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. 2004 Jun;74(6):1303-8.
doi: 10.1086/421530. Epub 2004 Apr 22.

Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial myopathy and sideroblastic anemia (MLASA)

Yelena Bykhovskaya  1 , Kari Casas, Emebet Mengesha, Aida Inbal, Nathan Fischel-Ghodsian
Affiliations

Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial myopathy and sideroblastic anemia (MLASA)

Yelena Bykhovskaya et al. Am J Hum Genet. 2004 Jun.

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.

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Figures

Figure 1
Figure 1
Homozygous mutation in PUS1 causes MLASA. A, Map of PUS1 with exons in dark blue. The start codon and mutated position 656 in exon3 are identified. B, Two pedigrees of MLASA families shown with their sequencing and RFLP results for the mutation at position 656 in the PUS1 gene. Affected individuals are indicated by dark blue symbols. The mutation abolishes the restriction site for NciI.
Figure 2
Figure 2
Evolutionary conservation of the human 116R (arginine) residue in the eukaryotic and prokaryotic homologues of PUS1p. Percent identity was calculated by ALIGN (Pearson et al. 1997). GenBank accession numbers of the sequences, in the order of appearance (top to bottom): Homo sapiens NP079491, Mus musculus NM019700, Rattus norvegicus XM222267, Bos taurus CB440130, Danio rerio BC050502, Drosophila melanogaster NM142642, Caenorhabditis elegans T26253, Saccharomyces cerevisiae Q12211, S. cerevisiae P53167, C. elegans Q09524, S. cerevisiae P31115, Methanothermobacter thermautotrophicus O26928, Arabidopsis thaliana O22928, Escherichia coli P07649, Clostridium perfringens Q8xlq0, Haemophilus influenzae p45291, Clostridium muridarum Q9PJT0.
Figure 3
Figure 3
Quantitative analysis of PUS1 expression in different tissues. dCt indicates the difference between Ct (PUS1) and Ct (GAPDH).
See this image and copyright information in PMC

References

Electronic-Database Information

    1. BLAST, http://www.ncbi.nlm.nih.gov/blast/index.html
    1. Celera, http://myscience.appliedbiosystems.com/navigation/cdsLogin.jsp
    1. Centre for Molecular and Biomolecular Informatics, BIOcomputing unit, http://www.cmbi.kun.nl/swift/future/aainfo/
    1. EMBL, database of amino acid properties, http://www.russell.embl-heidelberg.de/aas/aas.html
    1. Ensembl Genome Browser, http://www.ensembl.org/

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