in vivo were abolished by Gly80Arg missense mutation of the 5' end of the T-box. PCNA analysis in transgenic chick hearts revealed that TBX5 overexpression does suppress embryonic cardiomyocyte proliferation in vivo. Inhibitory effects of TBX5 on cardiomyocyte proliferation include a noncell autonomous process in vitro and in vivo. TBX5 inhibited proliferation of both nontransgenic cells cocultured with transgenic cells in vitro and nontransgenic cardiomyocytes in transgenic chick hearts with mosaic expression of TBX5 in vivo. Immunohistochemical studies of human embryonic tissues, including hearts, also demonstrated that TBX5 expression is inversely related to cellular proliferation. We propose that TBX5 can act as a cellular arrest signal during vertebrate cardiogenesis and thereby participate in modulation of cardiac growth and development.
Asunto(s)
Corazón/embriología , Miocardio/citología , Proteínas de Dominio T Box/metabolismo , Sustitución de Aminoácidos , Animales , Animales Modificados Genéticamente , División Celular , Línea Celular , Embrión de Pollo , Perros , Corazón Fetal/citología , Corazón Fetal/fisiología , Humanos , Mutagénesis Sitio-Dirigida , Mutación Missense , Osteosarcoma , Antígeno Nuclear de Célula en Proliferación/análisis , Codorniz , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Proteínas de Dominio T Box/química , Proteínas de Dominio T Box/genética , Transfección , Células Tumorales Cultivadas , beta-Galactosidasa/análisis , beta-Galactosidasa/genéticaRESUMEN
This unit describes several polymerase chain reaction (PCR)-based methods to obtain DNA fragments from clones with large inserts without prior knowledge of the insert DNA sequence. The protocols can be categorized into three groups: (1) methods to generate DNA fragments at random representing the entire length of the cloned insert, (2) methods to generate DNA fragments representing the extremities of an insert, and (3) methods to generate complex probes suitable for fluorescence in situ hybridization. Support protocols describe direct cloning of these PCR products and the isolation of total yeast DNA from yeast artificial chromosome (YAC) clones.
Asunto(s)
Técnicas de Sonda Molecular , Reacción en Cadena de la Polimerasa/métodos , Elementos Alu , Cromosomas Artificiales de Bacteriófagos P1/genética , Cromosomas Artificiales de Levadura/genética , Clonación Molecular , Sondas de ADN/genética , Sondas de ADN/aislamiento & purificación , Vectores Genéticos , Genética Médica , Humanos , Hibridación Fluorescente in SituRESUMEN
Cardiac myxomas are benign mesenchymal tumors that can present as components of the human autosomal dominant disorder Carney complex. Syndromic cardiac myxomas are associated with spotty pigmentation of the skin and endocrinopathy. Our linkage analysis mapped a Carney complex gene defect to chromosome 17q24. We now demonstrate that the PRKAR1alpha gene encoding the R1alpha regulatory subunit of cAMP-dependent protein kinase A (PKA) maps to this chromosome 17q24 locus. Furthermore, we show that PRKAR1alpha frameshift mutations in three unrelated families result in haploinsufficiency of R1alpha and cause Carney complex. We did not detect any truncated R1alpha protein encoded by mutant PRKAR1alpha. Although cardiac tumorigenesis may require a second somatic mutation, DNA and protein analyses of an atrial myxoma resected from a Carney complex patient with a PRKAR1alpha deletion revealed that the myxoma cells retain both the wild-type and the mutant PRKAR1alpha alleles and that wild-type R1alpha protein is stably expressed. However, in this atrial myxoma, we did observe a reversal of the ratio of R1alpha to R2beta regulatory subunit protein, which may contribute to tumorigenesis. Further investigation will elucidate the cell-specific effects of PRKAR1alpha haploinsufficiency on PKA activity and the role of PKA in cardiac growth and differentiation.
Asunto(s)
Anomalías Múltiples/genética , Proteínas Quinasas Dependientes de AMP Cíclico/genética , Mutación del Sistema de Lectura , Neoplasias Cardíacas/genética , Mixoma/genética , Trastornos de la Pigmentación/genética , Anomalías Múltiples/etiología , Cromosomas Humanos Par 17 , Clonación Molecular , Femenino , Neoplasias Cardíacas/etiología , Humanos , Masculino , Mixoma/etiología , Trastornos de la Pigmentación/etiología , Análisis de Secuencia de ADNRESUMEN
Mutations in the TBX5 transcription factor gene cause human cardiac malformation in Holt-Oram syndrome. To identify and localize TBX5 during cardiac morphogenesis, we performed immunohistochemical studies of TBX5 protein cardiac expression during human embryogenesis. Specific antibody to human TBX5 was generated in rabbits with a TBX5 synthetic peptide and affinity purification of antiserum. Anti-TBX5 was used in immunohistochemical analyses of human cardiac tissue. In embryonic and adult heart, TBX5 is expressed throughout the epicardium and in cardiomyocyte nuclei in myocardium of all four cardiac chambers. Endocardial expression of TBX5 is only present in left ventricle. Asymmetric left-sided transmyocardial gradients of TBX5 protein expression were observed in embryonic but not adult hearts. Human cardiac expression of TBX5 protein correlates with the cardiac manifestations of Holt-Oram syndrome. TBX5 transmyocardial protein gradients may contribute to normal patterning of the human heart during embryogenesis.
Asunto(s)
Embrión de Mamíferos/metabolismo , Corazón Fetal/química , Cardiopatías Congénitas/genética , Miocardio/química , Proteínas de Dominio T Box/análisis , Adulto , Animales , Western Blotting , Desarrollo Embrionario y Fetal , Endocardio/química , Regulación del Desarrollo de la Expresión Génica , Humanos , Inmunohistoquímica , Morfogénesis , Miocardio/citología , Pericardio/química , Conejos , Proteínas Recombinantes de Fusión , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/inmunologíaRESUMEN
Cardiac lipomas occur infrequently but account for a significant portion of rare cardiac tumors. Common cutaneous lipomas have previously been associated with rearrangements of chromosome band 12q15, which often disrupt the high-mobility-group protein gene HMGIC. In this report, we describe the cytogenetic analysis of an unusual giant cardiac lipoma that exhibited myocardial invasion in a patient with a history of multiple lipomatosis (cutaneous lipoma, lipomatous gynecomastia, lipomatous hypertrophy of the interatrial septum, and dyslipidemia). Cytogenetic studies of cells derived from the cardiac lipoma demonstrated no abnormalities of chromosome 12, but did reveal a t(2;19)(p13;p13.2). A liposarcoma-derived oncogene (p115-RhoGEF) previously mapped to chromosome 19 and the low-density lipoprotein receptor gene (LDLR) previously mapped to chromosome band 19p13 were evaluated to determine whether they were disrupted by this translocation. Fluorescence in situ hybridization analyses assigned p115-RhoGEF to chromosome 19 in bands q13.2-q13.3 and mapped the LDLR to chromosome arm 19p in segment 13.2, but centromeric to the t(2;19) breakpoint. Thus, these genes are unlikely to be involved in the t(2;19)(p13;p13.2). Further studies of the regions of chromosomes 2 and 19 perturbed by the translocation in this unusual infiltrating cardiac lipoma will identify gene(s) that participate in adipocyte growth and differentiation and may provide insight into syndromes of multiple lipomatosis.
Asunto(s)
Cromosomas Humanos Par 19/genética , Cromosomas Humanos Par 2/genética , Neoplasias Cardíacas/genética , Neoplasias Cardíacas/patología , Lipoma/genética , Lipoma/patología , Lipomatosis Simétrica Múltiple/genética , Lipomatosis Simétrica Múltiple/patología , Translocación Genética/genética , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Masculino , Persona de Mediana Edad , Invasividad NeoplásicaRESUMEN
Significant advances in the management of cardiovascular disease have been made possible by the development of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors--"statins." Initial studies explored the impact of statin therapy on coronary artery disease (CAD) progression and regression. Although the angiographic changes were small, associated clinical responses appeared significant. Subsequent large prospective placebo-controlled clinical trials with statins demonstrated benefit in the secondary and primary prevention of CAD in subjects with elevated cholesterol levels. More recently, the efficacy of statins has been extended to the primary prevention of CAD in subjects with average cholesterol levels. Recent studies also suggest that statins have benefits beyond the coronary vascular bed and are capable of reducing ischemic stroke risk by approximately one-third in patients with evidence of vascular disease. In addition to lowering low-density lipoprotein (LDL) cholesterol, statin therapy appears to exhibit pleiotropic effects on many components of atherosclerosis including plaque thrombogenicity, cellular migration, endothelial function and thrombotic tendency. Growing clinical and experimental evidence indicates that the beneficial actions of statins occur rapidly and yield potentially clinically important anti-ischemic effects as early as one month after commencement of therapy. Future investigations are warranted to determine threshold LDL values in primary prevention studies, and to elucidate effects of statins other than LDL lowering. Finally, given the rapid and protean effects of statins on determinants of platelet reactivity, coagulation, and endothelial function, further research may establish a role for statin therapy in acute coronary syndromes.
Asunto(s)
Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipercolesterolemia/tratamiento farmacológico , Hipolipemiantes/uso terapéutico , Accidente Cerebrovascular/tratamiento farmacológico , LDL-Colesterol/sangre , Ensayos Clínicos como Asunto , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/etiología , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Hipercolesterolemia/sangre , Hipercolesterolemia/complicaciones , Hipolipemiantes/efectos adversos , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/etiología , Resultado del TratamientoRESUMEN
Septation defects and patent ductus arteriosus are the most common human cardiovascular malformations (CVMs). Genetic factors play a major part in the origin of these malformations. Recent molecular analyses have shed light on several mendelian forms. In the autosomal dominant Holt-Oram syndrome, both atrial and ventricular septal defects are inherited in association with limb deformity as a result of mutations in the gene encoding the TBX5 transcription factor. Mutations in the NKX2.5 transcription factor gene cause autosomal dominant familial atrial septal defects in association with progressive atrioventricular block as well as complex congenital heart disease. Common atrial syndromes in autosomal dominant Ellis-van Creveld syndrome arise in the context of axial skeletal and limb malformation as a result of mutations in the EVC gene, whose function is unknown. Patent ductus arteriosus occurs in several syndromic forms of congenital heart disease, including Holt-Oram syndrome. Recent analyses of autosomal dominant Char syndrome, which includes, with variable penetrance, patent ductus arteriosus as well as craniofacial and hand malformations, have shown that the syndrome is caused by mutations in the TFAP2B transcription factor gene. Ongoing analyses are poised to determine the contribution of these genes as well as others yet to be identified to common, sporadic forms of congenital heart disease.
Asunto(s)
Conducto Arterioso Permeable/genética , Defectos del Tabique Interatrial/genética , Defectos del Tabique Interventricular/genética , Proteínas de Xenopus , Anomalías Múltiples/genética , Anomalías Múltiples/patología , Animales , Movimiento Celular , Embrión de Pollo , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/fisiología , Síndrome de Down/patología , Conducto Arterioso Permeable/embriología , Conducto Arterioso Permeable/epidemiología , Síndrome de Ellis-Van Creveld/genética , Síndrome de Ellis-Van Creveld/patología , Defectos de la Almohadilla Endocárdica/embriología , Defectos de la Almohadilla Endocárdica/genética , Femenino , Corazón Fetal/patología , Regulación del Desarrollo de la Expresión Génica , Genes Dominantes , Ligamiento Genético , Defectos del Tabique Interatrial/embriología , Defectos del Tabique Interventricular/embriología , Proteína Homeótica Nkx-2.5 , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/fisiología , Humanos , Masculino , Proteínas de la Membrana , Ratones , Modelos Animales , Cresta Neural/citología , Linaje , Proteínas/genética , Proteínas/fisiología , Síndrome , Proteínas de Dominio T Box/deficiencia , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/fisiología , Factor de Transcripción AP-2 , Factores de Transcripción/deficiencia , Factores de Transcripción/genética , Factores de Transcripción/fisiologíaRESUMEN
Molecular genetic analyses of human hereditary disorders that affect cardiac atrial structure and function have recently identified several genes that regulate atrial morphogenesis. Mutations of the TBX5, NKX2.5, EVC, and PRKAR1 alpha genes all result in abnormalities of human atrial growth and development, and mutations in at least one gene results in familial atrial fibrillation and is as yet unidentified. Ongoing studies to find interactions between these transcription factors and intracellular signaling molecules and other as yet unknown genes are establishing critical pathways in human cardiogenesis. Human investigation and experimental animal models of heart development synergize to elucidate etiologies of common congenital heart disease.
Asunto(s)
Atrios Cardíacos/embriología , Defectos del Tabique Interatrial/genética , Anomalías Múltiples/genética , Animales , Fibrilación Atrial/genética , Predisposición Genética a la Enfermedad , Bloqueo Cardíaco/genética , Neoplasias Cardíacas/genética , Defectos del Tabique Interatrial/embriología , Humanos , Mutación , Mixoma/genética , SíndromeRESUMEN
We describe an individual in whom molecular genetic testing provided a diagnosis of the Carney complex, an autosomal dominant syndrome comprising cutaneous and cardiac myxomas, spotty pigmentation of the skin, and endocrinopathy. Recently, we localized the Carney complex disease gene to chromosome region 17q2. Our patient was a member of a family segregating the Carney complex, but was not, himself, initially thought to be affected. Haplotype analysis based on genotyping studies with 17q2 microsatellites predicted that this individual was, in fact, affected by Carney complex and was at risk for development of myxomas. Further clinical evaluation and re-review of prior pathologic studies, then, confirmed the DNA-based diagnosis. This report highlights the difficulty in establishing a diagnosis of Carney complex based on clinical and pathologic findings alone, and we suggest that molecular genetic analyses provide an important diagnostic method for this familial myxoma syndrome.
Asunto(s)
Pruebas Genéticas , Mixoma/diagnóstico , Mixoma/genética , Adulto , Cromosomas Humanos Par 17/genética , Femenino , Genes Dominantes , Genotipo , Haplotipos , Humanos , Masculino , Repeticiones de Microsatélite/genética , Mixoma/patología , Núcleo Familiar , Linaje , SíndromeRESUMEN
Molecular genetic analyses have generated significant advances in our understanding of congenital heart disease. Techniques of genetic mapping with polymorphic microsatellites and fluorescence in situ hybridization (FISH) have provided informative tools for localization and identification of disease genes. Some cardiovascular diseases have proven to result from single gene defects. Others relate to more complex etiologies involving several genes and their interactions. Elucidation of the molecular genetic etiologies of congenital heart disease prompts consideration of DNA testing for cardiac disorders. Future integration of these diagnostic modalities with improved treatments may ultimately decrease morbidity and mortality from congenital heart diseases.
Asunto(s)
Cardiopatías Congénitas/genética , Animales , Femenino , Neoplasias Cardíacas/genética , Defectos de los Tabiques Cardíacos/genética , Válvulas Cardíacas/anomalías , Humanos , Masculino , Ratones , Biología Molecular , SíndromeRESUMEN
To better understand the role of TBX5, a T-box containing transcription factor in forelimb and heart development, we have studied the clinical features of Holt-Oram syndrome caused by 10 different TBX5 mutations. Defects predicted to create null alleles caused substantial abnormalities both in limb and heart. In contrast, missense mutations produced distinct phenotypes: Gly80Arg caused significant cardiac malformations but only minor skeletal abnormalities; and Arg237Gln and Arg237Trp caused extensive upper limb malformations but less significant cardiac abnormalities. Amino acids altered by missense mutations were located on the three-dimensional structure of a related T-box transcription factor, Xbra, bound to DNA. Residue 80 is highly conserved within T-box sequences that interact with the major groove of target DNA; residue 237 is located in the T-box domain that selectively binds to the minor groove of DNA. These structural data, taken together with the predominant cardiac or skeletal phenotype produced by each missense mutation, suggest that organ-specific gene activation by TBX5 is predicated on biophysical interactions with different target DNA sequences.