Published on June 1, 2004 in Am J Hum Genet volume 74(6).
PubMed ID: 15108122
Mitochondrial myopathy and sideroblastic anemia (MLASA) is a rare, autosomalrecessive oxidative phosphorylation disorder specific to skeletal muscle and bonemarrow. Linkage analysis and homozygosity testing of two families with MLASAlocalized the candidate region to 1.2 Mb on 12q24.33. Sequence analysis of each ofthe six known genes in this region, as well as four putative genes with expressionin bone marrow or muscle, identified a homozygous missense mutation in thepseudouridine 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 aknown polymorphism, and it is not found in 934 controls. The amino acid changeaffects a highly conserved amino acid, and appears to be in the catalytic center ofthe protein, PUS1p. PUS1 is widely expressed, and quantitative expression analysisof RNAs from liver, brain, heart, bone marrow, and skeletal muscle showed elevatedlevels of expression in skeletal muscle and brain. We propose deficientpseudouridylation of mitochondrial tRNAs as an etiology of MLASA. Identification ofthe pathophysiologic pathways of the mutation in these families may shed light onthe tissue specificity of oxidative phosphorylation disorders.