| Autor: |
Jackson CB; Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, Helsinki FIN, Finland., Huemer M; Division of Metabolism and Children's Research Center, University Children's Hospital Zürich, Zürich CH, Switzerland.; University Children's Hospital Basel, University of Basel, Switzerland., Bolognini R; Division of Human Genetics, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern CH, Switzerland., Martin F; CNRS, Architecture et Réactivité de l'ARN, Université de Strasbourg, UPR 9002, Strasbourg F, France., Szinnai G; University Children's Hospital Basel, University of Basel, Switzerland.; Division of Pediatric Endocrinology, University Children's Hospital Basel, Basel CH, Switzerland., Donner BC; Division of Cardiology, University of Basel, Basel CH, Switzerland., Richter U; Institute of Biotechnology, University of Helsinki, Helsinki, FIN, Finland., Battersby BJ; Institute of Biotechnology, University of Helsinki, Helsinki, FIN, Finland., Nuoffer JM; Institute of Clinical Chemistry, University of Bern, Inselspital, Bern CH, Switzerland.; Division of Endocrinology Diabetology and Metabolism, University Children's Hospital, University of Bern, Bern CH, Switzerland., Suomalainen A; Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, Helsinki FIN, Finland.; Neuroscience Center, University of Helsinki, Helsinki FIN, Finland., Schaller A; Division of Human Genetics, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern CH, Switzerland. |
| Abstrakt: |
Dysfunction of mitochondrial translation is an increasingly important molecular cause of human disease, but structural defects of mitochondrial ribosomal subunits are rare. We used next-generation sequencing to identify a homozygous variant in the mitochondrial small ribosomal protein 14 (MRPS14, uS14m) in a patient manifesting with perinatal hypertrophic cardiomyopathy, growth retardation, muscle hypotonia, elevated lactate, dysmorphy and mental retardation. In skeletal muscle and fibroblasts from the patient, there was biochemical deficiency in complex IV of the respiratory chain. In fibroblasts, mitochondrial translation was impaired, and ectopic expression of a wild-type MRPS14 cDNA functionally complemented this defect. Surprisingly, the mutant uS14m was stable and did not affect assembly of the small ribosomal subunit. Instead, structural modeling of the uS14m mutation predicted a disruption to the ribosomal mRNA channel.Collectively, our data demonstrate pathogenic mutations in MRPS14 can manifest as a perinatal-onset mitochondrial hypertrophic cardiomyopathy with a novel molecular pathogenic mechanism that impairs the function of mitochondrial ribosomes during translation elongation or mitochondrial mRNA recruitment rather than assembly. |
