title: Whole-exome sequencing identifies a mutation in the mitochondrial ribosome protein MRPL44 to underlie mitochondrial infantile cardiomyopathy.
abstract: 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.
  
  
  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.
authors: Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, r.C523B, Haartmaninkatu 8, Helsinki 00290, Finland. anu.wartiovaara@helsinki.fi
authors: Christopher J
authors: CJ
authors: Carroll
authors: Pirjo
authors: P
authors: Isohanni
authors: Rosanna
authors: R
authors: Pöyhönen
authors: Liliya
authors: L
authors: Euro
authors: Uwe
authors: U
authors: Richter
authors: Virginia
authors: V
authors: Brilhante
authors: Alexandra
authors: A
authors: Götz
authors: Taina
authors: T
authors: Lahtinen
authors: Anders
authors: A
authors: Paetau
authors: Helena
authors: H
authors: Pihko
authors: Brendan J
authors: BJ
authors: Battersby
authors: Henna
authors: H
authors: Tyynismaa
authors: Anu
authors: A
authors: Suomalainen
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D002312:Cardiomyopathy, Hypertrophic / Q000151:congenital / Q000235:genetics*; D051545:Cyclooxygenase 1; D042967:Electron Transport Complex I; D003576:Electron Transport Complex IV; D059472:Exome / Q000235:genetics; D017809:Fatal Outcome; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007223:Infant; D028361:Mitochondrial Diseases / Q000151:congenital / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000737:chemistry / Q000378:metabolism; D009154:Mutation; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism; D010375:Pedigree; D012269:Ribosomal Proteins / Q000235:genetics*; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA
chemical_list: D024101:Mitochondrial Proteins; D012269:Ribosomal Proteins; C584516:mitochondrial ribosomal protein L44, human; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human; D003576:Electron Transport Complex IV; D042967:Electron Transport Complex I