Introduction: 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. Subjects and 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.
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