title: Fatal neonatal lactic acidosis caused by a novel de novo mitochondrial G7453A tRNA-Serine ((UCN)) mutation.
abstract: BACKGROUND
  Heteroplasmic mitochondrial DNA (mtDNA) mutations are an important cause of childhood disorders, but the role of homoplasmic mtDNA mutations in severe neonatal manifestations is not well understood.
  
  
  METHODS
  The following were performed: full mtDNA sequencing for mutation detection, blue-native protein analysis of autopsy-derived tissues to detect respiratory chain (RC) deficiency, light and electron microscopy for morphologic analysis, and northern blot and computational modeling to study the effect of mtDNA mutations on transfer RNA (tRNA) stability.
  
  
  RESULTS
  We describe data from a patient with fatal neonatal lactic acidosis caused by a novel homoplasmic mutation at a highly conserved nucleotide G7453A within the tRNA(Ser (UCN)) in mtDNA. The patient's heart, skeletal muscle, brain, and liver showed severe combined complex I and IV (CI and CIV) deficiencies, accompanied by severe depletion of mature tRNA(Ser (UCN)). The mutation was absent in the patient's mother and in a placental sample from a subsequent pregnancy of the mother, suggesting a de novo mutation.
  
  
  CONCLUSIONS
  We conclude that the G7453A mutation of mtDNA manifests with exceptional severity as compared with other tRNA(Ser (UCN)) mutations, typically associated with sensorineural deafness. De novo homoplasmic mtDNA tRNA-mutations should be considered as a cause of fatal neonatal lactic acidosis.
authors.affiliation: Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Götz
authors.forename: Pirjo
authors.initials: P
authors.lastname: Isohanni
authors.forename: Brita
authors.initials: B
authors.lastname: Liljeström
authors.forename: Jaana
authors.initials: J
authors.lastname: Rummukainen
authors.forename: Kari
authors.initials: K
authors.lastname: Nikolajev
authors.forename: Eila
authors.initials: E
authors.lastname: Herrgård
authors.forename: Sanna
authors.initials: S
authors.lastname: Marjavaara
authors.forename: Anu
authors.initials: A
authors.lastname: Suomalainen
mesh_terms: D000140:Acidosis, Lactic / Q000235:genetics*; D020029:Base Pairing; D001483:Base Sequence; D015152:Blotting, Northern; D004272:DNA, Mitochondrial / Q000235:genetics*; D017809:Fatal Outcome; D006801:Humans; D007231:Infant, Newborn; D008957:Models, Genetic; D008969:Molecular Sequence Data; D010375:Pedigree; D017354:Point Mutation / Q000235:genetics*; D012362:RNA, Transfer, Ser / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D004272:DNA, Mitochondrial; D012362:RNA, Transfer, Ser