title: Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial myopathy and sideroblastic anemia (MLASA).
abstract: Mitochondrial myopathy and sideroblastic anemia (MLASA) is a rare, autosomal recessive oxidative phosphorylation disorder specific to skeletal muscle and bone marrow. Linkage analysis and homozygosity testing of two families with MLASA localized the candidate region to 1.2 Mb on 12q24.33. Sequence analysis of each of the six known genes in this region, as well as four putative genes with expression in bone marrow or muscle, identified a homozygous missense mutation in the pseudouridine synthase 1 gene (PUS1) in all patients with MLASA from these families. The mutation is the only amino acid coding change in these 10 genes that is not a known polymorphism, and it is not found in 934 controls. The amino acid change affects a highly conserved amino acid, and appears to be in the catalytic center of the protein, PUS1p. PUS1 is widely expressed, and quantitative expression analysis of RNAs from liver, brain, heart, bone marrow, and skeletal muscle showed elevated levels of expression in skeletal muscle and brain. We propose deficient pseudouridylation of mitochondrial tRNAs as an etiology of MLASA. Identification of the pathophysiologic pathways of the mutation in these families may shed light on the tissue specificity of oxidative phosphorylation disorders.
authors.affiliation: Ahmanson Department of Pediatrics, Steven Spielberg Pediatric Research Center, and Medical Genetics Birth Defects Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Yelena
authors.initials: Y
authors.lastname: Bykhovskaya
authors.forename: Kari
authors.initials: K
authors.lastname: Casas
authors.forename: Emebet
authors.initials: E
authors.lastname: Mengesha
authors.forename: Aida
authors.initials: A
authors.lastname: Inbal
authors.forename: Nathan
authors.initials: N
authors.lastname: Fischel-Ghodsian
mesh_terms: D000595:Amino Acid Sequence; D000756:Anemia, Sideroblastic / Q000235:genetics*; D005075:Biological Evolution; D001853:Bone Marrow / Q000201:enzymology; D002478:Cells, Cultured; D005260:Female; D008040:Genetic Linkage; D006720:Homozygote; D006801:Humans; D006836:Hydro-Lyases / Q000235:genetics*; D008297:Male; D017240:Mitochondrial Myopathies / Q000235:genetics*; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000201:enzymology; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D011560:Pseudouridine / Q000378:metabolism; D012343:RNA, Transfer / Q000235:genetics; D017386:Sequence Homology, Amino Acid
chemical_list: D011560:Pseudouridine; D012343:RNA, Transfer; D006836:Hydro-Lyases; C022479:pseudouridylate synthetase