Full text data of SEPSECS
SEPSECS
(TRNP48)
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
O-phosphoseryl-tRNA(Sec) selenium transferase; 2.9.1.2 (Liver-pancreas antigen; LP; SLA-p35; SLA/LP autoantigen; Selenocysteine synthase; Sec synthase; Selenocysteinyl-tRNA(Sec) synthase; Sep-tRNA:Sec-tRNA synthase; SepSecS; Soluble liver antigen; SLA; UGA suppressor tRNA-associated protein; tRNA(Ser/Sec)-associated antigenic protein)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
O-phosphoseryl-tRNA(Sec) selenium transferase; 2.9.1.2 (Liver-pancreas antigen; LP; SLA-p35; SLA/LP autoantigen; Selenocysteine synthase; Sec synthase; Selenocysteinyl-tRNA(Sec) synthase; Sep-tRNA:Sec-tRNA synthase; SepSecS; Soluble liver antigen; SLA; UGA suppressor tRNA-associated protein; tRNA(Ser/Sec)-associated antigenic protein)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q9HD40
ID SPCS_HUMAN Reviewed; 501 AA.
AC Q9HD40; A8K8W1; Q0D2P3; Q17RT1; Q9NXZ5; Q9UGM9; Q9Y353;
DT 29-MAR-2005, integrated into UniProtKB/Swiss-Prot.
read moreDT 29-MAR-2005, sequence version 2.
DT 22-JAN-2014, entry version 103.
DE RecName: Full=O-phosphoseryl-tRNA(Sec) selenium transferase;
DE EC=2.9.1.2;
DE AltName: Full=Liver-pancreas antigen;
DE Short=LP;
DE AltName: Full=SLA-p35;
DE AltName: Full=SLA/LP autoantigen;
DE AltName: Full=Selenocysteine synthase;
DE Short=Sec synthase;
DE AltName: Full=Selenocysteinyl-tRNA(Sec) synthase;
DE AltName: Full=Sep-tRNA:Sec-tRNA synthase;
DE Short=SepSecS;
DE AltName: Full=Soluble liver antigen;
DE Short=SLA;
DE AltName: Full=UGA suppressor tRNA-associated protein;
DE AltName: Full=tRNA(Ser/Sec)-associated antigenic protein;
GN Name=SEPSECS; Synonyms=TRNP48;
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).
RC TISSUE=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 [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Endometrium;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 3).
RC TISSUE=Brain, and Muscle;
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 [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 29-501 (ISOFORM 1), AND NUCLEOTIDE
RP SEQUENCE [MRNA] OF 29-501 (ISOFORM 2).
RC TISSUE=Liver, and T-cell lymphoma;
RX PubMed=10801173; DOI=10.1016/S0140-6736(00)02166-8;
RA Wies I., Brunner S., Henninger J., Herkel J., Kanzler S.,
RA Meyer zum Bueschenfelde K.-H., Lohse A.W.;
RT "Identification of target antigen for SLA/LP autoantibodies in
RT autoimmune hepatitis.";
RL Lancet 355:1510-1515(2000).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 61-501 (ISOFORM 1).
RC TISSUE=Liver;
RX PubMed=10931155; DOI=10.1046/j.1365-2249.2000.01280.x;
RA Costa M., Rodriguez-Sanchez J.L., Czaja A.J., Gelpi C.;
RT "Isolation and characterization of cDNA encoding the antigenic protein
RT of the human tRNP(Ser)Sec complex recognized by autoantibodies from
RT patients withtype-1 autoimmune hepatitis.";
RL Clin. Exp. Immunol. 121:364-374(2000).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 61-501 (ISOFORM 1).
RC TISSUE=Liver;
RA Seelig H.-P., Wiemann C., Plaikner M., Schranz P., Seelig R., Renz M.;
RT "Coding sequence of the human SLA/LP autoantigen.";
RL Submitted (JUN-2000) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 208-501.
RX PubMed=11230739; DOI=10.1053/jhep.2001.22218;
RA Volkmann M., Martin L., Baeurle A., Heid H., Strassburg C.P.,
RA Trautwein C., Fiehn W., Manns M.P.;
RT "Soluble liver antigen: isolation of a 35-kd recombinant protein (SLA-
RT p35) specifically recognizing sera from patients with autoimmune
RT hepatitis.";
RL Hepatology 33:591-596(2001).
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 434-493, AND SLA/LP EPITOPE MAPPING.
RX PubMed=11826415; DOI=10.1053/jhep.2002.30699;
RA Herkel J., Heidrich B., Nieraad N., Wies I., Rother M., Lohse A.W.;
RT "Fine specificity of autoantibodies to soluble liver antigen and
RT liver/pancreas.";
RL Hepatology 35:403-408(2002).
RN [11]
RP FUNCTION, COFACTOR, AND MUTAGENESIS OF LYS-284.
RX PubMed=17142313; DOI=10.1073/pnas.0609703104;
RA Yuan J., Palioura S., Salazar J.C., Su D., O'Donoghue P., Hohn M.J.,
RA Cardoso A.M., Whitman W.B., Soell D.;
RT "RNA-dependent conversion of phosphoserine forms selenocysteine in
RT eukaryotes and archaea.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:18923-18927(2006).
RN [12]
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 [13]
RP X-RAY CRYSTALLOGRAPHY (2.81 ANGSTROMS) IN COMPLEX WITH TRNA AND
RP PYRIDOXAL PHOSPHATE, SUBUNIT, SUBSTRATE-BINDING SITES, COFACTOR, AND
RP MUTAGENESIS OF ARG-75; ARG-97; GLN-105; LYS-173 AND ARG-313.
RX PubMed=19608919; DOI=10.1126/science.1173755;
RA Palioura S., Sherrer R.L., Steitz T.A., Soll D., Simonovic M.;
RT "The human SepSecS-tRNASec complex reveals the mechanism of
RT selenocysteine formation.";
RL Science 325:321-325(2009).
RN [14]
RP VARIANTS PCH2D THR-239 AND CYS-334, AND CHARACTERIZATION OF VARIANTS
RP PCH2D THR-239 AND CYS-334.
RX PubMed=20920667; DOI=10.1016/j.ajhg.2010.09.007;
RA Agamy O., Ben Zeev B., Lev D., Marcus B., Fine D., Su D., Narkis G.,
RA Ofir R., Hoffmann C., Leshinsky-Silver E., Flusser H., Sivan S.,
RA Soll D., Lerman-Sagie T., Birk O.S.;
RT "Mutations disrupting selenocysteine formation cause progressive
RT cerebello-cerebral atrophy.";
RL Am. J. Hum. Genet. 87:538-544(2010).
CC -!- FUNCTION: Converts O-phosphoseryl-tRNA(Sec) to selenocysteinyl-
CC tRNA(Sec) required for selenoprotein biosynthesis.
CC -!- CATALYTIC ACTIVITY: O-phospho-L-seryl-tRNA(Sec) + selenophosphate
CC = L-selenocysteinyl-tRNA(Sec) + phosphate.
CC -!- COFACTOR: Pyridoxal phosphate.
CC -!- PATHWAY: Aminoacyl-tRNA biosynthesis; selenocysteinyl-tRNA(Sec)
CC biosynthesis; selenocysteinyl-tRNA(Sec) from L-seryl-tRNA(Sec)
CC (archaeal/eukaryal route): step 2/2.
CC -!- SUBUNIT: Homotetramer formed by a catalytic dimer and a non-
CC catalytic dimer serving as a binding platform that orients tRNASec
CC for catalysis. Each tetramer binds the CCA ends of two tRNAs which
CC point to the active sites of the catalytic dimer.
CC -!- INTERACTION:
CC P04591:gag (xeno); NbExp=3; IntAct=EBI-6163446, EBI-6163428;
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q9HD40-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9HD40-2; Sequence=VSP_038078, VSP_038079;
CC Note=May be produced at very low levels due to a premature stop
CC codon in the mRNA, leading to nonsense-mediated mRNA decay. No
CC experimental confirmation available;
CC Name=3;
CC IsoId=Q9HD40-3; Sequence=VSP_038080;
CC -!- TISSUE SPECIFICITY: Primarily expressed in liver, pancreas, kidney
CC and lung. Overexpressed in PHA-stimulated T-cells.
CC -!- DISEASE: Pontocerebellar hypoplasia 2D (PCH2D) [MIM:613811]: A
CC disorder characterized by postnatal onset of progressive atrophy
CC of the cerebrum and cerebellum, microcephaly, profound mental
CC retardation, spasticity, and variable seizures. Note=The disease
CC is caused by mutations affecting the gene represented in this
CC entry.
CC -!- MISCELLANEOUS: Possible diagnostic marker for autoimmune hepatitis
CC (AIH).
CC -!- SIMILARITY: Belongs to the SepSecS family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAD33963.2; Type=Erroneous translation; Note=Wrong choice of CDS;
CC Sequence=AAH23539.1; Type=Erroneous translation; Note=Wrong choice of CDS;
CC Sequence=CAB62209.1; Type=Erroneous initiation; Note=Translation N-terminally shortened;
CC Sequence=CAB89517.1; Type=Frameshift; Positions=39;
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DR EMBL; AK292476; BAF85165.1; -; mRNA.
DR EMBL; BX648976; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AC007073; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC104662; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471069; EAW92832.1; -; Genomic_DNA.
DR EMBL; BC023539; AAH23539.1; ALT_SEQ; mRNA.
DR EMBL; BC117202; AAI17203.1; -; mRNA.
DR EMBL; AF146396; AAD33963.2; ALT_SEQ; mRNA.
DR EMBL; AJ277541; CAB89517.1; ALT_FRAME; mRNA.
DR EMBL; AJ238617; CAB62209.1; ALT_INIT; mRNA.
DR EMBL; AF282065; AAG00491.1; -; mRNA.
DR RefSeq; NP_058651.3; NM_016955.3.
DR RefSeq; XP_005248225.1; XM_005248168.1.
DR UniGene; Hs.253305; -.
DR PDB; 3HL2; X-ray; 2.81 A; A/B/C/D=1-501.
DR PDBsum; 3HL2; -.
DR ProteinModelPortal; Q9HD40; -.
DR SMR; Q9HD40; 20-464.
DR IntAct; Q9HD40; 1.
DR STRING; 9606.ENSP00000305956; -.
DR DrugBank; DB00114; Pyridoxal Phosphate.
DR PhosphoSite; Q9HD40; -.
DR DMDM; 62287911; -.
DR PaxDb; Q9HD40; -.
DR PRIDE; Q9HD40; -.
DR DNASU; 51091; -.
DR Ensembl; ENST00000302922; ENSP00000305956; ENSG00000109618.
DR Ensembl; ENST00000382103; ENSP00000371535; ENSG00000109618.
DR Ensembl; ENST00000514585; ENSP00000421880; ENSG00000109618.
DR GeneID; 51091; -.
DR KEGG; hsa:51091; -.
DR UCSC; uc003grg.3; human.
DR CTD; 51091; -.
DR GeneCards; GC04M025121; -.
DR HGNC; HGNC:30605; SEPSECS.
DR MIM; 613009; gene.
DR MIM; 613811; phenotype.
DR neXtProt; NX_Q9HD40; -.
DR Orphanet; 2524; Pontocerebellar hypoplasia type 2.
DR Orphanet; 247198; Progressive cerebello-cerebral atrophy.
DR PharmGKB; PA162402915; -.
DR eggNOG; COG0076; -.
DR HOGENOM; HOG000254245; -.
DR HOVERGEN; HBG061363; -.
DR InParanoid; Q9HD40; -.
DR KO; K03341; -.
DR OMA; NPISMAM; -.
DR OrthoDB; EOG71G9TX; -.
DR UniPathway; UPA00906; UER00898.
DR EvolutionaryTrace; Q9HD40; -.
DR GeneWiki; SEPSECS; -.
DR GenomeRNAi; 51091; -.
DR NextBio; 53771; -.
DR PRO; PR:Q9HD40; -.
DR ArrayExpress; Q9HD40; -.
DR Bgee; Q9HD40; -.
DR CleanEx; HS_SEPSECS; -.
DR Genevestigator; Q9HD40; -.
DR GO; GO:0005737; C:cytoplasm; ISS:HGNC.
DR GO; GO:0005634; C:nucleus; ISS:HGNC.
DR GO; GO:0030170; F:pyridoxal phosphate binding; IEA:InterPro.
DR GO; GO:0016785; F:transferase activity, transferring selenium-containing groups; IEA:InterPro.
DR GO; GO:0000049; F:tRNA binding; ISS:HGNC.
DR GO; GO:0001514; P:selenocysteine incorporation; ISS:HGNC.
DR GO; GO:0097056; P:selenocysteinyl-tRNA(Sec) biosynthetic process; IEA:UniProtKB-UniPathway.
DR Gene3D; 3.40.640.10; -; 1.
DR InterPro; IPR019793; Peroxidases_heam-ligand_BS.
DR InterPro; IPR015424; PyrdxlP-dep_Trfase.
DR InterPro; IPR015421; PyrdxlP-dep_Trfase_major_sub1.
DR InterPro; IPR019872; Sec-tRNA_Se_transferase.
DR InterPro; IPR008829; SLA/LP_auto_ag.
DR PANTHER; PTHR12944; PTHR12944; 1.
DR Pfam; PF05889; SLA_LP_auto_ag; 1.
DR PIRSF; PIRSF017689; SepSecS; 1.
DR SUPFAM; SSF53383; SSF53383; 1.
DR TIGRFAMs; TIGR03531; selenium_SpcS; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Complete proteome; Cytoplasm;
KW Disease mutation; Protein biosynthesis; Pyridoxal phosphate;
KW Reference proteome; RNA-binding; Selenium; Transferase; tRNA-binding.
FT CHAIN 1 501 O-phosphoseryl-tRNA(Sec) selenium
FT transferase.
FT /FTId=PRO_0000219875.
FT REGION 1 44 Tetramerization.
FT REGION 96 106 Phosphate loop (P-loop).
FT REGION 474 493 SLA/LP epitope.
FT BINDING 75 75 PLP (By similarity).
FT BINDING 97 97 Substrate.
FT BINDING 98 98 Substrate.
FT BINDING 105 105 Substrate.
FT BINDING 271 271 tRNA variable arm.
FT BINDING 313 313 Substrate.
FT BINDING 398 398 tRNA discriminator base.
FT BINDING 463 463 tRNA acceptor arm.
FT SITE 74 74 May act as a substrate filter by
FT repelling compounds with a negatively
FT charged alpha-carboxylate.
FT MOD_RES 284 284 N6-(pyridoxal phosphate)lysine.
FT VAR_SEQ 1 38 MNRESFAAGERLVSPAYVRQGCEARRSHEHLIRLLLEK ->
FT MQCDDLGSLQPPPPGFTPFACLSLPSSWDYRRPPPHP (in
FT isoform 3).
FT /FTId=VSP_038080.
FT VAR_SEQ 39 47 GKCPENGWD -> VHSWHWTIR (in isoform 2).
FT /FTId=VSP_038078.
FT VAR_SEQ 48 501 Missing (in isoform 2).
FT /FTId=VSP_038079.
FT VARIANT 239 239 A -> T (in PCH2D; abrogates enzyme
FT activity).
FT /FTId=VAR_065585.
FT VARIANT 334 334 Y -> C (in PCH2D; abrogates enzyme
FT activity).
FT /FTId=VAR_065586.
FT MUTAGEN 75 75 R->A: Inactive in vivo.
FT MUTAGEN 97 97 R->A: Indistinguishable from wild-type.
FT MUTAGEN 97 97 R->Q: Indistinguishable from wild-type.
FT MUTAGEN 105 105 Q->A: Inactive in vivo.
FT MUTAGEN 173 173 K->A: Indistinguishable from wild-type.
FT MUTAGEN 173 173 K->M: Indistinguishable from wild-type.
FT MUTAGEN 284 284 K->A: Loss of activity.
FT MUTAGEN 313 313 R->A: Inactive in vivo.
FT CONFLICT 98 98 S -> P (in Ref. 8; AAG00491).
FT CONFLICT 264 264 H -> R (in Ref. 1; BAF85165).
FT CONFLICT 398 398 R -> K (in Ref. 6; AAD33963/CAB89517).
FT CONFLICT 452 452 K -> N (in Ref. 6; AAD33963/CAB89517).
FT CONFLICT 467 467 K -> R (in Ref. 8; AAG00491).
FT HELIX 26 38
FT HELIX 48 59
FT HELIX 63 65
FT HELIX 82 87
FT TURN 88 90
FT HELIX 109 128
FT STRAND 136 142
FT HELIX 144 158
FT STRAND 164 168
FT HELIX 173 181
FT STRAND 185 189
FT STRAND 191 194
FT STRAND 197 200
FT HELIX 202 212
FT HELIX 214 216
FT STRAND 217 223
FT HELIX 235 245
FT STRAND 249 252
FT HELIX 260 272
FT STRAND 277 281
FT HELIX 282 286
FT STRAND 293 298
FT HELIX 300 308
FT HELIX 317 357
FT TURN 358 360
FT STRAND 370 376
FT TURN 382 384
FT HELIX 387 397
FT STRAND 404 406
FT STRAND 412 414
FT STRAND 417 421
FT TURN 422 425
FT STRAND 433 437
FT HELIX 444 462
SQ SEQUENCE 501 AA; 55726 MW; 7136FB390B18760B CRC64;
MNRESFAAGE RLVSPAYVRQ GCEARRSHEH LIRLLLEKGK CPENGWDEST LELFLHELAI
MDSNNFLGNC GVGEREGRVA SALVARRHYR FIHGIGRSGD ISAVQPKAAG SSLLNKITNS
LVLDIIKLAG VHTVANCFVV PMATGMSLTL CFLTLRHKRP KAKYIIWPRI DQKSCFKSMI
TAGFEPVVIE NVLEGDELRT DLKAVEAKVQ ELGPDCILCI HSTTSCFAPR VPDRLEELAV
ICANYDIPHI VNNAYGVQSS KCMHLIQQGA RVGRIDAFVQ SLDKNFMVPV GGAIIAGFND
SFIQEISKMY PGRASASPSL DVLITLLSLG SNGYKKLLKE RKEMFSYLSN QIKKLSEAYN
ERLLHTPHNP ISLAMTLKTL DEHRDKAVTQ LGSMLFTRQV SGARVVPLGS MQTVSGYTFR
GFMSHTNNYP CAYLNAASAI GMKMQDVDLF IKRLDRCLKA VRKERSKESD DNYDKTEDVD
IEEMALKLDN VLLDTYQDAS S
//
ID SPCS_HUMAN Reviewed; 501 AA.
AC Q9HD40; A8K8W1; Q0D2P3; Q17RT1; Q9NXZ5; Q9UGM9; Q9Y353;
DT 29-MAR-2005, integrated into UniProtKB/Swiss-Prot.
read moreDT 29-MAR-2005, sequence version 2.
DT 22-JAN-2014, entry version 103.
DE RecName: Full=O-phosphoseryl-tRNA(Sec) selenium transferase;
DE EC=2.9.1.2;
DE AltName: Full=Liver-pancreas antigen;
DE Short=LP;
DE AltName: Full=SLA-p35;
DE AltName: Full=SLA/LP autoantigen;
DE AltName: Full=Selenocysteine synthase;
DE Short=Sec synthase;
DE AltName: Full=Selenocysteinyl-tRNA(Sec) synthase;
DE AltName: Full=Sep-tRNA:Sec-tRNA synthase;
DE Short=SepSecS;
DE AltName: Full=Soluble liver antigen;
DE Short=SLA;
DE AltName: Full=UGA suppressor tRNA-associated protein;
DE AltName: Full=tRNA(Ser/Sec)-associated antigenic protein;
GN Name=SEPSECS; Synonyms=TRNP48;
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).
RC TISSUE=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 [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Endometrium;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 3).
RC TISSUE=Brain, and Muscle;
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 [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 29-501 (ISOFORM 1), AND NUCLEOTIDE
RP SEQUENCE [MRNA] OF 29-501 (ISOFORM 2).
RC TISSUE=Liver, and T-cell lymphoma;
RX PubMed=10801173; DOI=10.1016/S0140-6736(00)02166-8;
RA Wies I., Brunner S., Henninger J., Herkel J., Kanzler S.,
RA Meyer zum Bueschenfelde K.-H., Lohse A.W.;
RT "Identification of target antigen for SLA/LP autoantibodies in
RT autoimmune hepatitis.";
RL Lancet 355:1510-1515(2000).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 61-501 (ISOFORM 1).
RC TISSUE=Liver;
RX PubMed=10931155; DOI=10.1046/j.1365-2249.2000.01280.x;
RA Costa M., Rodriguez-Sanchez J.L., Czaja A.J., Gelpi C.;
RT "Isolation and characterization of cDNA encoding the antigenic protein
RT of the human tRNP(Ser)Sec complex recognized by autoantibodies from
RT patients withtype-1 autoimmune hepatitis.";
RL Clin. Exp. Immunol. 121:364-374(2000).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 61-501 (ISOFORM 1).
RC TISSUE=Liver;
RA Seelig H.-P., Wiemann C., Plaikner M., Schranz P., Seelig R., Renz M.;
RT "Coding sequence of the human SLA/LP autoantigen.";
RL Submitted (JUN-2000) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 208-501.
RX PubMed=11230739; DOI=10.1053/jhep.2001.22218;
RA Volkmann M., Martin L., Baeurle A., Heid H., Strassburg C.P.,
RA Trautwein C., Fiehn W., Manns M.P.;
RT "Soluble liver antigen: isolation of a 35-kd recombinant protein (SLA-
RT p35) specifically recognizing sera from patients with autoimmune
RT hepatitis.";
RL Hepatology 33:591-596(2001).
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 434-493, AND SLA/LP EPITOPE MAPPING.
RX PubMed=11826415; DOI=10.1053/jhep.2002.30699;
RA Herkel J., Heidrich B., Nieraad N., Wies I., Rother M., Lohse A.W.;
RT "Fine specificity of autoantibodies to soluble liver antigen and
RT liver/pancreas.";
RL Hepatology 35:403-408(2002).
RN [11]
RP FUNCTION, COFACTOR, AND MUTAGENESIS OF LYS-284.
RX PubMed=17142313; DOI=10.1073/pnas.0609703104;
RA Yuan J., Palioura S., Salazar J.C., Su D., O'Donoghue P., Hohn M.J.,
RA Cardoso A.M., Whitman W.B., Soell D.;
RT "RNA-dependent conversion of phosphoserine forms selenocysteine in
RT eukaryotes and archaea.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:18923-18927(2006).
RN [12]
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 [13]
RP X-RAY CRYSTALLOGRAPHY (2.81 ANGSTROMS) IN COMPLEX WITH TRNA AND
RP PYRIDOXAL PHOSPHATE, SUBUNIT, SUBSTRATE-BINDING SITES, COFACTOR, AND
RP MUTAGENESIS OF ARG-75; ARG-97; GLN-105; LYS-173 AND ARG-313.
RX PubMed=19608919; DOI=10.1126/science.1173755;
RA Palioura S., Sherrer R.L., Steitz T.A., Soll D., Simonovic M.;
RT "The human SepSecS-tRNASec complex reveals the mechanism of
RT selenocysteine formation.";
RL Science 325:321-325(2009).
RN [14]
RP VARIANTS PCH2D THR-239 AND CYS-334, AND CHARACTERIZATION OF VARIANTS
RP PCH2D THR-239 AND CYS-334.
RX PubMed=20920667; DOI=10.1016/j.ajhg.2010.09.007;
RA Agamy O., Ben Zeev B., Lev D., Marcus B., Fine D., Su D., Narkis G.,
RA Ofir R., Hoffmann C., Leshinsky-Silver E., Flusser H., Sivan S.,
RA Soll D., Lerman-Sagie T., Birk O.S.;
RT "Mutations disrupting selenocysteine formation cause progressive
RT cerebello-cerebral atrophy.";
RL Am. J. Hum. Genet. 87:538-544(2010).
CC -!- FUNCTION: Converts O-phosphoseryl-tRNA(Sec) to selenocysteinyl-
CC tRNA(Sec) required for selenoprotein biosynthesis.
CC -!- CATALYTIC ACTIVITY: O-phospho-L-seryl-tRNA(Sec) + selenophosphate
CC = L-selenocysteinyl-tRNA(Sec) + phosphate.
CC -!- COFACTOR: Pyridoxal phosphate.
CC -!- PATHWAY: Aminoacyl-tRNA biosynthesis; selenocysteinyl-tRNA(Sec)
CC biosynthesis; selenocysteinyl-tRNA(Sec) from L-seryl-tRNA(Sec)
CC (archaeal/eukaryal route): step 2/2.
CC -!- SUBUNIT: Homotetramer formed by a catalytic dimer and a non-
CC catalytic dimer serving as a binding platform that orients tRNASec
CC for catalysis. Each tetramer binds the CCA ends of two tRNAs which
CC point to the active sites of the catalytic dimer.
CC -!- INTERACTION:
CC P04591:gag (xeno); NbExp=3; IntAct=EBI-6163446, EBI-6163428;
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q9HD40-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9HD40-2; Sequence=VSP_038078, VSP_038079;
CC Note=May be produced at very low levels due to a premature stop
CC codon in the mRNA, leading to nonsense-mediated mRNA decay. No
CC experimental confirmation available;
CC Name=3;
CC IsoId=Q9HD40-3; Sequence=VSP_038080;
CC -!- TISSUE SPECIFICITY: Primarily expressed in liver, pancreas, kidney
CC and lung. Overexpressed in PHA-stimulated T-cells.
CC -!- DISEASE: Pontocerebellar hypoplasia 2D (PCH2D) [MIM:613811]: A
CC disorder characterized by postnatal onset of progressive atrophy
CC of the cerebrum and cerebellum, microcephaly, profound mental
CC retardation, spasticity, and variable seizures. Note=The disease
CC is caused by mutations affecting the gene represented in this
CC entry.
CC -!- MISCELLANEOUS: Possible diagnostic marker for autoimmune hepatitis
CC (AIH).
CC -!- SIMILARITY: Belongs to the SepSecS family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAD33963.2; Type=Erroneous translation; Note=Wrong choice of CDS;
CC Sequence=AAH23539.1; Type=Erroneous translation; Note=Wrong choice of CDS;
CC Sequence=CAB62209.1; Type=Erroneous initiation; Note=Translation N-terminally shortened;
CC Sequence=CAB89517.1; Type=Frameshift; Positions=39;
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DR EMBL; AK292476; BAF85165.1; -; mRNA.
DR EMBL; BX648976; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AC007073; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC104662; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471069; EAW92832.1; -; Genomic_DNA.
DR EMBL; BC023539; AAH23539.1; ALT_SEQ; mRNA.
DR EMBL; BC117202; AAI17203.1; -; mRNA.
DR EMBL; AF146396; AAD33963.2; ALT_SEQ; mRNA.
DR EMBL; AJ277541; CAB89517.1; ALT_FRAME; mRNA.
DR EMBL; AJ238617; CAB62209.1; ALT_INIT; mRNA.
DR EMBL; AF282065; AAG00491.1; -; mRNA.
DR RefSeq; NP_058651.3; NM_016955.3.
DR RefSeq; XP_005248225.1; XM_005248168.1.
DR UniGene; Hs.253305; -.
DR PDB; 3HL2; X-ray; 2.81 A; A/B/C/D=1-501.
DR PDBsum; 3HL2; -.
DR ProteinModelPortal; Q9HD40; -.
DR SMR; Q9HD40; 20-464.
DR IntAct; Q9HD40; 1.
DR STRING; 9606.ENSP00000305956; -.
DR DrugBank; DB00114; Pyridoxal Phosphate.
DR PhosphoSite; Q9HD40; -.
DR DMDM; 62287911; -.
DR PaxDb; Q9HD40; -.
DR PRIDE; Q9HD40; -.
DR DNASU; 51091; -.
DR Ensembl; ENST00000302922; ENSP00000305956; ENSG00000109618.
DR Ensembl; ENST00000382103; ENSP00000371535; ENSG00000109618.
DR Ensembl; ENST00000514585; ENSP00000421880; ENSG00000109618.
DR GeneID; 51091; -.
DR KEGG; hsa:51091; -.
DR UCSC; uc003grg.3; human.
DR CTD; 51091; -.
DR GeneCards; GC04M025121; -.
DR HGNC; HGNC:30605; SEPSECS.
DR MIM; 613009; gene.
DR MIM; 613811; phenotype.
DR neXtProt; NX_Q9HD40; -.
DR Orphanet; 2524; Pontocerebellar hypoplasia type 2.
DR Orphanet; 247198; Progressive cerebello-cerebral atrophy.
DR PharmGKB; PA162402915; -.
DR eggNOG; COG0076; -.
DR HOGENOM; HOG000254245; -.
DR HOVERGEN; HBG061363; -.
DR InParanoid; Q9HD40; -.
DR KO; K03341; -.
DR OMA; NPISMAM; -.
DR OrthoDB; EOG71G9TX; -.
DR UniPathway; UPA00906; UER00898.
DR EvolutionaryTrace; Q9HD40; -.
DR GeneWiki; SEPSECS; -.
DR GenomeRNAi; 51091; -.
DR NextBio; 53771; -.
DR PRO; PR:Q9HD40; -.
DR ArrayExpress; Q9HD40; -.
DR Bgee; Q9HD40; -.
DR CleanEx; HS_SEPSECS; -.
DR Genevestigator; Q9HD40; -.
DR GO; GO:0005737; C:cytoplasm; ISS:HGNC.
DR GO; GO:0005634; C:nucleus; ISS:HGNC.
DR GO; GO:0030170; F:pyridoxal phosphate binding; IEA:InterPro.
DR GO; GO:0016785; F:transferase activity, transferring selenium-containing groups; IEA:InterPro.
DR GO; GO:0000049; F:tRNA binding; ISS:HGNC.
DR GO; GO:0001514; P:selenocysteine incorporation; ISS:HGNC.
DR GO; GO:0097056; P:selenocysteinyl-tRNA(Sec) biosynthetic process; IEA:UniProtKB-UniPathway.
DR Gene3D; 3.40.640.10; -; 1.
DR InterPro; IPR019793; Peroxidases_heam-ligand_BS.
DR InterPro; IPR015424; PyrdxlP-dep_Trfase.
DR InterPro; IPR015421; PyrdxlP-dep_Trfase_major_sub1.
DR InterPro; IPR019872; Sec-tRNA_Se_transferase.
DR InterPro; IPR008829; SLA/LP_auto_ag.
DR PANTHER; PTHR12944; PTHR12944; 1.
DR Pfam; PF05889; SLA_LP_auto_ag; 1.
DR PIRSF; PIRSF017689; SepSecS; 1.
DR SUPFAM; SSF53383; SSF53383; 1.
DR TIGRFAMs; TIGR03531; selenium_SpcS; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Complete proteome; Cytoplasm;
KW Disease mutation; Protein biosynthesis; Pyridoxal phosphate;
KW Reference proteome; RNA-binding; Selenium; Transferase; tRNA-binding.
FT CHAIN 1 501 O-phosphoseryl-tRNA(Sec) selenium
FT transferase.
FT /FTId=PRO_0000219875.
FT REGION 1 44 Tetramerization.
FT REGION 96 106 Phosphate loop (P-loop).
FT REGION 474 493 SLA/LP epitope.
FT BINDING 75 75 PLP (By similarity).
FT BINDING 97 97 Substrate.
FT BINDING 98 98 Substrate.
FT BINDING 105 105 Substrate.
FT BINDING 271 271 tRNA variable arm.
FT BINDING 313 313 Substrate.
FT BINDING 398 398 tRNA discriminator base.
FT BINDING 463 463 tRNA acceptor arm.
FT SITE 74 74 May act as a substrate filter by
FT repelling compounds with a negatively
FT charged alpha-carboxylate.
FT MOD_RES 284 284 N6-(pyridoxal phosphate)lysine.
FT VAR_SEQ 1 38 MNRESFAAGERLVSPAYVRQGCEARRSHEHLIRLLLEK ->
FT MQCDDLGSLQPPPPGFTPFACLSLPSSWDYRRPPPHP (in
FT isoform 3).
FT /FTId=VSP_038080.
FT VAR_SEQ 39 47 GKCPENGWD -> VHSWHWTIR (in isoform 2).
FT /FTId=VSP_038078.
FT VAR_SEQ 48 501 Missing (in isoform 2).
FT /FTId=VSP_038079.
FT VARIANT 239 239 A -> T (in PCH2D; abrogates enzyme
FT activity).
FT /FTId=VAR_065585.
FT VARIANT 334 334 Y -> C (in PCH2D; abrogates enzyme
FT activity).
FT /FTId=VAR_065586.
FT MUTAGEN 75 75 R->A: Inactive in vivo.
FT MUTAGEN 97 97 R->A: Indistinguishable from wild-type.
FT MUTAGEN 97 97 R->Q: Indistinguishable from wild-type.
FT MUTAGEN 105 105 Q->A: Inactive in vivo.
FT MUTAGEN 173 173 K->A: Indistinguishable from wild-type.
FT MUTAGEN 173 173 K->M: Indistinguishable from wild-type.
FT MUTAGEN 284 284 K->A: Loss of activity.
FT MUTAGEN 313 313 R->A: Inactive in vivo.
FT CONFLICT 98 98 S -> P (in Ref. 8; AAG00491).
FT CONFLICT 264 264 H -> R (in Ref. 1; BAF85165).
FT CONFLICT 398 398 R -> K (in Ref. 6; AAD33963/CAB89517).
FT CONFLICT 452 452 K -> N (in Ref. 6; AAD33963/CAB89517).
FT CONFLICT 467 467 K -> R (in Ref. 8; AAG00491).
FT HELIX 26 38
FT HELIX 48 59
FT HELIX 63 65
FT HELIX 82 87
FT TURN 88 90
FT HELIX 109 128
FT STRAND 136 142
FT HELIX 144 158
FT STRAND 164 168
FT HELIX 173 181
FT STRAND 185 189
FT STRAND 191 194
FT STRAND 197 200
FT HELIX 202 212
FT HELIX 214 216
FT STRAND 217 223
FT HELIX 235 245
FT STRAND 249 252
FT HELIX 260 272
FT STRAND 277 281
FT HELIX 282 286
FT STRAND 293 298
FT HELIX 300 308
FT HELIX 317 357
FT TURN 358 360
FT STRAND 370 376
FT TURN 382 384
FT HELIX 387 397
FT STRAND 404 406
FT STRAND 412 414
FT STRAND 417 421
FT TURN 422 425
FT STRAND 433 437
FT HELIX 444 462
SQ SEQUENCE 501 AA; 55726 MW; 7136FB390B18760B CRC64;
MNRESFAAGE RLVSPAYVRQ GCEARRSHEH LIRLLLEKGK CPENGWDEST LELFLHELAI
MDSNNFLGNC GVGEREGRVA SALVARRHYR FIHGIGRSGD ISAVQPKAAG SSLLNKITNS
LVLDIIKLAG VHTVANCFVV PMATGMSLTL CFLTLRHKRP KAKYIIWPRI DQKSCFKSMI
TAGFEPVVIE NVLEGDELRT DLKAVEAKVQ ELGPDCILCI HSTTSCFAPR VPDRLEELAV
ICANYDIPHI VNNAYGVQSS KCMHLIQQGA RVGRIDAFVQ SLDKNFMVPV GGAIIAGFND
SFIQEISKMY PGRASASPSL DVLITLLSLG SNGYKKLLKE RKEMFSYLSN QIKKLSEAYN
ERLLHTPHNP ISLAMTLKTL DEHRDKAVTQ LGSMLFTRQV SGARVVPLGS MQTVSGYTFR
GFMSHTNNYP CAYLNAASAI GMKMQDVDLF IKRLDRCLKA VRKERSKESD DNYDKTEDVD
IEEMALKLDN VLLDTYQDAS S
//
MIM
613009
*RECORD*
*FIELD* NO
613009
*FIELD* TI
*613009 O-PHOSPHOSERINE tRNA-SELENOCYSTEINE tRNA SYNTHASE; SEPSECS
;;SOLUBLE LIVER ANTIGEN; SLA;;
read moreLIVER PANCREAS ANTIGEN; LP
*FIELD* TX
DESCRIPTION
The 21st amino acid, selenocysteine (sec), is distinct from other amino
acids because it lacks its own tRNA synthetase and is the only amino
acid synthesized on its cognate tRNA. Synthesis of sec begins with
acylation of tRNA(sec) (TRSP; 165060) by seryl-tRNA synthetase (SARS;
607529) to give ser-tRNA(sec), which is subsequently phosphorylated by
O-phosphoseryl-tRNA kinase (PSTK; 611310) to give
O-phosphoseryl-tRNA(sec). SEPSECS catalyzes the final step of sec
synthesis by converting O-phosphoseryl-tRNA(sec) to
selenocysteinyl-tRNA(sec) using selenophosphate as the selenium donor
(Palioura et al., 2009).
CLONING
Using sera from patients with autoimmune chronic active hepatitis, Gelpi
et al. (1992) identified an antigenic ribonucleoprotein containing
SEPSECS. Western blot analysis of HeLa cell extracts detected SEPSECS at
an apparent molecular mass of 48 kD.
Autoantibodies to soluble liver antigen (SLA) and to liver and pancreas
antigen (LP) occur in about 30% of all patients with autoimmune
hepatitis. Using ELISA, Wies et al. (2000) confirmed that the SLA and LP
autoantibodies are identical. By screening Jurkat and human liver cDNA
expression libraries with SLA/LP autoantibodies, Wies et al. (2000)
cloned SEPSECS, which they designated SLA/LP. The deduced 422-amino acid
protein has a possible peroxidase proximal heme-ligand signature near
its N terminus and a number of possible phosphorylation sites, but it
lacks typical transmembrane features. Wies et al. (2000) also cloned a
splice variant of SEPSECS that includes a 156-bp insertion within the
coding region that leads to an altered N terminus in the protein.
Western blot analysis detected a major protein of about 50 kD in human
liver cytosol and in lung, kidney, and pancreas. Expression was weak in
normal human lymphocytes, but it was elevated in activated lymphocytes.
MAPPING
By genomic sequence analysis, Wies et al. (2000) mapped the SEPSECS gene
to chromosome 4. Hartz (2009) mapped the SEPSECS gene to chromosome
4p15.2 based on an alignment of the SEPSECS sequence (GenBank GENBANK
AJ238617) with the genomic sequence (GRCh37).
GENE FUNCTION
Using mutation analysis, Wies et al. (2000) found that amino acids 371
to 409 of SLA/LP were critical for immune recognition by SLA/LP
autoantibodies.
Using mutation analysis, Palioura et al. (2009) showed that arg75,
gln105, and arg313 were required for conversion of
O-phosphoseryl-tRNA(sec) to sec-tRNA(sec) by SEPSECS. The reaction also
required pyridoxal phosphate as cofactor.
BIOCHEMICAL FEATURES
Palioura et al. (2009) noted that SEPSECS forms a stable tetramer and
acts on phosphoserine that is linked to tRNA(sec), but not on free
phosphoserine or ser-tRNA(sec). They determined the crystal structure of
the quaternary complex between human SEPSECS, unacylated tRNA(sec), and
a mixture of O-phosphoserine and thiophosphate to 2.8-angstrom
resolution. SEPSECS formed a tetramer that was bound to 2 tRNA(sec)
molecules. SEPSECS tetramers were made up of 2 SEPSECS homodimers that
interacted via their N-terminal alpha(1)-loop-alpha(2) motifs. The CCA
ends of both tRNA(sec) molecules pointed to the active sites of the same
homodimer, which the authors called the catalytic dimer. The
noncatalytic homodimer served as a binding platform to orient tRNA(sec)
for catalysis.
MOLECULAR GENETICS
In 2 unrelated patients of Jewish Iraqi ancestry with progressive
cerebellocerebral atrophy, profound mental retardation, and spasticity,
most consistent with pontocerebellar hypoplasia type 2 (PCH2D; 613811),
previously reported by Ben-Zeev et al. (2003), Agamy et al. (2010)
identified homozygous or compound heterozygous mutations in the SEPSECS
gene (613009.0001 and 613009.0002). Both mutations were demonstrated to
abolish enzyme activity, resulting in the disruption of the sole route
to selenocysteine biosynthesis and the generation of essential
selenoenzymes. The findings indicated that selenium and selenoproteins
are critical to brain development and function.
*FIELD* AV
.0001
PONTOCEREBELLAR HYPOPLASIA, TYPE 2D
SEPSECS, TYR334CYS
In 2 unrelated patients of Jewish Iraqi ancestry with progressive
cerebellocerebral atrophy and a clinical phenotype most consistent with
pontocerebellar hypoplasia type 2 (PCH2D; 613811), previously reported
by Ben-Zeev et al. (2003), Agamy et al. (2010) identified a homozygous
1001A-G transition in exon 8 of the SEPSECS gene, resulting in a
tyr334-to-cys (Y334C) substitution in a conserved residue.
Heterozygosity for the Y334C mutation was found in 3 of 127 Jewish Iraqi
individuals. Two additional unrelated patients of mixed Iraqi and
Moroccan ancestry with PCH2D were found to be compound heterozygous for
the Y334C mutation and a 715G-A transition in exon 6, resulting in an
ala239-to-thr (A239T; 613009.0002) substitution. The Y334C allele was
inherited from the unaffected Iraqi parent in both cases, suggesting a
founder effect. Heterozygosity for the A239T mutation was found in 6 of
261 unrelated Jewish Moroccan individuals. Anaerobic assays in
transformed E. coli showed that both mutations abrogated SEPSECS
activity. The A239T mutation was predicted to introduce steric clashes
that disrupt interactions between 2 helices in the core of the enzyme,
and the Y334C mutation was predicted to disturb the architecture of the
active site and the position of pyridoxal phosphate. Thus, both
mutations disrupted the sole route to selenocysteine biosynthesis and
the generation of essential selenoenzymes.
.0002
PONTOCEREBELLAR HYPOPLASIA, TYPE 2D
SEPSECS, ALA239THR
See 613009.0001 and Agamy et al. (2010).
*FIELD* RF
1. Agamy, O.; Ben Zeev, B.; Lev, D.; Marcus, B.; Fine, D.; Su, D.;
Narkis, G.; Ofir, R.; Hoffmann, C.; Leshinsky-Silver, E.; Flusser,
H.; Sivan, S.; Soll, D.; Lerman-Sagie, T.; Birk, O. S.: Mutations
disrupting selenocysteine formation cause progressive cerebello-cerebral
atrophy. Am. J. Hum. Genet. 87: 538-544, 2010.
2. Ben-Zeev, B.; Hoffman, C.; Lev, D.; Watemberg, N.; Malinger, G.;
Brand, N.; Lerman-Sagie, T.: Progressive cerebellocerebral atrophy:
a new syndrome with microcephaly, mental retardation, and spastic
quadriplegia. J. Med. Genet. 40: e96, 2003. Note: Electronic Article.
3. Gelpi, C.; Sontheimer, E. J.; Rodriguez-Sanchez, J. L.: Autoantibodies
against a serine tRNA-protein complex implicated in cotranslational
selenocysteine insertion. Proc. Nat. Acad. Sci. 89: 9739-9743, 1992.
4. Hartz, P. A.: Personal Communication. Baltimore, Md. 9/9/2009.
5. Palioura, S.; Sherrer, R. L.; Steitz, T. A.; Soll, D.; Simonovic,
M.: The human SepSecS-tRNA(Sec) complex reveals the mechanism of
selenocysteine formation. Science 325: 321-325, 2009.
6. Wies, I.; Brunner, S.; Henninger, J.; Herkel, J.; Kanzler, S.;
Buschenfelde, K.-H. M.; Lohse, A. W.: Identification of target antigen
for SLA/LP autoantibodies in autoimmune hepatitis. Lancet 355: 1510-1515,
2000.
*FIELD* CN
Cassandra L. Kniffin - updated: 11/12/2010
*FIELD* CD
Patricia A. Hartz: 9/10/2009
*FIELD* ED
terry: 04/22/2011
wwang: 3/25/2011
ckniffin: 3/15/2011
wwang: 3/10/2011
carol: 12/23/2010
ckniffin: 11/12/2010
mgross: 9/10/2009
*RECORD*
*FIELD* NO
613009
*FIELD* TI
*613009 O-PHOSPHOSERINE tRNA-SELENOCYSTEINE tRNA SYNTHASE; SEPSECS
;;SOLUBLE LIVER ANTIGEN; SLA;;
read moreLIVER PANCREAS ANTIGEN; LP
*FIELD* TX
DESCRIPTION
The 21st amino acid, selenocysteine (sec), is distinct from other amino
acids because it lacks its own tRNA synthetase and is the only amino
acid synthesized on its cognate tRNA. Synthesis of sec begins with
acylation of tRNA(sec) (TRSP; 165060) by seryl-tRNA synthetase (SARS;
607529) to give ser-tRNA(sec), which is subsequently phosphorylated by
O-phosphoseryl-tRNA kinase (PSTK; 611310) to give
O-phosphoseryl-tRNA(sec). SEPSECS catalyzes the final step of sec
synthesis by converting O-phosphoseryl-tRNA(sec) to
selenocysteinyl-tRNA(sec) using selenophosphate as the selenium donor
(Palioura et al., 2009).
CLONING
Using sera from patients with autoimmune chronic active hepatitis, Gelpi
et al. (1992) identified an antigenic ribonucleoprotein containing
SEPSECS. Western blot analysis of HeLa cell extracts detected SEPSECS at
an apparent molecular mass of 48 kD.
Autoantibodies to soluble liver antigen (SLA) and to liver and pancreas
antigen (LP) occur in about 30% of all patients with autoimmune
hepatitis. Using ELISA, Wies et al. (2000) confirmed that the SLA and LP
autoantibodies are identical. By screening Jurkat and human liver cDNA
expression libraries with SLA/LP autoantibodies, Wies et al. (2000)
cloned SEPSECS, which they designated SLA/LP. The deduced 422-amino acid
protein has a possible peroxidase proximal heme-ligand signature near
its N terminus and a number of possible phosphorylation sites, but it
lacks typical transmembrane features. Wies et al. (2000) also cloned a
splice variant of SEPSECS that includes a 156-bp insertion within the
coding region that leads to an altered N terminus in the protein.
Western blot analysis detected a major protein of about 50 kD in human
liver cytosol and in lung, kidney, and pancreas. Expression was weak in
normal human lymphocytes, but it was elevated in activated lymphocytes.
MAPPING
By genomic sequence analysis, Wies et al. (2000) mapped the SEPSECS gene
to chromosome 4. Hartz (2009) mapped the SEPSECS gene to chromosome
4p15.2 based on an alignment of the SEPSECS sequence (GenBank GENBANK
AJ238617) with the genomic sequence (GRCh37).
GENE FUNCTION
Using mutation analysis, Wies et al. (2000) found that amino acids 371
to 409 of SLA/LP were critical for immune recognition by SLA/LP
autoantibodies.
Using mutation analysis, Palioura et al. (2009) showed that arg75,
gln105, and arg313 were required for conversion of
O-phosphoseryl-tRNA(sec) to sec-tRNA(sec) by SEPSECS. The reaction also
required pyridoxal phosphate as cofactor.
BIOCHEMICAL FEATURES
Palioura et al. (2009) noted that SEPSECS forms a stable tetramer and
acts on phosphoserine that is linked to tRNA(sec), but not on free
phosphoserine or ser-tRNA(sec). They determined the crystal structure of
the quaternary complex between human SEPSECS, unacylated tRNA(sec), and
a mixture of O-phosphoserine and thiophosphate to 2.8-angstrom
resolution. SEPSECS formed a tetramer that was bound to 2 tRNA(sec)
molecules. SEPSECS tetramers were made up of 2 SEPSECS homodimers that
interacted via their N-terminal alpha(1)-loop-alpha(2) motifs. The CCA
ends of both tRNA(sec) molecules pointed to the active sites of the same
homodimer, which the authors called the catalytic dimer. The
noncatalytic homodimer served as a binding platform to orient tRNA(sec)
for catalysis.
MOLECULAR GENETICS
In 2 unrelated patients of Jewish Iraqi ancestry with progressive
cerebellocerebral atrophy, profound mental retardation, and spasticity,
most consistent with pontocerebellar hypoplasia type 2 (PCH2D; 613811),
previously reported by Ben-Zeev et al. (2003), Agamy et al. (2010)
identified homozygous or compound heterozygous mutations in the SEPSECS
gene (613009.0001 and 613009.0002). Both mutations were demonstrated to
abolish enzyme activity, resulting in the disruption of the sole route
to selenocysteine biosynthesis and the generation of essential
selenoenzymes. The findings indicated that selenium and selenoproteins
are critical to brain development and function.
*FIELD* AV
.0001
PONTOCEREBELLAR HYPOPLASIA, TYPE 2D
SEPSECS, TYR334CYS
In 2 unrelated patients of Jewish Iraqi ancestry with progressive
cerebellocerebral atrophy and a clinical phenotype most consistent with
pontocerebellar hypoplasia type 2 (PCH2D; 613811), previously reported
by Ben-Zeev et al. (2003), Agamy et al. (2010) identified a homozygous
1001A-G transition in exon 8 of the SEPSECS gene, resulting in a
tyr334-to-cys (Y334C) substitution in a conserved residue.
Heterozygosity for the Y334C mutation was found in 3 of 127 Jewish Iraqi
individuals. Two additional unrelated patients of mixed Iraqi and
Moroccan ancestry with PCH2D were found to be compound heterozygous for
the Y334C mutation and a 715G-A transition in exon 6, resulting in an
ala239-to-thr (A239T; 613009.0002) substitution. The Y334C allele was
inherited from the unaffected Iraqi parent in both cases, suggesting a
founder effect. Heterozygosity for the A239T mutation was found in 6 of
261 unrelated Jewish Moroccan individuals. Anaerobic assays in
transformed E. coli showed that both mutations abrogated SEPSECS
activity. The A239T mutation was predicted to introduce steric clashes
that disrupt interactions between 2 helices in the core of the enzyme,
and the Y334C mutation was predicted to disturb the architecture of the
active site and the position of pyridoxal phosphate. Thus, both
mutations disrupted the sole route to selenocysteine biosynthesis and
the generation of essential selenoenzymes.
.0002
PONTOCEREBELLAR HYPOPLASIA, TYPE 2D
SEPSECS, ALA239THR
See 613009.0001 and Agamy et al. (2010).
*FIELD* RF
1. Agamy, O.; Ben Zeev, B.; Lev, D.; Marcus, B.; Fine, D.; Su, D.;
Narkis, G.; Ofir, R.; Hoffmann, C.; Leshinsky-Silver, E.; Flusser,
H.; Sivan, S.; Soll, D.; Lerman-Sagie, T.; Birk, O. S.: Mutations
disrupting selenocysteine formation cause progressive cerebello-cerebral
atrophy. Am. J. Hum. Genet. 87: 538-544, 2010.
2. Ben-Zeev, B.; Hoffman, C.; Lev, D.; Watemberg, N.; Malinger, G.;
Brand, N.; Lerman-Sagie, T.: Progressive cerebellocerebral atrophy:
a new syndrome with microcephaly, mental retardation, and spastic
quadriplegia. J. Med. Genet. 40: e96, 2003. Note: Electronic Article.
3. Gelpi, C.; Sontheimer, E. J.; Rodriguez-Sanchez, J. L.: Autoantibodies
against a serine tRNA-protein complex implicated in cotranslational
selenocysteine insertion. Proc. Nat. Acad. Sci. 89: 9739-9743, 1992.
4. Hartz, P. A.: Personal Communication. Baltimore, Md. 9/9/2009.
5. Palioura, S.; Sherrer, R. L.; Steitz, T. A.; Soll, D.; Simonovic,
M.: The human SepSecS-tRNA(Sec) complex reveals the mechanism of
selenocysteine formation. Science 325: 321-325, 2009.
6. Wies, I.; Brunner, S.; Henninger, J.; Herkel, J.; Kanzler, S.;
Buschenfelde, K.-H. M.; Lohse, A. W.: Identification of target antigen
for SLA/LP autoantibodies in autoimmune hepatitis. Lancet 355: 1510-1515,
2000.
*FIELD* CN
Cassandra L. Kniffin - updated: 11/12/2010
*FIELD* CD
Patricia A. Hartz: 9/10/2009
*FIELD* ED
terry: 04/22/2011
wwang: 3/25/2011
ckniffin: 3/15/2011
wwang: 3/10/2011
carol: 12/23/2010
ckniffin: 11/12/2010
mgross: 9/10/2009
MIM
613811
*RECORD*
*FIELD* NO
613811
*FIELD* TI
#613811 PONTOCEREBELLAR HYPOPLASIA, TYPE 2D; PCH2D
;;CEREBELLOCEREBRAL ATROPHY, PROGRESSIVE; PCCA;;
read moreCEREBELLO-CEREBRAL ATROPHY, PROGRESSIVE
*FIELD* TX
A number sign (#) is used with this entry because pontocerebellar
hypoplasia type 2D (PCH2D), also known as progressive cerebellocerebral
atrophy (PCCA), is caused by homozygous or compound heterozygous
mutation in the SEPSECS gene (613009) on chromosome 4p14.
DESCRIPTION
PCH2D is an autosomal recessive disorder characterized by progressive
microcephaly, postnatal onset of progressive atrophy of the cerebrum and
cerebellum, profound mental retardation, spasticity, and variable
seizures (summary by Ben-Zeev et al., 2003).
For a general phenotypic description and a discussion of genetic
heterogeneity of pontocerebellar hypoplasia type 2, see PCH2A (277470).
CLINICAL FEATURES
Ben-Zeev et al. (2003) reported 4 unrelated patients with profound
mental retardation, postnatal progressive microcephaly, spasticity, and
progressive cerebellocerebral atrophy (PCCA). All patients were from
nonconsanguineous Sephardic Jewish families: 2 were of Iraqi origin, and
2 were of combined Iraqi and Moroccan origin. All had normal head
circumference at birth, but progressive microcephaly became apparent
during the first year of life. All showed severe developmental delay,
with 2 patients achieving smiling only. Progressive spasticity resulting
in painful contractures and clonus developed during the first year of
life. Two patients showed mild and intermittent choreiform movements,
but none had dyskinesias. Two patients had seizures, including
generalized tonic-clonic and myoclonic. Other features included sleep
disorders and severe irritability. Brain imaging showed atrophy of both
the cerebrum and cerebellum, with progression in an anterior to
posterior direction, and atrophy of the vermis before atrophy of the
cerebellar hemispheres. There was a gradual decrease in white matter
volume with thinning of the corpus callosum, and 3 patients showed
delayed myelination. None had dysmorphic features, and metabolic studies
were all normal. Ben-Zeev et al. (2003) noted that there was some
phenotypic overlap with pontocerebellar hypoplasia type 2 (see 277470)
but considered the phenotype in the Sephardic Jewish families to be
distinct, mainly due to the lack of ataxia and dystonia, lack of pontine
involvement, and subtle differences in neuroimaging findings.
MOLECULAR GENETICS
By genomewide linkage analysis followed by candidate gene sequencing,
Agamy et al. (2010) identified homozygous or compound heterozygous
mutations in the SEPSECS gene (613009.0001 and 613009.0002) on
chromosome 4p15 in 4 unrelated patients of Iraqi or Iraqi/Moroccan
descent with progressive cerebellocerebral atrophy previously reported
by Ben-Zeev et al. (2003). Both mutations were demonstrated to abolish
enzyme activity, resulting in the disruption of the sole route to
selenocysteine biosynthesis and the generation of essential
selenoenzymes. The findings indicated that selenium and selenoproteins
are critical to brain development and function. Agamy et al. (2010)
noted the phenotypic similarity to other forms of PCH2 (see, e.g.,
PCH2A; 277400), which are also caused by mutation in genes involved in
tRNA processing. SEPSECS mutations were not found in 3 additional
patients from 2 families of purely Moroccan origin, also previously
reported by Ben-Zeev et al. (2003), suggesting genetic heterogeneity.
*FIELD* RF
1. Agamy, O.; Ben Zeev, B.; Lev, D.; Marcus, B.; Fine, D.; Su, D.;
Narkis, G.; Ofir, R.; Hoffmann, C.; Leshinsky-Silver, E.; Flusser,
H.; Sivan, S.; Soll, D.; Lerman-Sagie, T.; Birk, O. S.: Mutations
disrupting selenocysteine formation cause progressive cerebello-cerebral
atrophy. Am. J. Hum. Genet. 87: 538-544, 2010.
2. Ben-Zeev, B.; Hoffman, C.; Lev, D.; Watemberg, N.; Malinger, G.;
Brand, N.; Lerman-Sagie, T.: Progressive cerebellocerebral atrophy:
a new syndrome with microcephaly, mental retardation, and spastic
quadriplegia. J. Med. Genet. 40: e96, 2003. Note: Electronic Article.
*FIELD* CS
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Head];
Microcephaly, postnatal, progressive
SKELETAL:
[Limbs];
Contractures
NEUROLOGIC:
[Central nervous system];
Mental retardation (profound);
Lack of psychomotor development;
Spastic quadriplegia, progressive;
Clonus;
Seizures;
Chorea, mild (in some);
Sleep disturbances;
Cerebellar atrophy, progressive (cerebellar vermal atrophy before
cerebral atrophy);
Cerebral atrophy, progressive, from anterior to posterior;
Delayed myelination;
Decreased white matter volume;
Thin corpus callosum;
Periventricular white matter abnormalities;
[Behavioral/psychiatric manifestations];
Irritability
MISCELLANEOUS:
Onset in infancy;
Reported in individuals of Sephardic Jewish ancestry
MOLECULAR BASIS:
Caused by mutation in the O-phosphoserine tRNA-selenocysteine tRNA
synthase gene (SEPSECS, 613009.0001)
*FIELD* CD
Cassandra L. Kniffin: 3/15/2011
*FIELD* ED
joanna: 04/11/2011
ckniffin: 3/15/2011
*FIELD* CD
Cassandra L. Kniffin: 3/15/2011
*FIELD* ED
wwang: 05/11/2011
terry: 4/22/2011
wwang: 3/25/2011
ckniffin: 3/15/2011
*RECORD*
*FIELD* NO
613811
*FIELD* TI
#613811 PONTOCEREBELLAR HYPOPLASIA, TYPE 2D; PCH2D
;;CEREBELLOCEREBRAL ATROPHY, PROGRESSIVE; PCCA;;
read moreCEREBELLO-CEREBRAL ATROPHY, PROGRESSIVE
*FIELD* TX
A number sign (#) is used with this entry because pontocerebellar
hypoplasia type 2D (PCH2D), also known as progressive cerebellocerebral
atrophy (PCCA), is caused by homozygous or compound heterozygous
mutation in the SEPSECS gene (613009) on chromosome 4p14.
DESCRIPTION
PCH2D is an autosomal recessive disorder characterized by progressive
microcephaly, postnatal onset of progressive atrophy of the cerebrum and
cerebellum, profound mental retardation, spasticity, and variable
seizures (summary by Ben-Zeev et al., 2003).
For a general phenotypic description and a discussion of genetic
heterogeneity of pontocerebellar hypoplasia type 2, see PCH2A (277470).
CLINICAL FEATURES
Ben-Zeev et al. (2003) reported 4 unrelated patients with profound
mental retardation, postnatal progressive microcephaly, spasticity, and
progressive cerebellocerebral atrophy (PCCA). All patients were from
nonconsanguineous Sephardic Jewish families: 2 were of Iraqi origin, and
2 were of combined Iraqi and Moroccan origin. All had normal head
circumference at birth, but progressive microcephaly became apparent
during the first year of life. All showed severe developmental delay,
with 2 patients achieving smiling only. Progressive spasticity resulting
in painful contractures and clonus developed during the first year of
life. Two patients showed mild and intermittent choreiform movements,
but none had dyskinesias. Two patients had seizures, including
generalized tonic-clonic and myoclonic. Other features included sleep
disorders and severe irritability. Brain imaging showed atrophy of both
the cerebrum and cerebellum, with progression in an anterior to
posterior direction, and atrophy of the vermis before atrophy of the
cerebellar hemispheres. There was a gradual decrease in white matter
volume with thinning of the corpus callosum, and 3 patients showed
delayed myelination. None had dysmorphic features, and metabolic studies
were all normal. Ben-Zeev et al. (2003) noted that there was some
phenotypic overlap with pontocerebellar hypoplasia type 2 (see 277470)
but considered the phenotype in the Sephardic Jewish families to be
distinct, mainly due to the lack of ataxia and dystonia, lack of pontine
involvement, and subtle differences in neuroimaging findings.
MOLECULAR GENETICS
By genomewide linkage analysis followed by candidate gene sequencing,
Agamy et al. (2010) identified homozygous or compound heterozygous
mutations in the SEPSECS gene (613009.0001 and 613009.0002) on
chromosome 4p15 in 4 unrelated patients of Iraqi or Iraqi/Moroccan
descent with progressive cerebellocerebral atrophy previously reported
by Ben-Zeev et al. (2003). Both mutations were demonstrated to abolish
enzyme activity, resulting in the disruption of the sole route to
selenocysteine biosynthesis and the generation of essential
selenoenzymes. The findings indicated that selenium and selenoproteins
are critical to brain development and function. Agamy et al. (2010)
noted the phenotypic similarity to other forms of PCH2 (see, e.g.,
PCH2A; 277400), which are also caused by mutation in genes involved in
tRNA processing. SEPSECS mutations were not found in 3 additional
patients from 2 families of purely Moroccan origin, also previously
reported by Ben-Zeev et al. (2003), suggesting genetic heterogeneity.
*FIELD* RF
1. Agamy, O.; Ben Zeev, B.; Lev, D.; Marcus, B.; Fine, D.; Su, D.;
Narkis, G.; Ofir, R.; Hoffmann, C.; Leshinsky-Silver, E.; Flusser,
H.; Sivan, S.; Soll, D.; Lerman-Sagie, T.; Birk, O. S.: Mutations
disrupting selenocysteine formation cause progressive cerebello-cerebral
atrophy. Am. J. Hum. Genet. 87: 538-544, 2010.
2. Ben-Zeev, B.; Hoffman, C.; Lev, D.; Watemberg, N.; Malinger, G.;
Brand, N.; Lerman-Sagie, T.: Progressive cerebellocerebral atrophy:
a new syndrome with microcephaly, mental retardation, and spastic
quadriplegia. J. Med. Genet. 40: e96, 2003. Note: Electronic Article.
*FIELD* CS
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Head];
Microcephaly, postnatal, progressive
SKELETAL:
[Limbs];
Contractures
NEUROLOGIC:
[Central nervous system];
Mental retardation (profound);
Lack of psychomotor development;
Spastic quadriplegia, progressive;
Clonus;
Seizures;
Chorea, mild (in some);
Sleep disturbances;
Cerebellar atrophy, progressive (cerebellar vermal atrophy before
cerebral atrophy);
Cerebral atrophy, progressive, from anterior to posterior;
Delayed myelination;
Decreased white matter volume;
Thin corpus callosum;
Periventricular white matter abnormalities;
[Behavioral/psychiatric manifestations];
Irritability
MISCELLANEOUS:
Onset in infancy;
Reported in individuals of Sephardic Jewish ancestry
MOLECULAR BASIS:
Caused by mutation in the O-phosphoserine tRNA-selenocysteine tRNA
synthase gene (SEPSECS, 613009.0001)
*FIELD* CD
Cassandra L. Kniffin: 3/15/2011
*FIELD* ED
joanna: 04/11/2011
ckniffin: 3/15/2011
*FIELD* CD
Cassandra L. Kniffin: 3/15/2011
*FIELD* ED
wwang: 05/11/2011
terry: 4/22/2011
wwang: 3/25/2011
ckniffin: 3/15/2011