Mitochondrial myopathy and sideroblastic anemia (MLASA): missense mutation in the pseudouridine synthase 1 (PUS1) gene is associated with the loss of tRNA pseudouridylation

J Biol Chem. 2005 May 20;280(20):19823-8. doi: 10.1074/jbc.M500216200. Epub 2005 Mar 16.


A missense mutation in the PUS1 gene affecting a highly conserved amino acid has been associated with mitochondrial myopathy and sideroblastic anemia (MLASA), a rare autosomal recessive oxidative phosphorylation disorder. The PUS1 gene encodes the enzyme pseudouridine synthase 1 (Pus1p) that is known to pseudouridylate tRNAs in other species. Total RNA was isolated from lymphoblastoid cell lines established from patients, parents, unaffected siblings, and unrelated controls, and the tRNAs were assayed for the presence of pseudouridine (Psi) at the expected positions. Mitochondrial and cytoplasmic tRNAs from MLASA patients are lacking modification at sites normally modified by Pus1p, whereas tRNAs from controls, unaffected siblings, or parents all have Psi at these positions. In addition, there was no Pus1p activity in an extract made from a cell line derived from a patient with MLASA. Immunohistochemical staining of Pus1p in cell lines showed nuclear, cytoplasmic, and mitochondrial distribution of the protein, and there is no difference in staining between patients and unaffected family members. MLASA is thus associated with absent or greatly reduced tRNA pseudouridylation at specific sites, implicating this pathway in its molecular pathogenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Anemia, Sideroblastic / complications
  • Anemia, Sideroblastic / enzymology*
  • Anemia, Sideroblastic / genetics*
  • Base Sequence
  • Cell Line
  • Genes, Recessive
  • Humans
  • Hydro-Lyases / genetics*
  • Mitochondrial Myopathies / complications
  • Mitochondrial Myopathies / enzymology*
  • Mitochondrial Myopathies / genetics*
  • Molecular Sequence Data
  • Mutation, Missense
  • Nucleic Acid Conformation
  • Pseudouridine / chemistry
  • RNA, Transfer / chemistry
  • RNA, Transfer / genetics
  • RNA, Transfer, Lys / chemistry
  • RNA, Transfer, Lys / genetics
  • RNA, Transfer, Ser / chemistry
  • RNA, Transfer, Ser / genetics


  • RNA, Transfer, Lys
  • RNA, Transfer, Ser
  • Pseudouridine
  • RNA, Transfer
  • Hydro-Lyases
  • pseudouridylate synthetase