title: Nonsense mutation in pseudouridylate synthase 1 (PUS1) in two brothers affected by myopathy, lactic acidosis and sideroblastic anaemia (MLASA).
abstract: BACKGROUND
  Myopathy, lactic acidosis and sideroblastic anaemia (MLASA) is a rare condition that combines early-onset myopathy with lactic acidosis and sideroblastic anaemia. MLASA has been associated with a missense mutation in pseudouridylate synthase 1 (PUS1), an enzyme located in both nucleus and mitochondria, which converts uridine into pseudouridine in several cytosolic and mitochondrial tRNA positions and increases the efficiency of protein synthesis in both compartments.
  
  
  METHODS
  We have identified two Italian brothers, offspring of distantly related parents, both of whom are affected by MLASA. The six exons of the PUS1 gene were analysed by automated sequencing.
  
  
  RESULTS
  We found combined defects in mitochondrial respiratory chain complexes in muscle and fibroblast homogenates of both patients, and low levels of mtDNA translation products in fibroblast mitochondria. A novel, homozygous stop mutation was present in PUS1 (E220X). We have investigated the structural and mechanistic aspects of the double localisation of PUS1, demonstrating that the isoform located in the nucleus contains an N-terminal extension which is absent in the mature mitochondrial isoform.
  
  
  CONCLUSIONS
  The stop mutation in PUS1 is likely to determine the loss of function of the protein, since it predicts the synthesis of a protein missing 208/427 amino acid residues on the C terminus, and was associated with low mtDNA translation. The structural differences in nuclear versus mitochondrial isoforms of PUS1 may be implicated in the variability of the clinical presentations in MLASA.
authors.affiliation: Division of Molecular Neurogenetics, Pierfranco and Luisa Mariani Center for the Study of Mitochondrial Disorders of Infancy and Childhood, National Institute of Neurology C. Besta, Milan, Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: Fernandez-Vizarra
authors.forename: Angela
authors.initials: A
authors.lastname: Berardinelli
authors.forename: Lucia
authors.initials: L
authors.lastname: Valente
authors.forename: Valeria
authors.initials: V
authors.lastname: Tiranti
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
mesh_terms: D000140:Acidosis, Lactic / Q000201:enzymology / Q000235:genetics*; D000595:Amino Acid Sequence; D000756:Anemia, Sideroblastic / Q000201:enzymology / Q000235:genetics*; D002467:Cell Nucleus / Q000201:enzymology; D018389:Codon, Nonsense; D003241:Consanguinity; D030401:Cytochrome-c Oxidase Deficiency / Q000235:genetics; D042967:Electron Transport Complex I / Q000172:deficiency; D017809:Fatal Outcome; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D006367:HeLa Cells; D019382:Human Growth Hormone / Q000172:deficiency; D006801:Humans; D006836:Hydro-Lyases / Q000737:chemistry / Q000172:deficiency / Q000235:genetics*; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D008931:Mitochondria, Muscle / Q000201:enzymology; D017240:Mitochondrial Myopathies / Q000201:enzymology / Q000235:genetics*; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000201:enzymology / Q000473:pathology; D010641:Phenotype; D020033:Protein Isoforms / Q000032:analysis / Q000235:genetics; D011498:Protein Precursors / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D021381:Protein Transport / Q000187:drug effects; D013577:Syndrome; D014158:Transcription, Genetic; D014162:Transfection; D014634:Valinomycin / Q000494:pharmacology
chemical_list: D018389:Codon, Nonsense; D020033:Protein Isoforms; D011498:Protein Precursors; D019382:Human Growth Hormone; D014634:Valinomycin; D006836:Hydro-Lyases; C022479:pseudouridylate synthetase; D042967:Electron Transport Complex I