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Whole-exome sequencing identifies a mutation in the mitochondrial ribosome protein MRPL44 to underlie mitochondrial infantile cardiomyopathy
  1. Christopher J Carroll1,
  2. Pirjo Isohanni1,2,
  3. Rosanna Pöyhönen1,
  4. Liliya Euro1,
  5. Uwe Richter1,
  6. Virginia Brilhante1,
  7. Alexandra Götz1,
  8. Taina Lahtinen1,
  9. Anders Paetau3,
  10. Helena Pihko2,
  11. Brendan J Battersby1,4,
  12. Henna Tyynismaa1,5,
  13. Anu Suomalainen1,6
  1. 1Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland
  2. 2Department of Pediatric Neurology, Hospital for Children and Adolescents, Helsinki University Central Hospital, Helsinki, Finland
  3. 3Department of Pathology, University of Helsinki, Helsinki, Finland
  4. 4Institute of Biomedicine, University of Helsinki, Helsinki, Finland
  5. 5Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland
  6. 6Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland
  1. Correspondence to Professor Anu Suomalainen-Wartiovaara, Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, r.C523B, Haartmaninkatu 8, Helsinki 00290, Finland; anu.wartiovaara{at}


Background The genetic complexity of infantile cardiomyopathies is remarkable, and the importance of mitochondrial translation defects as a causative factor is only starting to be recognised. We investigated the genetic basis for infantile onset recessive hypertrophic cardiomyopathy in two siblings.

Methods and results Analysis of respiratory chain enzymes revealed a combined deficiency of complexes I and IV in the heart and skeletal muscle. Exome sequencing uncovered a homozygous mutation (L156R) in MRPL44 of both siblings. MRPL44 encodes a protein in the large subunit of the mitochondrial ribosome and is suggested to locate in close proximity to the tunnel exit of the yeast mitochondrial ribosome. We found severely reduced MRPL44 levels in the patient's heart, skeletal muscle and fibroblasts suggesting that the missense mutation affected the protein stability. In patient fibroblasts, decreased MRPL44 affected assembly of the large ribosomal subunit and stability of 16S rRNA leading to complex IV deficiency. Despite this assembly defect, de novo mitochondrial translation was only mildly affected in fibroblasts suggesting that MRPL44 may have a function in the assembly/stability of nascent mitochondrial polypeptides exiting the ribosome. Retroviral expression of wild-type MRPL44 in patient fibroblasts rescued the large ribosome assembly defect and COX deficiency.

Conclusions These findings indicate that mitochondrial ribosomal subunit defects can generate tissue-specific manifestations, such as cardiomyopathy.

  • Cardiomyopathy
  • Cell biology
  • Diagnosis
  • Molecular genetics
  • Metabolic disorders

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