RESUMEN
Distinct stressors may induce heart failure. As compensation, ß-adrenergic stimulation enhances myocardial contractility by elevating cardiomyocyte intracellular Ca(2+) ([Ca(2+)]i). However, chronic ß-adrenergic stimulation promotes adverse cardiac remodelling. Cardiac expression of nuclear receptor Nur77 is enhanced by ß-adrenergic stimulation, but its role in cardiac remodelling is still unclear. We show high and rapid Nur77 upregulation in cardiomyocytes stimulated with ß-adrenergic agonist isoproterenol. Nur77 knockdown in culture resulted in hypertrophic cardiomyocytes. Ventricular cardiomyocytes from Nur77-deficient (Nur77-KO) mice exhibited elevated diastolic and systolic [Ca(2+)]i and prolonged action potentials compared to wild type (WT). In vivo, these differences resulted in larger cardiomyocytes, increased expression of hypertrophic genes, and more cardiac fibrosis in Nur77-KO mice upon chronic isoproterenol stimulation. In line with the observed elevated [Ca(2+)]i, Ca(2+)-activated phosphatase calcineurin was more active in Nur77-KO mice compared to WT. In contrast, after cardiac pressure overload by aortic constriction, Nur77-KO mice exhibited attenuated remodelling compared to WT. Concluding, Nur77-deficiency results in significantly altered cardiac Ca(2+) homeostasis and distinct remodelling outcome depending on the type of insult. Detailed knowledge on the role of Nur77 in maintaining cardiomyocyte Ca(2+) homeostasis and the dual role Nur77 plays in cardiac remodelling will aid in developing personalized therapies against heart failure.
Asunto(s)
Insuficiencia Cardíaca/genética , Contracción Miocárdica/genética , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Remodelación Ventricular/genética , Agonistas Adrenérgicos beta/administración & dosificación , Animales , Calcio/metabolismo , Insuficiencia Cardíaca/fisiopatología , Homeostasis , Humanos , Isoproterenol/administración & dosificación , Ratones , Ratones Noqueados , Contracción Miocárdica/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Remodelación Ventricular/fisiologíaRESUMEN
In several individuals with a Charcot-Marie-Tooth (CMT) phenotype, we found a copy number variation (CNV) on chromosome 17p12 in the direct vicinity of the peripheral myelin protein 22 (PMP22) gene. The exact borders and size of this CNV were determined by Southern blot analysis, MLPA, vectorette PCR, and microarray hybridization analyses. All patients from six apparently unrelated families carried an identical 186-kb duplication different from the commonly reported 1.5-Mb duplication associated with CMT1A. This ancestral mutation that was not reported in the human structural variation database was only detected in affected individuals and family members. It was absent in 2124 control chromosomes and 40 patients with a chronic inflammatory demyelinating polyneuropathy (CIDP) and therefore should be regarded as causative for the disease. This variant escapes most routine diagnostic screens for CMT1A, because copy numbers of PMP22 probes were all normal. No indications were found for the involvement of the genes that are located within this duplication. A possible association of this duplication with a mutation in the PMP22 coding regions was also excluded. We suggest that this CNV proximal of the PMP22 gene leads to CMT through an unknown mechanism affecting PMP22 expression.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Dosificación de Gen/genética , Variación Genética/genética , Proteínas de Microtúbulos/genética , Proteínas de la Mielina/metabolismo , Adulto , Southern Blotting , Segregación Cromosómica , Hibridación Genómica Comparativa , Femenino , Duplicación de Gen , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Mutación/genética , Proteínas de la Mielina/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Linaje , Fenotipo , Reacción en Cadena de la Polimerasa , Adulto JovenRESUMEN
A 2-year-old boy presented with early-onset Charcot-Marie-Tooth disease (CMT). His parents had not been diagnosed previously with CMT, but on careful examination they showed clinical signs of CMT and reduced nerve conduction velocities. Genetic analysis identified the boy as a heterozygote for both a peripheral myelin protein 22 (PMP22) duplication and a mutation in the lipopolysaccharide-induced-tumour-necrosis-factor-alpha-factor (LITAF) gene, whereas each parent only had one mutated CMT gene. This suggests that LITAF mutations can severely affect the CMT phenotype caused by a PMP22 duplication.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Proteínas de la Mielina/genética , Proteínas Nucleares/genética , Factores de Transcripción/genética , Southern Blotting , Enfermedad de Charcot-Marie-Tooth/patología , Preescolar , Análisis Mutacional de ADN , Femenino , Duplicación de Gen , Genotipo , Humanos , Masculino , Mutación , Linaje , FenotipoRESUMEN
Fifteen Moroccan families with a phenotype resembling Friedreich Ataxia (FA) were studied. Seven families (13 patients) had the 744 del A mutation in the alpha-tocopherol transfer protein (alpha-TTP) gene, characteristic of ataxia with vitamin E deficiency (AVED). The other eight families (16 patients) had GAA expansions in the first intron of the frataxin gene. The clinical differences between the two groups differed. AVED caused by the 744 del A could be distinguished by head titubation, lower frequency of the neuropathy and slower disease progression, decreased visual activity and retinitis pigmentosa, which has also been associated with a His(101) Gln missense mutation in the alpha-TTP gene. The neurological disorder associated with vitamin E deficiency can be improved by the alpha-tocopherol treatment.