Full text data of PUS1
PUS1
[Confidence: low (only semi-automatic identification from reviews)]
tRNA pseudouridine synthase A, mitochondrial; 5.4.99.12 (tRNA pseudouridine(38-40) synthase; tRNA pseudouridylate synthase I; tRNA-uridine isomerase I; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
tRNA pseudouridine synthase A, mitochondrial; 5.4.99.12 (tRNA pseudouridine(38-40) synthase; tRNA pseudouridylate synthase I; tRNA-uridine isomerase I; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q9Y606
ID TRUA_HUMAN Reviewed; 427 AA.
AC Q9Y606; A8K877; B3KQC1; Q8WYT2; Q9BU44;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
read moreDT 05-SEP-2006, sequence version 3.
DT 22-JAN-2014, entry version 126.
DE RecName: Full=tRNA pseudouridine synthase A, mitochondrial;
DE EC=5.4.99.12;
DE AltName: Full=tRNA pseudouridine(38-40) synthase;
DE AltName: Full=tRNA pseudouridylate synthase I;
DE AltName: Full=tRNA-uridine isomerase I;
DE Flags: Precursor;
GN Name=PUS1; ORFNames=PP8985;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=15498874; DOI=10.1073/pnas.0404089101;
RA Wan D., Gong Y., Qin W., Zhang P., Li J., Wei L., Zhou X., Li H.,
RA Qiu X., Zhong F., He L., Yu J., Yao G., Jiang H., Qian L., Yu Y.,
RA Shu H., Chen X., Xu H., Guo M., Pan Z., Chen Y., Ge C., Yang S.,
RA Gu J.;
RT "Large-scale cDNA transfection screening for genes related to cancer
RT development and progression.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:15724-15729(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Mammary gland, and Testis;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Lung;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 63-427.
RC TISSUE=Cervix carcinoma;
RX PubMed=10094309; DOI=10.1017/S1355838299981591;
RA Chen J., Patton J.R.;
RT "Cloning and characterization of a mammalian pseudouridine synthase.";
RL RNA 5:409-419(1999).
RN [5]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-420 AND THR-426, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [6]
RP SUBCELLULAR LOCATION (ISOFORMS 1 AND 2).
RX PubMed=17056637; DOI=10.1136/jmg.2006.045252;
RA Fernandez-Vizarra E., Berardinelli A., Valente L., Tiranti V.,
RA Zeviani M.;
RT "Nonsense mutation in pseudouridylate synthase 1 (PUS1) in two
RT brothers affected by myopathy, lactic acidosis and sideroblastic
RT anaemia (MLASA).";
RL J. Med. Genet. 44:173-180(2007).
RN [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-420 AND THR-426, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-415; SER-420 AND
RP THR-426, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-420 AND THR-426, AND
RP MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [13]
RP VARIANT MLASA1 TRP-144, AND TISSUE SPECIFICITY.
RX PubMed=15108122; DOI=10.1086/421530;
RA Bykhovskaya Y., Casas K., Mengesha E., Inbal A., Fischel-Ghodsian N.;
RT "Missense mutation in pseudouridine synthase 1 (PUS1) causes
RT mitochondrial myopathy and sideroblastic anemia (MLASA).";
RL Am. J. Hum. Genet. 74:1303-1308(2004).
RN [14]
RP VARIANT [LARGE SCALE ANALYSIS] ASN-133.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: Converts specific uridines to PSI in a number of tRNA
CC substrates. Acts on positions 27/28 in the anticodon stem and also
CC positions 34 and 36 in the anticodon of an intron containing tRNA.
CC Involved in regulation of nuclear receptor activity possibly
CC through pseudouridylation of SRA1 RNA (By similarity).
CC -!- CATALYTIC ACTIVITY: tRNA uridine(38-40) = tRNA pseudouridine(38-
CC 40).
CC -!- SUBUNIT: Forms a complex with RARG and the SRA1 RNA in the nucleus
CC (By similarity).
CC -!- SUBCELLULAR LOCATION: Isoform 1: Mitochondrion.
CC -!- SUBCELLULAR LOCATION: Isoform 2: Nucleus.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9Y606-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9Y606-2; Sequence=VSP_020116;
CC -!- TISSUE SPECIFICITY: Widely expressed. High levels of expression
CC found in brain and skeletal muscle.
CC -!- DISEASE: Myopathy with lactic acidosis and sideroblastic anemia 1
CC (MLASA1) [MIM:600462]: A rare oxidative phosphorylation disorder
CC specific to skeletal muscle and bone marrow. Affected individuals
CC manifest progressive muscle weakness, exercise intolerance, lactic
CC acidosis, sideroblastic anemia and delayed growth. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the tRNA pseudouridine synthase TruA
CC family.
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DR EMBL; AF318369; AAL55876.1; -; mRNA.
DR EMBL; AK074659; BAG51983.1; -; mRNA.
DR EMBL; AK292242; BAF84931.1; -; mRNA.
DR EMBL; BC002901; AAH02901.1; -; mRNA.
DR EMBL; BC009505; AAH09505.2; -; mRNA.
DR EMBL; BC019320; AAH19320.2; -; mRNA.
DR EMBL; AF116238; AAD21042.1; -; mRNA.
DR RefSeq; NP_001002019.1; NM_001002019.2.
DR RefSeq; NP_001002020.1; NM_001002020.2.
DR RefSeq; NP_079491.2; NM_025215.5.
DR UniGene; Hs.592004; -.
DR PDB; 4IQM; X-ray; 1.80 A; A=79-408.
DR PDB; 4ITS; X-ray; 1.85 A; A=79-408.
DR PDB; 4J37; X-ray; 1.75 A; A=79-408.
DR PDBsum; 4IQM; -.
DR PDBsum; 4ITS; -.
DR PDBsum; 4J37; -.
DR ProteinModelPortal; Q9Y606; -.
DR SMR; Q9Y606; 81-407.
DR IntAct; Q9Y606; 1.
DR MINT; MINT-2823994; -.
DR STRING; 9606.ENSP00000365837; -.
DR PhosphoSite; Q9Y606; -.
DR DMDM; 114152895; -.
DR PaxDb; Q9Y606; -.
DR PRIDE; Q9Y606; -.
DR DNASU; 80324; -.
DR Ensembl; ENST00000376649; ENSP00000365837; ENSG00000177192.
DR Ensembl; ENST00000440818; ENSP00000400032; ENSG00000177192.
DR Ensembl; ENST00000443358; ENSP00000392451; ENSG00000177192.
DR GeneID; 80324; -.
DR KEGG; hsa:80324; -.
DR UCSC; uc001ujf.3; human.
DR CTD; 80324; -.
DR GeneCards; GC12P132413; -.
DR HGNC; HGNC:15508; PUS1.
DR HPA; HPA051636; -.
DR MIM; 600462; phenotype.
DR MIM; 608109; gene.
DR neXtProt; NX_Q9Y606; -.
DR Orphanet; 2598; Mitochondrial myopathy and sideroblastic anemia.
DR PharmGKB; PA34047; -.
DR eggNOG; COG0101; -.
DR HOGENOM; HOG000031229; -.
DR HOVERGEN; HBG000489; -.
DR InParanoid; Q9Y606; -.
DR KO; K06173; -.
DR OMA; KNFHNFT; -.
DR OrthoDB; EOG79KPFG; -.
DR BRENDA; 5.4.99.12; 2681.
DR ChiTaRS; PUS1; human.
DR GeneWiki; PUS1; -.
DR GenomeRNAi; 80324; -.
DR NextBio; 70847; -.
DR PRO; PR:Q9Y606; -.
DR ArrayExpress; Q9Y606; -.
DR Bgee; Q9Y606; -.
DR CleanEx; HS_PUS1; -.
DR Genevestigator; Q9Y606; -.
DR GO; GO:0005739; C:mitochondrion; IEA:UniProtKB-SubCell.
DR GO; GO:0005730; C:nucleolus; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; NAS:UniProtKB.
DR GO; GO:0005667; C:transcription factor complex; IEA:Ensembl.
DR GO; GO:0003677; F:DNA binding; IEA:Ensembl.
DR GO; GO:0030374; F:ligand-dependent nuclear receptor transcription coactivator activity; IEA:Ensembl.
DR GO; GO:0009982; F:pseudouridine synthase activity; IEA:UniProtKB-EC.
DR GO; GO:0004730; F:pseudouridylate synthase activity; NAS:UniProtKB.
DR GO; GO:0003723; F:RNA binding; IEA:InterPro.
DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IEA:Ensembl.
DR GO; GO:0008033; P:tRNA processing; NAS:UniProtKB.
DR GO; GO:0031119; P:tRNA pseudouridine synthesis; IEA:Ensembl.
DR Gene3D; 3.30.70.580; -; 1.
DR Gene3D; 3.30.70.660; -; 1.
DR InterPro; IPR020103; PsdUridine_synth_cat_dom.
DR InterPro; IPR001406; PsdUridine_synth_TruA.
DR InterPro; IPR020097; PsdUridine_synth_TruA_a/b_dom.
DR InterPro; IPR020095; PsdUridine_synth_TruA_C.
DR InterPro; IPR020094; PsdUridine_synth_TruA_N.
DR PANTHER; PTHR11142; PTHR11142; 1.
DR Pfam; PF01416; PseudoU_synth_1; 2.
DR SUPFAM; SSF55120; SSF55120; 1.
DR TIGRFAMs; TIGR00071; hisT_truA; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Complete proteome;
KW Disease mutation; Isomerase; Mitochondrion; Nucleus; Phosphoprotein;
KW Polymorphism; Reference proteome; Transit peptide; tRNA processing.
FT TRANSIT 1 ? Mitochondrion (Potential).
FT CHAIN ? 427 tRNA pseudouridine synthase A,
FT mitochondrial.
FT /FTId=PRO_0000057517.
FT ACT_SITE 146 146 Nucleophile (By similarity).
FT BINDING 201 201 Substrate (By similarity).
FT MOD_RES 415 415 Phosphoserine.
FT MOD_RES 420 420 Phosphoserine.
FT MOD_RES 426 426 Phosphothreonine.
FT VAR_SEQ 1 28 Missing (in isoform 2).
FT /FTId=VSP_020116.
FT VARIANT 133 133 D -> N (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_036447.
FT VARIANT 144 144 R -> W (in MLASA1).
FT /FTId=VAR_021788.
FT CONFLICT 70 70 K -> R (in Ref. 4; AAD21042).
FT STRAND 83 92
FT STRAND 99 101
FT HELIX 112 122
FT HELIX 128 132
FT HELIX 134 137
FT STRAND 140 142
FT STRAND 150 161
FT HELIX 166 172
FT STRAND 178 186
FT HELIX 192 195
FT STRAND 198 206
FT HELIX 207 210
FT TURN 213 215
FT HELIX 226 238
FT STRAND 241 244
FT HELIX 246 248
FT STRAND 249 251
FT STRAND 252 254
FT HELIX 257 259
FT STRAND 260 268
FT STRAND 272 274
FT STRAND 277 288
FT HELIX 293 305
FT HELIX 313 317
FT STRAND 319 321
FT STRAND 333 338
FT HELIX 341 344
FT HELIX 359 361
FT HELIX 362 371
FT HELIX 373 384
FT HELIX 386 391
FT HELIX 392 396
FT HELIX 401 404
SQ SEQUENCE 427 AA; 47470 MW; ACE9FA6AE0F178BA CRC64;
MGLQLRALLG AFGRWTLRLG PRPSCSPRMA GNAEPPPAGA ACPQDRRSCS GRAGGDRVWE
DGEHPAKKLK SGGDEERREK PPKRKIVLLM AYSGKGYHGM QRNVGSSQFK TIEDDLVSAL
VRSGCIPENH GEDMRKMSFQ RCARTDKGVS AAGQVVSLKV WLIDDILEKI NSHLPSHIRI
LGLKRVTGGF NSKNRCDART YCYLLPTFAF AHKDRDVQDE TYRLSAETLQ QVNRLLACYK
GTHNFHNFTS QKGPQDPSAC RYILEMYCEE PFVREGLEFA VIRVKGQSFM MHQIRKMVGL
VVAIVKGYAP ESVLERSWGT EKVDVPKAPG LGLVLERVHF EKYNQRFGND GLHEPLDWAQ
EEGKVAAFKE EHIYPTIIGT ERDERSMAQW LSTLPIHNFS ATALTAGGTG AKVPSPLEGS
EGDGDTD
//
ID TRUA_HUMAN Reviewed; 427 AA.
AC Q9Y606; A8K877; B3KQC1; Q8WYT2; Q9BU44;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
read moreDT 05-SEP-2006, sequence version 3.
DT 22-JAN-2014, entry version 126.
DE RecName: Full=tRNA pseudouridine synthase A, mitochondrial;
DE EC=5.4.99.12;
DE AltName: Full=tRNA pseudouridine(38-40) synthase;
DE AltName: Full=tRNA pseudouridylate synthase I;
DE AltName: Full=tRNA-uridine isomerase I;
DE Flags: Precursor;
GN Name=PUS1; ORFNames=PP8985;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=15498874; DOI=10.1073/pnas.0404089101;
RA Wan D., Gong Y., Qin W., Zhang P., Li J., Wei L., Zhou X., Li H.,
RA Qiu X., Zhong F., He L., Yu J., Yao G., Jiang H., Qian L., Yu Y.,
RA Shu H., Chen X., Xu H., Guo M., Pan Z., Chen Y., Ge C., Yang S.,
RA Gu J.;
RT "Large-scale cDNA transfection screening for genes related to cancer
RT development and progression.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:15724-15729(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Mammary gland, and Testis;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Lung;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 63-427.
RC TISSUE=Cervix carcinoma;
RX PubMed=10094309; DOI=10.1017/S1355838299981591;
RA Chen J., Patton J.R.;
RT "Cloning and characterization of a mammalian pseudouridine synthase.";
RL RNA 5:409-419(1999).
RN [5]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-420 AND THR-426, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [6]
RP SUBCELLULAR LOCATION (ISOFORMS 1 AND 2).
RX PubMed=17056637; DOI=10.1136/jmg.2006.045252;
RA Fernandez-Vizarra E., Berardinelli A., Valente L., Tiranti V.,
RA Zeviani M.;
RT "Nonsense mutation in pseudouridylate synthase 1 (PUS1) in two
RT brothers affected by myopathy, lactic acidosis and sideroblastic
RT anaemia (MLASA).";
RL J. Med. Genet. 44:173-180(2007).
RN [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-420 AND THR-426, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-415; SER-420 AND
RP THR-426, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-420 AND THR-426, AND
RP MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [13]
RP VARIANT MLASA1 TRP-144, AND TISSUE SPECIFICITY.
RX PubMed=15108122; DOI=10.1086/421530;
RA Bykhovskaya Y., Casas K., Mengesha E., Inbal A., Fischel-Ghodsian N.;
RT "Missense mutation in pseudouridine synthase 1 (PUS1) causes
RT mitochondrial myopathy and sideroblastic anemia (MLASA).";
RL Am. J. Hum. Genet. 74:1303-1308(2004).
RN [14]
RP VARIANT [LARGE SCALE ANALYSIS] ASN-133.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: Converts specific uridines to PSI in a number of tRNA
CC substrates. Acts on positions 27/28 in the anticodon stem and also
CC positions 34 and 36 in the anticodon of an intron containing tRNA.
CC Involved in regulation of nuclear receptor activity possibly
CC through pseudouridylation of SRA1 RNA (By similarity).
CC -!- CATALYTIC ACTIVITY: tRNA uridine(38-40) = tRNA pseudouridine(38-
CC 40).
CC -!- SUBUNIT: Forms a complex with RARG and the SRA1 RNA in the nucleus
CC (By similarity).
CC -!- SUBCELLULAR LOCATION: Isoform 1: Mitochondrion.
CC -!- SUBCELLULAR LOCATION: Isoform 2: Nucleus.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9Y606-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9Y606-2; Sequence=VSP_020116;
CC -!- TISSUE SPECIFICITY: Widely expressed. High levels of expression
CC found in brain and skeletal muscle.
CC -!- DISEASE: Myopathy with lactic acidosis and sideroblastic anemia 1
CC (MLASA1) [MIM:600462]: A rare oxidative phosphorylation disorder
CC specific to skeletal muscle and bone marrow. Affected individuals
CC manifest progressive muscle weakness, exercise intolerance, lactic
CC acidosis, sideroblastic anemia and delayed growth. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the tRNA pseudouridine synthase TruA
CC family.
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; AF318369; AAL55876.1; -; mRNA.
DR EMBL; AK074659; BAG51983.1; -; mRNA.
DR EMBL; AK292242; BAF84931.1; -; mRNA.
DR EMBL; BC002901; AAH02901.1; -; mRNA.
DR EMBL; BC009505; AAH09505.2; -; mRNA.
DR EMBL; BC019320; AAH19320.2; -; mRNA.
DR EMBL; AF116238; AAD21042.1; -; mRNA.
DR RefSeq; NP_001002019.1; NM_001002019.2.
DR RefSeq; NP_001002020.1; NM_001002020.2.
DR RefSeq; NP_079491.2; NM_025215.5.
DR UniGene; Hs.592004; -.
DR PDB; 4IQM; X-ray; 1.80 A; A=79-408.
DR PDB; 4ITS; X-ray; 1.85 A; A=79-408.
DR PDB; 4J37; X-ray; 1.75 A; A=79-408.
DR PDBsum; 4IQM; -.
DR PDBsum; 4ITS; -.
DR PDBsum; 4J37; -.
DR ProteinModelPortal; Q9Y606; -.
DR SMR; Q9Y606; 81-407.
DR IntAct; Q9Y606; 1.
DR MINT; MINT-2823994; -.
DR STRING; 9606.ENSP00000365837; -.
DR PhosphoSite; Q9Y606; -.
DR DMDM; 114152895; -.
DR PaxDb; Q9Y606; -.
DR PRIDE; Q9Y606; -.
DR DNASU; 80324; -.
DR Ensembl; ENST00000376649; ENSP00000365837; ENSG00000177192.
DR Ensembl; ENST00000440818; ENSP00000400032; ENSG00000177192.
DR Ensembl; ENST00000443358; ENSP00000392451; ENSG00000177192.
DR GeneID; 80324; -.
DR KEGG; hsa:80324; -.
DR UCSC; uc001ujf.3; human.
DR CTD; 80324; -.
DR GeneCards; GC12P132413; -.
DR HGNC; HGNC:15508; PUS1.
DR HPA; HPA051636; -.
DR MIM; 600462; phenotype.
DR MIM; 608109; gene.
DR neXtProt; NX_Q9Y606; -.
DR Orphanet; 2598; Mitochondrial myopathy and sideroblastic anemia.
DR PharmGKB; PA34047; -.
DR eggNOG; COG0101; -.
DR HOGENOM; HOG000031229; -.
DR HOVERGEN; HBG000489; -.
DR InParanoid; Q9Y606; -.
DR KO; K06173; -.
DR OMA; KNFHNFT; -.
DR OrthoDB; EOG79KPFG; -.
DR BRENDA; 5.4.99.12; 2681.
DR ChiTaRS; PUS1; human.
DR GeneWiki; PUS1; -.
DR GenomeRNAi; 80324; -.
DR NextBio; 70847; -.
DR PRO; PR:Q9Y606; -.
DR ArrayExpress; Q9Y606; -.
DR Bgee; Q9Y606; -.
DR CleanEx; HS_PUS1; -.
DR Genevestigator; Q9Y606; -.
DR GO; GO:0005739; C:mitochondrion; IEA:UniProtKB-SubCell.
DR GO; GO:0005730; C:nucleolus; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; NAS:UniProtKB.
DR GO; GO:0005667; C:transcription factor complex; IEA:Ensembl.
DR GO; GO:0003677; F:DNA binding; IEA:Ensembl.
DR GO; GO:0030374; F:ligand-dependent nuclear receptor transcription coactivator activity; IEA:Ensembl.
DR GO; GO:0009982; F:pseudouridine synthase activity; IEA:UniProtKB-EC.
DR GO; GO:0004730; F:pseudouridylate synthase activity; NAS:UniProtKB.
DR GO; GO:0003723; F:RNA binding; IEA:InterPro.
DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IEA:Ensembl.
DR GO; GO:0008033; P:tRNA processing; NAS:UniProtKB.
DR GO; GO:0031119; P:tRNA pseudouridine synthesis; IEA:Ensembl.
DR Gene3D; 3.30.70.580; -; 1.
DR Gene3D; 3.30.70.660; -; 1.
DR InterPro; IPR020103; PsdUridine_synth_cat_dom.
DR InterPro; IPR001406; PsdUridine_synth_TruA.
DR InterPro; IPR020097; PsdUridine_synth_TruA_a/b_dom.
DR InterPro; IPR020095; PsdUridine_synth_TruA_C.
DR InterPro; IPR020094; PsdUridine_synth_TruA_N.
DR PANTHER; PTHR11142; PTHR11142; 1.
DR Pfam; PF01416; PseudoU_synth_1; 2.
DR SUPFAM; SSF55120; SSF55120; 1.
DR TIGRFAMs; TIGR00071; hisT_truA; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Complete proteome;
KW Disease mutation; Isomerase; Mitochondrion; Nucleus; Phosphoprotein;
KW Polymorphism; Reference proteome; Transit peptide; tRNA processing.
FT TRANSIT 1 ? Mitochondrion (Potential).
FT CHAIN ? 427 tRNA pseudouridine synthase A,
FT mitochondrial.
FT /FTId=PRO_0000057517.
FT ACT_SITE 146 146 Nucleophile (By similarity).
FT BINDING 201 201 Substrate (By similarity).
FT MOD_RES 415 415 Phosphoserine.
FT MOD_RES 420 420 Phosphoserine.
FT MOD_RES 426 426 Phosphothreonine.
FT VAR_SEQ 1 28 Missing (in isoform 2).
FT /FTId=VSP_020116.
FT VARIANT 133 133 D -> N (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_036447.
FT VARIANT 144 144 R -> W (in MLASA1).
FT /FTId=VAR_021788.
FT CONFLICT 70 70 K -> R (in Ref. 4; AAD21042).
FT STRAND 83 92
FT STRAND 99 101
FT HELIX 112 122
FT HELIX 128 132
FT HELIX 134 137
FT STRAND 140 142
FT STRAND 150 161
FT HELIX 166 172
FT STRAND 178 186
FT HELIX 192 195
FT STRAND 198 206
FT HELIX 207 210
FT TURN 213 215
FT HELIX 226 238
FT STRAND 241 244
FT HELIX 246 248
FT STRAND 249 251
FT STRAND 252 254
FT HELIX 257 259
FT STRAND 260 268
FT STRAND 272 274
FT STRAND 277 288
FT HELIX 293 305
FT HELIX 313 317
FT STRAND 319 321
FT STRAND 333 338
FT HELIX 341 344
FT HELIX 359 361
FT HELIX 362 371
FT HELIX 373 384
FT HELIX 386 391
FT HELIX 392 396
FT HELIX 401 404
SQ SEQUENCE 427 AA; 47470 MW; ACE9FA6AE0F178BA CRC64;
MGLQLRALLG AFGRWTLRLG PRPSCSPRMA GNAEPPPAGA ACPQDRRSCS GRAGGDRVWE
DGEHPAKKLK SGGDEERREK PPKRKIVLLM AYSGKGYHGM QRNVGSSQFK TIEDDLVSAL
VRSGCIPENH GEDMRKMSFQ RCARTDKGVS AAGQVVSLKV WLIDDILEKI NSHLPSHIRI
LGLKRVTGGF NSKNRCDART YCYLLPTFAF AHKDRDVQDE TYRLSAETLQ QVNRLLACYK
GTHNFHNFTS QKGPQDPSAC RYILEMYCEE PFVREGLEFA VIRVKGQSFM MHQIRKMVGL
VVAIVKGYAP ESVLERSWGT EKVDVPKAPG LGLVLERVHF EKYNQRFGND GLHEPLDWAQ
EEGKVAAFKE EHIYPTIIGT ERDERSMAQW LSTLPIHNFS ATALTAGGTG AKVPSPLEGS
EGDGDTD
//
MIM
600462
*RECORD*
*FIELD* NO
600462
*FIELD* TI
#600462 MYOPATHY, LACTIC ACIDOSIS, AND SIDEROBLASTIC ANEMIA 1; MLASA1
;;MITOCHONDRIAL MYOPATHY AND SIDEROBLASTIC ANEMIA
read more*FIELD* TX
A number sign (#) is used with this entry because myopathy, lactic
acidosis, and sideroblastic anemia-1 (MLASA1) can be caused by
homozygous mutation in the PUS1 gene (608109) on chromosome 12q24.33.
DESCRIPTION
Myopathy, lactic acidosis, and sideroblastic anemia (MLASA) is a rare
autosomal recessive oxidative phosphorylation disorder specific to
skeletal muscle and bone marrow (Bykhovskaya et al., 2004).
- Genetic Heterogeneity of MLASA
MLASA2 (613561) is caused by homozygous mutation in the YARS2 gene
(610957) on chromosome 12p.11.21.
CLINICAL FEATURES
Rawles and Weller (1974) reported 2 brothers with myopathy, lactic
acidosis, and sideroblastic anemia with ringed sideroblasts. Both
reported exercise intolerance beginning in childhood. The first was
studied at age 19 because of breathlessness on exertion and ankle edema.
A high cardiac output was the only finding; cardiac catheterization
ruled out a cardiac disorder. Electron microscopy of muscle from one of
the brothers showed paracrystalline inclusion bodies in mitochondria.
The asymptomatic father of the boys had chronic lactic acidosis.
Among 6 offspring of first-cousin parents, Inbal et al. (1995)
identified a brother and sister with a seemingly 'new' syndrome featured
by myopathy, sideroblastic anemia, lactic acidosis, mental retardation,
microcephaly, high palate, high philtrum, distichiasis, and
micrognathia. The patients' muscle mitochondria contained very low
levels of cytochromes a, b, and c. Deposition of iron within the
mitochondria of bone marrow erythroblasts was observed on electron
microscopy. Irregular and enlarged mitochondria with paracrystalline
inclusions were also seen on electron microscopy of muscle. However,
examination of DNA from the affected sibs showed no deletions in the
mitochondrial DNA and no mutations of the type identified in the
syndrome of mitochondrial myopathy, encephalopathy, lactic acidosis, and
stroke-like episodes (MELAS; 540000) or the syndrome of myoclonus and
epilepsy associated with ragged-red fibers (MERRF; 545000).
Casas and Fischel-Ghodsian (2004) described this disorder in a Jewish
Iranian family with 4 affected individuals living in the United States.
Hallmark features included progressive exercise intolerance during
childhood, onset of sideroblastic anemia around adolescence, basal
lactic acidemia, and mitochondrial myopathy. The presence of 2 affected
sib pairs, unaffected parents, an unaffected sib, and parental
consanguinity suggested autosomal recessive inheritance.
MAPPING
Casas et al. (2004) applied linkage analysis and homozygosity testing in
the families of Casas and Fischel-Ghodsian (2004) and in the family
reported in Israel by Inbal et al. (1995), both of which originated from
the same Iranian town, and localized a candidate region of 1.2 Mb within
12q24.33.
MOLECULAR GENETICS
By sequence analysis of each of the 6 known genes in the 12q24.33 MLASA
candidate region defined by Casas et al. (2004), as well as of 4
putative genes with expression in bone marrow or muscle, Bykhovskaya et
al. (2004) identified a homozygous missense mutation in the PUS1 gene,
encoding pseudouridine synthase-1 (608109.0001), in all patients with
MLASA from the families described by Inbal et al. (1995) and Casas and
Fischel-Ghodsian (2004). The amino acid change affects a highly
conserved residue and appears to be in the catalytic center of the
protein.
In 2 Italian brothers with MLASA, born of sixth-cousin parents,
Fernandez-Vizarra et al. (2007) identified homozygosity for a nonsense
mutation in the PUS1 gene (E220X; 608109.0002). The hematologic and
neurologic presentation was markedly different in the 2 brothers: the
older brother had a very severe mitochondrial myopathy with muscle
wasting, severe sideroblastic anemia requiring multiple blood
transfusions, and severe growth retardation due to complete deficiency
of growth hormone, but had normal psychomotor development and
above-normal intelligence. He died of respiratory failure at 12 years of
age. The younger brother, who was still alive at 13 years of age, had a
much milder neuromuscular syndrome with no muscle wasting and did not
require transfusions for his sideroblastic anemia; however, he had
cognitive and behavioral abnormalities with moderate mental retardation,
hyperactivity, and panic attacks.
PATHOGENESIS
Patton et al. (2005) isolated total RNA from lymphoblastoid cell lines
from MLASA patients with the R116W mutation, their parents, unaffected
sibs, and controls. They found that mitochondrial and cytoplasmic tRNAs
from MLASA patients lacked modification at sites normally modified by
PUS1, whereas tRNAs from controls, unaffected sibs, or parents all had
pseudouridine at those positions. Immunohistochemical staining showed
nuclear, cytoplasmic, and mitochondrial distribution of the PUS1
protein, and there was no difference between patients and unaffected
family members. Patton et al. (2005) concluded that MLASA is associated
with absent or greatly reduced tRNA pseudouridylation at specific sites.
*FIELD* RF
1. Bykhovskaya, Y.; Casas, K.; Mengesha, E.; Inbal, A.; Fischel-Ghodsian,
N.: Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial
myopathy and sideroblastic anemia (MLASA). Am. J. Hum. Genet. 74:
1303-1308, 2004.
2. Casas, K.; Bykhovskaya, Y.; Mengesha, E.; Wang, D.; Yang, H.; Taylor,
K.; Inbal, A.; Fischel-Ghodsian, N.: Gene responsible for mitochondrial
myopathy and sideroblastic anemia (MSA) maps to chromosome 12q24.33. Am.
J. Med. Genet. 127A: 44-49, 2004.
3. Casas, K.; Fischel-Ghodsian, N.: Mitochondrial myopathy and sideroblastic
anemia. Am. J. Med. Genet. 125: 201-204, 2004.
4. Fernandez-Vizarra, E.; Berardinelli, A.; Valente, L.; Tiranti,
V.; Zeviani, M.: Nonsense mutation in pseudouridylate synthase 1
(PUS1) in two brothers affected by myopathy, lactic acidosis and sideroblastic
anaemia (MLASA). J. Med. Genet. 44: 173-180, 2007.
5. Inbal, A.; Avissar, N.; Shaklai, M.; Kuritzky, A.; Schejter, A.;
Ben-David, E.; Shanske, S.; Garty, B.-Z.: Myopathy, lactic acidosis,
and sideroblastic anemia: a new syndrome. Am. J. Med. Genet. 55:
372-378, 1995.
6. Patton, J. R.; Bykhovskaya, Y.; Mengesha, E.; Bertolotto, C.; Fischel-Ghodsian,
N.: 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. 280: 19823-19828,
2005.
7. Rawles, J. M.; Weller, R. O.: Familial association of metabolic
myopathy, lactic acidosis and sideroblastic anemia. Am. J. Med. 56:
891-897, 1974.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Delayed growth;
Delayed pubertal development
HEAD AND NECK:
[Head];
Microcephaly (reported in 1 family);
[Face];
Micrognathia (1 family);
High philtrum (1 family);
[Eyes];
Distichiasis (double row of eyelashes, 1 family);
[Mouth];
High-arched palate (1 family)
SKIN, NAILS, HAIR:
[Skin];
Pallor
MUSCLE, SOFT TISSUE:
Exercise intolerance;
Muscle weakness, progressive;
Generalized limb muscle atrophy;
Skeletal muscle biopsy shows fat droplets in sarcoplasm and mitochondria;
Skeletal muscle biopsy shows decreased cytochrome C oxidase activity;
Mitochondrial paracrystalline inclusion bodies
NEUROLOGIC:
[Central nervous system];
Mental retardation (1 family)
METABOLIC FEATURES:
Lactic acidosis
HEMATOLOGY:
Sideroblastic anemia;
Microcytic anemia;
Hypochromic anemia;
Bone marrow biopsy shows erythroid hyperplasia;
Ringed sideroblasts on peripheral smear and bone marrow;
Pappenheimer bodies;
Electron microscopy shows iron-loaded mitochondria
LABORATORY ABNORMALITIES:
Increased serum lactate;
Increased serum ferritin
MISCELLANEOUS:
Onset late childhood (8 to 14 years)
MOLECULAR BASIS:
Caused by mutation in the pseudouridine synthase-1 gene (PUS1, 608109.0001)
*FIELD* CD
Cassandra L. Kniffin: 7/20/2005
*FIELD* ED
joanna: 07/02/2013
joanna: 3/8/2007
ckniffin: 7/21/2005
alopez: 5/26/2004
*FIELD* CN
Marla J. F. O'Neill - updated: 6/7/2007
Victor A. McKusick - updated: 5/21/2004
*FIELD* CD
Victor A. McKusick: 3/22/1995
*FIELD* ED
terry: 12/21/2010
wwang: 9/17/2010
ckniffin: 9/17/2010
wwang: 6/12/2007
terry: 6/7/2007
ckniffin: 7/22/2005
ckniffin: 7/21/2005
terry: 4/7/2005
terry: 11/2/2004
alopez: 5/26/2004
terry: 5/24/2004
terry: 5/21/2004
mimadm: 11/3/1995
mark: 3/24/1995
mark: 3/22/1995
*RECORD*
*FIELD* NO
600462
*FIELD* TI
#600462 MYOPATHY, LACTIC ACIDOSIS, AND SIDEROBLASTIC ANEMIA 1; MLASA1
;;MITOCHONDRIAL MYOPATHY AND SIDEROBLASTIC ANEMIA
read more*FIELD* TX
A number sign (#) is used with this entry because myopathy, lactic
acidosis, and sideroblastic anemia-1 (MLASA1) can be caused by
homozygous mutation in the PUS1 gene (608109) on chromosome 12q24.33.
DESCRIPTION
Myopathy, lactic acidosis, and sideroblastic anemia (MLASA) is a rare
autosomal recessive oxidative phosphorylation disorder specific to
skeletal muscle and bone marrow (Bykhovskaya et al., 2004).
- Genetic Heterogeneity of MLASA
MLASA2 (613561) is caused by homozygous mutation in the YARS2 gene
(610957) on chromosome 12p.11.21.
CLINICAL FEATURES
Rawles and Weller (1974) reported 2 brothers with myopathy, lactic
acidosis, and sideroblastic anemia with ringed sideroblasts. Both
reported exercise intolerance beginning in childhood. The first was
studied at age 19 because of breathlessness on exertion and ankle edema.
A high cardiac output was the only finding; cardiac catheterization
ruled out a cardiac disorder. Electron microscopy of muscle from one of
the brothers showed paracrystalline inclusion bodies in mitochondria.
The asymptomatic father of the boys had chronic lactic acidosis.
Among 6 offspring of first-cousin parents, Inbal et al. (1995)
identified a brother and sister with a seemingly 'new' syndrome featured
by myopathy, sideroblastic anemia, lactic acidosis, mental retardation,
microcephaly, high palate, high philtrum, distichiasis, and
micrognathia. The patients' muscle mitochondria contained very low
levels of cytochromes a, b, and c. Deposition of iron within the
mitochondria of bone marrow erythroblasts was observed on electron
microscopy. Irregular and enlarged mitochondria with paracrystalline
inclusions were also seen on electron microscopy of muscle. However,
examination of DNA from the affected sibs showed no deletions in the
mitochondrial DNA and no mutations of the type identified in the
syndrome of mitochondrial myopathy, encephalopathy, lactic acidosis, and
stroke-like episodes (MELAS; 540000) or the syndrome of myoclonus and
epilepsy associated with ragged-red fibers (MERRF; 545000).
Casas and Fischel-Ghodsian (2004) described this disorder in a Jewish
Iranian family with 4 affected individuals living in the United States.
Hallmark features included progressive exercise intolerance during
childhood, onset of sideroblastic anemia around adolescence, basal
lactic acidemia, and mitochondrial myopathy. The presence of 2 affected
sib pairs, unaffected parents, an unaffected sib, and parental
consanguinity suggested autosomal recessive inheritance.
MAPPING
Casas et al. (2004) applied linkage analysis and homozygosity testing in
the families of Casas and Fischel-Ghodsian (2004) and in the family
reported in Israel by Inbal et al. (1995), both of which originated from
the same Iranian town, and localized a candidate region of 1.2 Mb within
12q24.33.
MOLECULAR GENETICS
By sequence analysis of each of the 6 known genes in the 12q24.33 MLASA
candidate region defined by Casas et al. (2004), as well as of 4
putative genes with expression in bone marrow or muscle, Bykhovskaya et
al. (2004) identified a homozygous missense mutation in the PUS1 gene,
encoding pseudouridine synthase-1 (608109.0001), in all patients with
MLASA from the families described by Inbal et al. (1995) and Casas and
Fischel-Ghodsian (2004). The amino acid change affects a highly
conserved residue and appears to be in the catalytic center of the
protein.
In 2 Italian brothers with MLASA, born of sixth-cousin parents,
Fernandez-Vizarra et al. (2007) identified homozygosity for a nonsense
mutation in the PUS1 gene (E220X; 608109.0002). The hematologic and
neurologic presentation was markedly different in the 2 brothers: the
older brother had a very severe mitochondrial myopathy with muscle
wasting, severe sideroblastic anemia requiring multiple blood
transfusions, and severe growth retardation due to complete deficiency
of growth hormone, but had normal psychomotor development and
above-normal intelligence. He died of respiratory failure at 12 years of
age. The younger brother, who was still alive at 13 years of age, had a
much milder neuromuscular syndrome with no muscle wasting and did not
require transfusions for his sideroblastic anemia; however, he had
cognitive and behavioral abnormalities with moderate mental retardation,
hyperactivity, and panic attacks.
PATHOGENESIS
Patton et al. (2005) isolated total RNA from lymphoblastoid cell lines
from MLASA patients with the R116W mutation, their parents, unaffected
sibs, and controls. They found that mitochondrial and cytoplasmic tRNAs
from MLASA patients lacked modification at sites normally modified by
PUS1, whereas tRNAs from controls, unaffected sibs, or parents all had
pseudouridine at those positions. Immunohistochemical staining showed
nuclear, cytoplasmic, and mitochondrial distribution of the PUS1
protein, and there was no difference between patients and unaffected
family members. Patton et al. (2005) concluded that MLASA is associated
with absent or greatly reduced tRNA pseudouridylation at specific sites.
*FIELD* RF
1. Bykhovskaya, Y.; Casas, K.; Mengesha, E.; Inbal, A.; Fischel-Ghodsian,
N.: Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial
myopathy and sideroblastic anemia (MLASA). Am. J. Hum. Genet. 74:
1303-1308, 2004.
2. Casas, K.; Bykhovskaya, Y.; Mengesha, E.; Wang, D.; Yang, H.; Taylor,
K.; Inbal, A.; Fischel-Ghodsian, N.: Gene responsible for mitochondrial
myopathy and sideroblastic anemia (MSA) maps to chromosome 12q24.33. Am.
J. Med. Genet. 127A: 44-49, 2004.
3. Casas, K.; Fischel-Ghodsian, N.: Mitochondrial myopathy and sideroblastic
anemia. Am. J. Med. Genet. 125: 201-204, 2004.
4. Fernandez-Vizarra, E.; Berardinelli, A.; Valente, L.; Tiranti,
V.; Zeviani, M.: Nonsense mutation in pseudouridylate synthase 1
(PUS1) in two brothers affected by myopathy, lactic acidosis and sideroblastic
anaemia (MLASA). J. Med. Genet. 44: 173-180, 2007.
5. Inbal, A.; Avissar, N.; Shaklai, M.; Kuritzky, A.; Schejter, A.;
Ben-David, E.; Shanske, S.; Garty, B.-Z.: Myopathy, lactic acidosis,
and sideroblastic anemia: a new syndrome. Am. J. Med. Genet. 55:
372-378, 1995.
6. Patton, J. R.; Bykhovskaya, Y.; Mengesha, E.; Bertolotto, C.; Fischel-Ghodsian,
N.: 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. 280: 19823-19828,
2005.
7. Rawles, J. M.; Weller, R. O.: Familial association of metabolic
myopathy, lactic acidosis and sideroblastic anemia. Am. J. Med. 56:
891-897, 1974.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Delayed growth;
Delayed pubertal development
HEAD AND NECK:
[Head];
Microcephaly (reported in 1 family);
[Face];
Micrognathia (1 family);
High philtrum (1 family);
[Eyes];
Distichiasis (double row of eyelashes, 1 family);
[Mouth];
High-arched palate (1 family)
SKIN, NAILS, HAIR:
[Skin];
Pallor
MUSCLE, SOFT TISSUE:
Exercise intolerance;
Muscle weakness, progressive;
Generalized limb muscle atrophy;
Skeletal muscle biopsy shows fat droplets in sarcoplasm and mitochondria;
Skeletal muscle biopsy shows decreased cytochrome C oxidase activity;
Mitochondrial paracrystalline inclusion bodies
NEUROLOGIC:
[Central nervous system];
Mental retardation (1 family)
METABOLIC FEATURES:
Lactic acidosis
HEMATOLOGY:
Sideroblastic anemia;
Microcytic anemia;
Hypochromic anemia;
Bone marrow biopsy shows erythroid hyperplasia;
Ringed sideroblasts on peripheral smear and bone marrow;
Pappenheimer bodies;
Electron microscopy shows iron-loaded mitochondria
LABORATORY ABNORMALITIES:
Increased serum lactate;
Increased serum ferritin
MISCELLANEOUS:
Onset late childhood (8 to 14 years)
MOLECULAR BASIS:
Caused by mutation in the pseudouridine synthase-1 gene (PUS1, 608109.0001)
*FIELD* CD
Cassandra L. Kniffin: 7/20/2005
*FIELD* ED
joanna: 07/02/2013
joanna: 3/8/2007
ckniffin: 7/21/2005
alopez: 5/26/2004
*FIELD* CN
Marla J. F. O'Neill - updated: 6/7/2007
Victor A. McKusick - updated: 5/21/2004
*FIELD* CD
Victor A. McKusick: 3/22/1995
*FIELD* ED
terry: 12/21/2010
wwang: 9/17/2010
ckniffin: 9/17/2010
wwang: 6/12/2007
terry: 6/7/2007
ckniffin: 7/22/2005
ckniffin: 7/21/2005
terry: 4/7/2005
terry: 11/2/2004
alopez: 5/26/2004
terry: 5/24/2004
terry: 5/21/2004
mimadm: 11/3/1995
mark: 3/24/1995
mark: 3/22/1995
MIM
608109
*RECORD*
*FIELD* NO
608109
*FIELD* TI
*608109 PSEUDOURIDINE SYNTHASE 1; PUS1
*FIELD* TX
DESCRIPTION
PUS1 converts uridine into pseudouridine after the nucleotide has been
read moreincorporated into RNA. Pseudouridine may have a functional role in tRNAs
and may assist in the peptidyl transfer reaction of rRNAs (Chen and
Patton, 1999).
CLONING
By searching for sequences similar to yeast Pus1, Chen and Patton (1999)
identified and cloned mouse Pus1. The deduced mouse protein contains 393
amino acids. They cloned human PUS1 by screening a HeLa cell library and
by 5-prime RACE. The deduced human protein contains 348 amino acids and
shares 92% identity with mouse Pus1. Northern blot analysis detected
transcripts of 1.4, 1.6, and 4.3 kb in all mouse tissues examined
(liver, heart, kidney, and spleen) and in a mouse monocytic cell line.
The 4.3-kb transcript was seen only in whole RNA and not in mRNA.
Fernandez-Vizarra et al. (2007) identified and cloned 3 splice variants
of PUS1. PUS1-1 encodes a protein with an N-terminal mitochondrial
leader peptide. Western blot analysis detected full-length PUS1-1 at an
apparent molecular mass of 47 kD, and the mature protein, lacking the
mitochondrial localization signal, was about 37 kD. The PUS1-2 and
PUS1-3 transcripts differ in the 5-prime untranslated region but encode
the same protein that begins with an internal methionine (met29)
relative to PUS1-1. Immunofluorescence localized PUS1-1 to mitochondria
and PUS1-2 and PUS1-3 to nuclei.
GENE FUNCTION
Chen and Patton (1999) assayed recombinant mouse Pus1 following
expression in E. coli. The purified protein converted uridine to
pseudouridine in a number of tRNA substrates. Chen and Patton (1999)
were unable to measure enzymatic activity for recombinant human PUS1,
and they attributed this to the lack of 45 N-terminal amino acids in the
human protein compared with the mouse protein.
By in organello import assay, Fernandez-Vizarra et al. (2007) showed
that PUS1-1 was imported into mitochondria by the TOM/TIM protein
translocation system (see TIMM10; 602251), which is driven by the
mitochondrial membrane potential. Mature PUS1-1 was internalized within
the inner mitochondrial compartment. Pharmacologic block of the
mitochondrial membrane potential prevented PUS1-1 import.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the PUS1
gene to chromosome 12 (TMAP stSG4720).
Bykhovskaya et al. (2004) identified the PUS1 gene within the critical
region for mitochondrial myopathy and sideroblastic anemia (MLASA1;
600462) on 12q24.33.
MOLECULAR GENETICS
In all affected members of 2 Iranian Jewish families with MLASA1,
Bykhovskaya et al. (2004) found a homozygous missense mutation in the
PUS1 gene (R116W; 608109.0001). Mutation in another pseudouridine
synthase, that encoded by the dyskerin gene (DKC1; 300126), is involved
in 2 human diseases associated with bone marrow dysfunction: X-linked
dyskeratosis congenita (305000) and Hoyeraal-Hreidarsson (300240)
syndrome.
Patton et al. (2005) isolated total RNA from lymphoblastoid cell lines
from MLASA1 patients with the R116W mutation, their parents, unaffected
sibs, and controls. They found that mitochondrial and cytoplasmic tRNAs
from MLASA1 patients lacked modification at sites normally modified by
PUS1, whereas tRNAs from controls, unaffected sibs, or parents all had
pseudouridine at those positions. Immunohistochemical staining showed
nuclear, cytoplasmic, and mitochondrial distribution of the PUS1
protein, and there was no difference between patients and unaffected
family members. Patton et al. (2005) concluded that MLASA1 is associated
with absent or greatly reduced tRNA pseudouridylation at specific sites.
Fernandez-Vizarra et al. (2007) reported 2 Italian brothers with MLASA1
in whom they identified homozygosity for a nonsense mutation in the PUS1
gene (608109.0002).
*FIELD* AV
.0001
MYOPATHY, LACTIC ACIDOSIS, AND SIDEROBLASTIC ANEMIA 1
PUS1, ARG116TRP
In affected individuals from 2 Jewish families of Iranian extraction
with mitochondrial myopathy and sideroblastic anemia (MLASA1; 600462),
previously described by Inbal et al. (1995) and Casas and
Fischel-Ghodsian (2004), respectively, Bykhovskaya et al. (2004)
demonstrated homozygosity for an arg116-to-trp (R116W) mutation
resulting from a 656C-T transition in exon 3 of the PUS1 gene as the
cause of the disorder. The mutation results in a nonconservative amino
acid change in the catalytic center of pseudouridine synthase-1.
.0002
MYOPATHY, LACTIC ACIDOSIS, AND SIDEROBLASTIC ANEMIA 1
PUS1, GLU220TER
In 2 Italian brothers with mitochondrial myopathy and sideroblastic
anemia (MLASA1; 600462), born of sixth-cousin parents, Fernandez-Vizarra
et al. (2007) identified homozygosity for a 658G-T transversion in the
PUS1 gene, resulting in a glu220-to-ter (E220X) substitution in the
PUS1-1 isoform. The parents were heterozygous for the mutation. The
older brother, who had above-normal intelligence, died at 12 years of
age from respiratory failure; his younger brother, who was mentally
retarded, had no muscle wasting and was alive at 13 years of age.
*FIELD* RF
1. Bykhovskaya, Y.; Casas, K.; Mengesha, E.; Inbal, A.; Fischel-Ghodsian,
N.: Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial
myopathy and sideroblastic anemia (MLASA). Am. J. Hum. Genet. 74:
1303-1308, 2004.
2. Casas, K.; Fischel-Ghodsian, N.: Mitochondrial myopathy and sideroblastic
anemia. Am. J. Med. Genet. 125: 201-204, 2004.
3. Chen, J.; Patton, J. R.: Cloning and characterization of a mammalian
pseudouridine synthase. RNA 5: 409-419, 1999.
4. Fernandez-Vizarra, E.; Berardinelli, A.; Valente, L.; Tiranti,
V.; Zeviani, M.: Nonsense mutation in pseudouridylate synthase 1
(PUS1) in two brothers affected by myopathy, lactic acidosis and sideroblastic
anaemia (MLASA). J. Med. Genet. 44: 173-180, 2007.
5. Inbal, A.; Avissar, N.; Shaklai, M.; Kuritzky, A.; Schejter, A.;
Ben-David, E.; Shanske, S.; Garty, B.-Z.: Myopathy, lactic acidosis,
and sideroblastic anemia: a new syndrome. Am. J. Med. Genet. 55:
372-378, 1995.
6. Patton, J. R.; Bykhovskaya, Y.; Mengesha, E.; Bertolotto, C.; Fischel-Ghodsian,
N.: 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. 280: 19823-19828,
2005.
*FIELD* CN
Patricia A. Hartz - updated: 6/12/2007
Marla J. F. O'Neill - updated: 6/7/2007
Victor A. McKusick - updated: 5/21/2004
*FIELD* CD
Patricia A. Hartz: 9/23/2003
*FIELD* ED
terry: 12/21/2010
wwang: 9/17/2010
wwang: 6/12/2007
terry: 6/7/2007
alopez: 5/26/2004
terry: 5/21/2004
mgross: 9/23/2003
*RECORD*
*FIELD* NO
608109
*FIELD* TI
*608109 PSEUDOURIDINE SYNTHASE 1; PUS1
*FIELD* TX
DESCRIPTION
PUS1 converts uridine into pseudouridine after the nucleotide has been
read moreincorporated into RNA. Pseudouridine may have a functional role in tRNAs
and may assist in the peptidyl transfer reaction of rRNAs (Chen and
Patton, 1999).
CLONING
By searching for sequences similar to yeast Pus1, Chen and Patton (1999)
identified and cloned mouse Pus1. The deduced mouse protein contains 393
amino acids. They cloned human PUS1 by screening a HeLa cell library and
by 5-prime RACE. The deduced human protein contains 348 amino acids and
shares 92% identity with mouse Pus1. Northern blot analysis detected
transcripts of 1.4, 1.6, and 4.3 kb in all mouse tissues examined
(liver, heart, kidney, and spleen) and in a mouse monocytic cell line.
The 4.3-kb transcript was seen only in whole RNA and not in mRNA.
Fernandez-Vizarra et al. (2007) identified and cloned 3 splice variants
of PUS1. PUS1-1 encodes a protein with an N-terminal mitochondrial
leader peptide. Western blot analysis detected full-length PUS1-1 at an
apparent molecular mass of 47 kD, and the mature protein, lacking the
mitochondrial localization signal, was about 37 kD. The PUS1-2 and
PUS1-3 transcripts differ in the 5-prime untranslated region but encode
the same protein that begins with an internal methionine (met29)
relative to PUS1-1. Immunofluorescence localized PUS1-1 to mitochondria
and PUS1-2 and PUS1-3 to nuclei.
GENE FUNCTION
Chen and Patton (1999) assayed recombinant mouse Pus1 following
expression in E. coli. The purified protein converted uridine to
pseudouridine in a number of tRNA substrates. Chen and Patton (1999)
were unable to measure enzymatic activity for recombinant human PUS1,
and they attributed this to the lack of 45 N-terminal amino acids in the
human protein compared with the mouse protein.
By in organello import assay, Fernandez-Vizarra et al. (2007) showed
that PUS1-1 was imported into mitochondria by the TOM/TIM protein
translocation system (see TIMM10; 602251), which is driven by the
mitochondrial membrane potential. Mature PUS1-1 was internalized within
the inner mitochondrial compartment. Pharmacologic block of the
mitochondrial membrane potential prevented PUS1-1 import.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the PUS1
gene to chromosome 12 (TMAP stSG4720).
Bykhovskaya et al. (2004) identified the PUS1 gene within the critical
region for mitochondrial myopathy and sideroblastic anemia (MLASA1;
600462) on 12q24.33.
MOLECULAR GENETICS
In all affected members of 2 Iranian Jewish families with MLASA1,
Bykhovskaya et al. (2004) found a homozygous missense mutation in the
PUS1 gene (R116W; 608109.0001). Mutation in another pseudouridine
synthase, that encoded by the dyskerin gene (DKC1; 300126), is involved
in 2 human diseases associated with bone marrow dysfunction: X-linked
dyskeratosis congenita (305000) and Hoyeraal-Hreidarsson (300240)
syndrome.
Patton et al. (2005) isolated total RNA from lymphoblastoid cell lines
from MLASA1 patients with the R116W mutation, their parents, unaffected
sibs, and controls. They found that mitochondrial and cytoplasmic tRNAs
from MLASA1 patients lacked modification at sites normally modified by
PUS1, whereas tRNAs from controls, unaffected sibs, or parents all had
pseudouridine at those positions. Immunohistochemical staining showed
nuclear, cytoplasmic, and mitochondrial distribution of the PUS1
protein, and there was no difference between patients and unaffected
family members. Patton et al. (2005) concluded that MLASA1 is associated
with absent or greatly reduced tRNA pseudouridylation at specific sites.
Fernandez-Vizarra et al. (2007) reported 2 Italian brothers with MLASA1
in whom they identified homozygosity for a nonsense mutation in the PUS1
gene (608109.0002).
*FIELD* AV
.0001
MYOPATHY, LACTIC ACIDOSIS, AND SIDEROBLASTIC ANEMIA 1
PUS1, ARG116TRP
In affected individuals from 2 Jewish families of Iranian extraction
with mitochondrial myopathy and sideroblastic anemia (MLASA1; 600462),
previously described by Inbal et al. (1995) and Casas and
Fischel-Ghodsian (2004), respectively, Bykhovskaya et al. (2004)
demonstrated homozygosity for an arg116-to-trp (R116W) mutation
resulting from a 656C-T transition in exon 3 of the PUS1 gene as the
cause of the disorder. The mutation results in a nonconservative amino
acid change in the catalytic center of pseudouridine synthase-1.
.0002
MYOPATHY, LACTIC ACIDOSIS, AND SIDEROBLASTIC ANEMIA 1
PUS1, GLU220TER
In 2 Italian brothers with mitochondrial myopathy and sideroblastic
anemia (MLASA1; 600462), born of sixth-cousin parents, Fernandez-Vizarra
et al. (2007) identified homozygosity for a 658G-T transversion in the
PUS1 gene, resulting in a glu220-to-ter (E220X) substitution in the
PUS1-1 isoform. The parents were heterozygous for the mutation. The
older brother, who had above-normal intelligence, died at 12 years of
age from respiratory failure; his younger brother, who was mentally
retarded, had no muscle wasting and was alive at 13 years of age.
*FIELD* RF
1. Bykhovskaya, Y.; Casas, K.; Mengesha, E.; Inbal, A.; Fischel-Ghodsian,
N.: Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial
myopathy and sideroblastic anemia (MLASA). Am. J. Hum. Genet. 74:
1303-1308, 2004.
2. Casas, K.; Fischel-Ghodsian, N.: Mitochondrial myopathy and sideroblastic
anemia. Am. J. Med. Genet. 125: 201-204, 2004.
3. Chen, J.; Patton, J. R.: Cloning and characterization of a mammalian
pseudouridine synthase. RNA 5: 409-419, 1999.
4. Fernandez-Vizarra, E.; Berardinelli, A.; Valente, L.; Tiranti,
V.; Zeviani, M.: Nonsense mutation in pseudouridylate synthase 1
(PUS1) in two brothers affected by myopathy, lactic acidosis and sideroblastic
anaemia (MLASA). J. Med. Genet. 44: 173-180, 2007.
5. Inbal, A.; Avissar, N.; Shaklai, M.; Kuritzky, A.; Schejter, A.;
Ben-David, E.; Shanske, S.; Garty, B.-Z.: Myopathy, lactic acidosis,
and sideroblastic anemia: a new syndrome. Am. J. Med. Genet. 55:
372-378, 1995.
6. Patton, J. R.; Bykhovskaya, Y.; Mengesha, E.; Bertolotto, C.; Fischel-Ghodsian,
N.: 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. 280: 19823-19828,
2005.
*FIELD* CN
Patricia A. Hartz - updated: 6/12/2007
Marla J. F. O'Neill - updated: 6/7/2007
Victor A. McKusick - updated: 5/21/2004
*FIELD* CD
Patricia A. Hartz: 9/23/2003
*FIELD* ED
terry: 12/21/2010
wwang: 9/17/2010
wwang: 6/12/2007
terry: 6/7/2007
alopez: 5/26/2004
terry: 5/21/2004
mgross: 9/23/2003