RESUMO
The human mitochondrial genome encodes RNA components of its own translational machinery to produce the 13 mitochondrial-encoded subunits of the respiratory chain. Nuclear-encoded gene products are essential for all processes within the organelle, including RNA processing. Transcription of the mitochondrial genome generates large polycistronic transcripts punctuated by the 22 mitochondrial (mt) tRNAs that are conventionally cleaved by the RNase P-complex and the RNase Z activity of ELAC2 at 5' and 3' ends, respectively. We report the identification of mutations in ELAC2 in five individuals with infantile hypertrophic cardiomyopathy and complex I deficiency. We observed accumulated mtRNA precursors in affected individuals muscle and fibroblasts. Although mature mt-tRNA, mt-mRNA, and mt-rRNA levels were not decreased in fibroblasts, the processing defect was associated with impaired mitochondrial translation. Complementation experiments in mutant cell lines restored RNA processing and a yeast model provided additional evidence for the disease-causal role of defective ELAC2, thereby linking mtRNA processing to human disease.
Assuntos
Cardiomiopatia Hipertrófica/genética , Mitocôndrias/genética , Mutação , Proteínas de Neoplasias/genética , Processamento Pós-Transcricional do RNA , RNA Mensageiro/genética , Sequência de Aminoácidos , Cardiomiopatia Hipertrófica/metabolismo , Cardiomiopatia Hipertrófica/patologia , Núcleo Celular/genética , Núcleo Celular/metabolismo , Transporte de Elétrons/genética , Endorribonucleases/genética , Endorribonucleases/metabolismo , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Teste de Complementação Genética , Humanos , Lactente , Masculino , Mitocôndrias/metabolismo , Dados de Sequência Molecular , Músculos/metabolismo , Músculos/patologia , Proteínas de Neoplasias/metabolismo , Linhagem , RNA Mensageiro/metabolismo , RNA Mitocondrial , RNA Ribossômico/genética , RNA Ribossômico/metabolismo , RNA de Transferência/genética , RNA de Transferência/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismoRESUMO
Primary aldosteronism is the most prevalent form of secondary hypertension. To explore molecular mechanisms of autonomous aldosterone secretion, we performed exome sequencing of aldosterone-producing adenomas (APAs). We identified somatic hotspot mutations in the ATP1A1 (encoding an Na(+)/K(+) ATPase α subunit) and ATP2B3 (encoding a Ca(2+) ATPase) genes in three and two of the nine APAs, respectively. These ATPases are expressed in adrenal cells and control sodium, potassium and calcium ion homeostasis. Functional in vitro studies of ATP1A1 mutants showed loss of pump activity and strongly reduced affinity for potassium. Electrophysiological ex vivo studies on primary adrenal adenoma cells provided further evidence for inappropriate depolarization of cells with ATPase alterations. In a collection of 308 APAs, we found 16 (5.2%) somatic mutations in ATP1A1 and 5 (1.6%) in ATP2B3. Mutation-positive cases showed male dominance, increased plasma aldosterone concentrations and lower potassium concentrations compared with mutation-negative cases. In summary, dominant somatic alterations in two members of the ATPase gene family result in autonomous aldosterone secretion.