Full text data of CISD2
CISD2
(CDGSH2, ERIS, ZCD2)
[Confidence: high (present in two of the MS resources)]
CDGSH iron-sulfur domain-containing protein 2 (Endoplasmic reticulum intermembrane small protein; MitoNEET-related 1 protein; Miner1; Nutrient-deprivation autophagy factor-1; NAF-1)
CDGSH iron-sulfur domain-containing protein 2 (Endoplasmic reticulum intermembrane small protein; MitoNEET-related 1 protein; Miner1; Nutrient-deprivation autophagy factor-1; NAF-1)
hRBCD
IPI00166865
IPI00166865 Similar to RIKEN cDNA 1500009M05 gene Similar to RIKEN cDNA 1500009M05 gene membrane n/a n/a 1 n/a 1 n/a n/a n/a 3 n/a n/a 1 2 n/a n/a n/a n/a n/a n/a n/a not mentioned n/a found at its expected molecular weight found at molecular weight
IPI00166865 Similar to RIKEN cDNA 1500009M05 gene Similar to RIKEN cDNA 1500009M05 gene membrane n/a n/a 1 n/a 1 n/a n/a n/a 3 n/a n/a 1 2 n/a n/a n/a n/a n/a n/a n/a not mentioned n/a found at its expected molecular weight found at molecular weight
UniProt
Q8N5K1
ID CISD2_HUMAN Reviewed; 135 AA.
AC Q8N5K1; Q7Z3D5;
DT 15-JAN-2008, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-2002, sequence version 1.
DT 22-JAN-2014, entry version 86.
DE RecName: Full=CDGSH iron-sulfur domain-containing protein 2;
DE AltName: Full=Endoplasmic reticulum intermembrane small protein;
DE AltName: Full=MitoNEET-related 1 protein;
DE Short=Miner1;
DE AltName: Full=Nutrient-deprivation autophagy factor-1;
DE Short=NAF-1;
GN Name=CISD2; Synonyms=CDGSH2, ERIS, ZCD2;
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 [MRNA], FUNCTION, SUBCELLULAR LOCATION, TISSUE
RP SPECIFICITY, AND INVOLVEMENT IN WFS2.
RX PubMed=17846994; DOI=10.1086/520961;
RA Amr S., Heisey C., Zhang M., Xia X.J., Shows K.H., Ajlouni K.,
RA Pandya A., Satin L.S., El-Shanti H., Shiang R.;
RT "A homozygous mutation in a novel zinc-finger protein, ERIS, is
RT responsible for Wolfram syndrome 2.";
RL Am. J. Hum. Genet. 81:673-683(2007).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Synovium;
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].
RC TISSUE=Retina;
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 [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].
RC TISSUE=Cervix;
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 PROTEIN SEQUENCE OF 21-32; 82-95 AND 117-131, AND MASS SPECTROMETRY.
RC TISSUE=B-cell lymphoma;
RA Bienvenut W.V.;
RL Submitted (JUN-2005) to UniProtKB.
RN [7]
RP COFACTOR, AND SUBCELLULAR LOCATION.
RX PubMed=17376863; DOI=10.1073/pnas.0701078104;
RA Wiley S.E., Murphy A.N., Ross S.A., van der Geer P., Dixon J.E.;
RT "MitoNEET is an iron-containing outer mitochondrial membrane protein
RT that regulates oxidative capacity.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:5318-5323(2007).
RN [8]
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH BCL2; BCL2L1 AND
RP ITPR1, AND MUTAGENESIS OF CYS-99; CYS-101; CYS-110 AND HIS-114.
RX PubMed=20010695; DOI=10.1038/emboj.2009.369;
RA Chang N.C., Nguyen M., Germain M., Shore G.C.;
RT "Antagonism of Beclin 1-dependent autophagy by BCL-2 at the
RT endoplasmic reticulum requires NAF-1.";
RL EMBO J. 29:606-618(2010).
RN [9]
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 [10]
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 [11]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 57-135 OF MUTANT CYS-92 IN
RP COMPLEX WITH 2FE-2S, BIOPHYSICOCHEMICAL PROPERTIES, AND MUTAGENESIS OF
RP CYS-92.
RX PubMed=19580816; DOI=10.1016/j.jmb.2009.06.079;
RA Conlan A.R., Axelrod H.L., Cohen A.E., Abresch E.C., Zuris J., Yee D.,
RA Nechushtai R., Jennings P.A., Paddock M.L.;
RT "Crystal structure of Miner1: The redox-active 2Fe-2S protein
RT causative in Wolfram Syndrome 2.";
RL J. Mol. Biol. 392:143-153(2009).
CC -!- FUNCTION: Regulator of autophagy that contributes to antagonize
CC BECN1-mediated cellular autophagy at the endoplasmic reticulum.
CC Participates in the interaction of BCL2 with BECN1 and is required
CC for BCL2-mediated depression of endoplasmic reticulum Ca(2+)
CC stores during autophagy. Contributes to BIK-initiated autophagy,
CC while it is not involved in BIK-dependent activation of caspases.
CC Involved in life span control, probably via its function as
CC regulator of autophagy.
CC -!- COFACTOR: Binds 1 2Fe-2S cluster.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Redox potential:
CC E is 0 +/- 10 mV for 2Fe-2S at pH 7.5;
CC -!- SUBUNIT: Homodimer. Interacts with BCL2; the interaction is direct
CC and disrupted by BIK interaction with BCL2. Interacts with BCL2L1.
CC Interacts with ITPR1.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Single-pass
CC membrane protein. Mitochondrion outer membrane; Single-pass
CC membrane protein. Note=According to PubMed:20010695, it mainly
CC localizes to the endoplasmic reticulum. However, experiments in
CC mouse showed that it mainly localizes to the mitochondrion outer
CC membrane.
CC -!- TISSUE SPECIFICITY: Testis, small intestine, kidney, lung, brain,
CC heart, pancreas and platelets.
CC -!- DISEASE: Wolfram syndrome 2 (WFS2) [MIM:604928]: A rare disorder
CC characterized by juvenile-onset insulin-dependent diabetes
CC mellitus with optic atrophy. Other manifestations include diabetes
CC insipidus, sensorineural deafness, dementia, psychiatric
CC illnesses. WFS2 patients additionally show a strong bleeding
CC tendency and gastrointestinal ulceration. Diabetes insipidus may
CC be absent. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- SIMILARITY: Belongs to the CISD protein family. CISD2 subfamily.
CC -!- CAUTION: Although initially thought (PubMed:17846994) to be a
CC zinc-finger protein, it was later shown (PubMed:17376863) that it
CC binds 1 2Fe-2S cluster instead.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAD97935.1; Type=Erroneous initiation;
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DR EMBL; AK292134; BAF84823.1; -; mRNA.
DR EMBL; BX537971; CAD97935.1; ALT_INIT; mRNA.
DR EMBL; CH471057; EAX06148.1; -; Genomic_DNA.
DR EMBL; BC032300; AAH32300.1; -; mRNA.
DR RefSeq; NP_001008389.1; NM_001008388.4.
DR UniGene; Hs.444955; -.
DR UniGene; Hs.745013; -.
DR PDB; 3FNV; X-ray; 2.10 A; A/B=57-135.
DR PDBsum; 3FNV; -.
DR ProteinModelPortal; Q8N5K1; -.
DR SMR; Q8N5K1; 68-135.
DR MINT; MINT-4722106; -.
DR STRING; 9606.ENSP00000273986; -.
DR PhosphoSite; Q8N5K1; -.
DR DMDM; 74729013; -.
DR PaxDb; Q8N5K1; -.
DR PeptideAtlas; Q8N5K1; -.
DR PRIDE; Q8N5K1; -.
DR DNASU; 493856; -.
DR Ensembl; ENST00000273986; ENSP00000273986; ENSG00000145354.
DR GeneID; 493856; -.
DR KEGG; hsa:493856; -.
DR UCSC; uc003hwt.4; human.
DR CTD; 493856; -.
DR GeneCards; GC04P103790; -.
DR HGNC; HGNC:24212; CISD2.
DR HPA; HPA015914; -.
DR MIM; 604928; phenotype.
DR MIM; 611507; gene.
DR neXtProt; NX_Q8N5K1; -.
DR Orphanet; 3463; Wolfram syndrome.
DR PharmGKB; PA162382300; -.
DR eggNOG; NOG236423; -.
DR HOGENOM; HOG000242301; -.
DR HOVERGEN; HBG052444; -.
DR InParanoid; Q8N5K1; -.
DR OMA; PVCDKSH; -.
DR OrthoDB; EOG7GQXZ6; -.
DR PhylomeDB; Q8N5K1; -.
DR ChiTaRS; CISD2; human.
DR EvolutionaryTrace; Q8N5K1; -.
DR GenomeRNAi; 493856; -.
DR NextBio; 111774; -.
DR PRO; PR:Q8N5K1; -.
DR ArrayExpress; Q8N5K1; -.
DR Bgee; Q8N5K1; -.
DR CleanEx; HS_CISD2; -.
DR Genevestigator; Q8N5K1; -.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0005741; C:mitochondrial outer membrane; ISS:UniProtKB.
DR GO; GO:0043234; C:protein complex; IDA:LIFEdb.
DR GO; GO:0051537; F:2 iron, 2 sulfur cluster binding; IDA:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0000422; P:mitochondrion degradation; IEA:Ensembl.
DR GO; GO:0010259; P:multicellular organismal aging; ISS:UniProtKB.
DR GO; GO:0010506; P:regulation of autophagy; IMP:UniProtKB.
DR InterPro; IPR018967; FeS-contain_CDGSH-typ.
DR InterPro; IPR006622; FeS-contain_CDGSH-typ_subfam.
DR InterPro; IPR019610; FeS-contain_mitoNEET_N.
DR Pfam; PF10660; MitoNEET_N; 1.
DR Pfam; PF09360; zf-CDGSH; 1.
DR SMART; SM00704; ZnF_CDGSH; 1.
PE 1: Evidence at protein level;
KW 2Fe-2S; 3D-structure; Autophagy; Complete proteome; Deafness;
KW Diabetes mellitus; Direct protein sequencing; Endoplasmic reticulum;
KW Iron; Iron-sulfur; Membrane; Metal-binding; Mitochondrion;
KW Mitochondrion outer membrane; Reference proteome; Transmembrane;
KW Transmembrane helix.
FT CHAIN 1 135 CDGSH iron-sulfur domain-containing
FT protein 2.
FT /FTId=PRO_0000316005.
FT TOPO_DOM 1 37 Lumenal (Potential).
FT TRANSMEM 38 60 Helical; (Potential).
FT TOPO_DOM 61 135 Cytoplasmic (Potential).
FT METAL 99 99 Iron-sulfur (2Fe-2S).
FT METAL 101 101 Iron-sulfur (2Fe-2S).
FT METAL 110 110 Iron-sulfur (2Fe-2S).
FT METAL 114 114 Iron-sulfur (2Fe-2S); via pros nitrogen.
FT MUTAGEN 92 92 C->S: Has the same optical signature of
FT the native protein and improves yields of
FT purified protein and a decreased tendency
FT to aggregate.
FT MUTAGEN 99 99 C->S: Impairs interaction with BCL2; when
FT associated with S-101; S-110 and Q-114.
FT MUTAGEN 101 101 C->S: Impairs interaction with BCL2; when
FT associated with S-99; S-110 and Q-114.
FT MUTAGEN 110 110 C->S: Impairs interaction with BCL2; when
FT associated with S-99; S-101 and Q-114.
FT MUTAGEN 114 114 H->Q: Impairs interaction with BCL2; when
FT associated with S-99; S-101 and S-110.
FT STRAND 73 75
FT STRAND 79 87
FT HELIX 88 90
FT STRAND 93 98
FT STRAND 100 102
FT TURN 105 108
FT HELIX 113 121
FT STRAND 125 131
SQ SEQUENCE 135 AA; 15278 MW; 44AD1817D6C536D6 CRC64;
MVLESVARIV KVQLPAYLKR LPVPESITGF ARLTVSEWLR LLPFLGVLAL LGYLAVRPFL
PKKKQQKDSL INLKIQKENP KVVNEINIED LCLTKAAYCR CWRSKTFPAC DGSHNKHNEL
TGDNVGPLIL KKKEV
//
ID CISD2_HUMAN Reviewed; 135 AA.
AC Q8N5K1; Q7Z3D5;
DT 15-JAN-2008, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-2002, sequence version 1.
DT 22-JAN-2014, entry version 86.
DE RecName: Full=CDGSH iron-sulfur domain-containing protein 2;
DE AltName: Full=Endoplasmic reticulum intermembrane small protein;
DE AltName: Full=MitoNEET-related 1 protein;
DE Short=Miner1;
DE AltName: Full=Nutrient-deprivation autophagy factor-1;
DE Short=NAF-1;
GN Name=CISD2; Synonyms=CDGSH2, ERIS, ZCD2;
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 [MRNA], FUNCTION, SUBCELLULAR LOCATION, TISSUE
RP SPECIFICITY, AND INVOLVEMENT IN WFS2.
RX PubMed=17846994; DOI=10.1086/520961;
RA Amr S., Heisey C., Zhang M., Xia X.J., Shows K.H., Ajlouni K.,
RA Pandya A., Satin L.S., El-Shanti H., Shiang R.;
RT "A homozygous mutation in a novel zinc-finger protein, ERIS, is
RT responsible for Wolfram syndrome 2.";
RL Am. J. Hum. Genet. 81:673-683(2007).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Synovium;
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].
RC TISSUE=Retina;
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 [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].
RC TISSUE=Cervix;
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 PROTEIN SEQUENCE OF 21-32; 82-95 AND 117-131, AND MASS SPECTROMETRY.
RC TISSUE=B-cell lymphoma;
RA Bienvenut W.V.;
RL Submitted (JUN-2005) to UniProtKB.
RN [7]
RP COFACTOR, AND SUBCELLULAR LOCATION.
RX PubMed=17376863; DOI=10.1073/pnas.0701078104;
RA Wiley S.E., Murphy A.N., Ross S.A., van der Geer P., Dixon J.E.;
RT "MitoNEET is an iron-containing outer mitochondrial membrane protein
RT that regulates oxidative capacity.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:5318-5323(2007).
RN [8]
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH BCL2; BCL2L1 AND
RP ITPR1, AND MUTAGENESIS OF CYS-99; CYS-101; CYS-110 AND HIS-114.
RX PubMed=20010695; DOI=10.1038/emboj.2009.369;
RA Chang N.C., Nguyen M., Germain M., Shore G.C.;
RT "Antagonism of Beclin 1-dependent autophagy by BCL-2 at the
RT endoplasmic reticulum requires NAF-1.";
RL EMBO J. 29:606-618(2010).
RN [9]
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 [10]
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 [11]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 57-135 OF MUTANT CYS-92 IN
RP COMPLEX WITH 2FE-2S, BIOPHYSICOCHEMICAL PROPERTIES, AND MUTAGENESIS OF
RP CYS-92.
RX PubMed=19580816; DOI=10.1016/j.jmb.2009.06.079;
RA Conlan A.R., Axelrod H.L., Cohen A.E., Abresch E.C., Zuris J., Yee D.,
RA Nechushtai R., Jennings P.A., Paddock M.L.;
RT "Crystal structure of Miner1: The redox-active 2Fe-2S protein
RT causative in Wolfram Syndrome 2.";
RL J. Mol. Biol. 392:143-153(2009).
CC -!- FUNCTION: Regulator of autophagy that contributes to antagonize
CC BECN1-mediated cellular autophagy at the endoplasmic reticulum.
CC Participates in the interaction of BCL2 with BECN1 and is required
CC for BCL2-mediated depression of endoplasmic reticulum Ca(2+)
CC stores during autophagy. Contributes to BIK-initiated autophagy,
CC while it is not involved in BIK-dependent activation of caspases.
CC Involved in life span control, probably via its function as
CC regulator of autophagy.
CC -!- COFACTOR: Binds 1 2Fe-2S cluster.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Redox potential:
CC E is 0 +/- 10 mV for 2Fe-2S at pH 7.5;
CC -!- SUBUNIT: Homodimer. Interacts with BCL2; the interaction is direct
CC and disrupted by BIK interaction with BCL2. Interacts with BCL2L1.
CC Interacts with ITPR1.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Single-pass
CC membrane protein. Mitochondrion outer membrane; Single-pass
CC membrane protein. Note=According to PubMed:20010695, it mainly
CC localizes to the endoplasmic reticulum. However, experiments in
CC mouse showed that it mainly localizes to the mitochondrion outer
CC membrane.
CC -!- TISSUE SPECIFICITY: Testis, small intestine, kidney, lung, brain,
CC heart, pancreas and platelets.
CC -!- DISEASE: Wolfram syndrome 2 (WFS2) [MIM:604928]: A rare disorder
CC characterized by juvenile-onset insulin-dependent diabetes
CC mellitus with optic atrophy. Other manifestations include diabetes
CC insipidus, sensorineural deafness, dementia, psychiatric
CC illnesses. WFS2 patients additionally show a strong bleeding
CC tendency and gastrointestinal ulceration. Diabetes insipidus may
CC be absent. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- SIMILARITY: Belongs to the CISD protein family. CISD2 subfamily.
CC -!- CAUTION: Although initially thought (PubMed:17846994) to be a
CC zinc-finger protein, it was later shown (PubMed:17376863) that it
CC binds 1 2Fe-2S cluster instead.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAD97935.1; Type=Erroneous initiation;
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
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DR EMBL; AK292134; BAF84823.1; -; mRNA.
DR EMBL; BX537971; CAD97935.1; ALT_INIT; mRNA.
DR EMBL; CH471057; EAX06148.1; -; Genomic_DNA.
DR EMBL; BC032300; AAH32300.1; -; mRNA.
DR RefSeq; NP_001008389.1; NM_001008388.4.
DR UniGene; Hs.444955; -.
DR UniGene; Hs.745013; -.
DR PDB; 3FNV; X-ray; 2.10 A; A/B=57-135.
DR PDBsum; 3FNV; -.
DR ProteinModelPortal; Q8N5K1; -.
DR SMR; Q8N5K1; 68-135.
DR MINT; MINT-4722106; -.
DR STRING; 9606.ENSP00000273986; -.
DR PhosphoSite; Q8N5K1; -.
DR DMDM; 74729013; -.
DR PaxDb; Q8N5K1; -.
DR PeptideAtlas; Q8N5K1; -.
DR PRIDE; Q8N5K1; -.
DR DNASU; 493856; -.
DR Ensembl; ENST00000273986; ENSP00000273986; ENSG00000145354.
DR GeneID; 493856; -.
DR KEGG; hsa:493856; -.
DR UCSC; uc003hwt.4; human.
DR CTD; 493856; -.
DR GeneCards; GC04P103790; -.
DR HGNC; HGNC:24212; CISD2.
DR HPA; HPA015914; -.
DR MIM; 604928; phenotype.
DR MIM; 611507; gene.
DR neXtProt; NX_Q8N5K1; -.
DR Orphanet; 3463; Wolfram syndrome.
DR PharmGKB; PA162382300; -.
DR eggNOG; NOG236423; -.
DR HOGENOM; HOG000242301; -.
DR HOVERGEN; HBG052444; -.
DR InParanoid; Q8N5K1; -.
DR OMA; PVCDKSH; -.
DR OrthoDB; EOG7GQXZ6; -.
DR PhylomeDB; Q8N5K1; -.
DR ChiTaRS; CISD2; human.
DR EvolutionaryTrace; Q8N5K1; -.
DR GenomeRNAi; 493856; -.
DR NextBio; 111774; -.
DR PRO; PR:Q8N5K1; -.
DR ArrayExpress; Q8N5K1; -.
DR Bgee; Q8N5K1; -.
DR CleanEx; HS_CISD2; -.
DR Genevestigator; Q8N5K1; -.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0005741; C:mitochondrial outer membrane; ISS:UniProtKB.
DR GO; GO:0043234; C:protein complex; IDA:LIFEdb.
DR GO; GO:0051537; F:2 iron, 2 sulfur cluster binding; IDA:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0000422; P:mitochondrion degradation; IEA:Ensembl.
DR GO; GO:0010259; P:multicellular organismal aging; ISS:UniProtKB.
DR GO; GO:0010506; P:regulation of autophagy; IMP:UniProtKB.
DR InterPro; IPR018967; FeS-contain_CDGSH-typ.
DR InterPro; IPR006622; FeS-contain_CDGSH-typ_subfam.
DR InterPro; IPR019610; FeS-contain_mitoNEET_N.
DR Pfam; PF10660; MitoNEET_N; 1.
DR Pfam; PF09360; zf-CDGSH; 1.
DR SMART; SM00704; ZnF_CDGSH; 1.
PE 1: Evidence at protein level;
KW 2Fe-2S; 3D-structure; Autophagy; Complete proteome; Deafness;
KW Diabetes mellitus; Direct protein sequencing; Endoplasmic reticulum;
KW Iron; Iron-sulfur; Membrane; Metal-binding; Mitochondrion;
KW Mitochondrion outer membrane; Reference proteome; Transmembrane;
KW Transmembrane helix.
FT CHAIN 1 135 CDGSH iron-sulfur domain-containing
FT protein 2.
FT /FTId=PRO_0000316005.
FT TOPO_DOM 1 37 Lumenal (Potential).
FT TRANSMEM 38 60 Helical; (Potential).
FT TOPO_DOM 61 135 Cytoplasmic (Potential).
FT METAL 99 99 Iron-sulfur (2Fe-2S).
FT METAL 101 101 Iron-sulfur (2Fe-2S).
FT METAL 110 110 Iron-sulfur (2Fe-2S).
FT METAL 114 114 Iron-sulfur (2Fe-2S); via pros nitrogen.
FT MUTAGEN 92 92 C->S: Has the same optical signature of
FT the native protein and improves yields of
FT purified protein and a decreased tendency
FT to aggregate.
FT MUTAGEN 99 99 C->S: Impairs interaction with BCL2; when
FT associated with S-101; S-110 and Q-114.
FT MUTAGEN 101 101 C->S: Impairs interaction with BCL2; when
FT associated with S-99; S-110 and Q-114.
FT MUTAGEN 110 110 C->S: Impairs interaction with BCL2; when
FT associated with S-99; S-101 and Q-114.
FT MUTAGEN 114 114 H->Q: Impairs interaction with BCL2; when
FT associated with S-99; S-101 and S-110.
FT STRAND 73 75
FT STRAND 79 87
FT HELIX 88 90
FT STRAND 93 98
FT STRAND 100 102
FT TURN 105 108
FT HELIX 113 121
FT STRAND 125 131
SQ SEQUENCE 135 AA; 15278 MW; 44AD1817D6C536D6 CRC64;
MVLESVARIV KVQLPAYLKR LPVPESITGF ARLTVSEWLR LLPFLGVLAL LGYLAVRPFL
PKKKQQKDSL INLKIQKENP KVVNEINIED LCLTKAAYCR CWRSKTFPAC DGSHNKHNEL
TGDNVGPLIL KKKEV
//
MIM
604928
*RECORD*
*FIELD* NO
604928
*FIELD* TI
#604928 WOLFRAM SYNDROME 2; WFS2
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read moreWolfram syndrome-2 is caused by mutation in the CISD2 gene (611507),
which encodes an endoplasmic reticulum intermembrane small protein.
CLINICAL FEATURES
Although Wolfram syndrome (222300) is also referred to as DIDMOAD (for
diabetes insipidus, diabetes mellitus, optic atrophy, and deafness),
only insulin-dependent diabetes mellitus and optic atrophy are
considered necessary to make the diagnosis. One form of Wolfram syndrome
is caused by mutation in the WFS1 gene (606201) on chromosome 4p16.1. To
pursue the possibility of locus heterogeneity, El-Shanti et al. (2000)
studied 4 consanguineous families containing 16 patients with WFS. These
patients had features in addition to those previously described in
Wolfram syndrome. There was absence of diabetes insipidus in all
affected family members. Several patients had profound upper
gastrointestinal ulceration and bleeding.
MAPPING
With the use of 3 microsatellite markers reported to be linked to the
4p16.1 locus, El-Shanti et al. (2000) excluded linkage in 3 of the 4
families. Two affected individuals in 1 family showed homozygosity for
all 3 markers from the region of linkage on 4p16.1. For the other 3
families, genetic heterogeneity for Wolfram syndrome was verified with
demonstration of linkage to 4q22-q24.
MOLECULAR GENETICS
Amr et al. (2007) identified a single missense mutation in the CISD2
gene (611507), in 3 consanguineous families of Jordanian descent with
Wolfram syndrome studied by El-Shanti et al. (2000). A G-to-C
transversion at nucleotide 109 predicted an amino acid change from
glutamic acid to glutamine (E37Q; 611507.0001). The mutation disrupted
the mRNA splicing by eliminating exon 2, and resulted in the
introduction of a premature stop codon. Like wolframin, the
CISD2-encoded protein, ERIS (endoplasmic reticulum intermembrane small
protein), also localizes to the endoplasmic reticulum.
ANIMAL MODEL
Chen et al. (2009) provided evidence that the Cisd2 gene is involved in
mammalian life span control. In mice, Cisd2 was primarily localized to
the mitochondria and associated with the outer mitochondrial membrane.
Cisd2-null mice showed early senescence and shortened life span compared
to wildtype mice. Features included prominent eyes, protruding ears,
corneal opacities and degeneration, thinner bones and hair, and
decreased muscle mass, which are all consistent with premature aging.
Tissue from mutant mice showed progressive mitochondrial breakdown and
dysfunction accompanied by autophagic cell death, which preceded nerve
and muscle degeneration. Mitochondria isolated from the mutant mice
showed a defect in respiration. Together, the phenotype was suggestive
of premature aging with some features of Wolfram syndrome. The findings
suggested that Wolfram syndrome-2 is in part a mitochondria-mediated
disorder. Chen et al. (2009) also noted that the human CISD2 gene maps
to chromosome 4q22-q24, close to a region implicated in human longevity
(152430).
*FIELD* RF
1. Amr, S.; Heisey, C.; Zhang, M.; Xia, X.-J.; Shows, K. H.; Ajlouni,
K.; Pandya, A.; Satin, L. S.; El-Shanti, H.; Shiang, R.: A homozygous
mutation in a novel zinc-finger protein, ERIS, is responsible for
Wolfram syndrome 2. Am. J. Hum. Genet. 81: 673-683, 2007.
2. Chen, Y.-F.; Kao, C.-H.; Chen, Y.-T.; Wang, C.-H.; Wu, C.-Y.; Tsai,
C.-Y.; Liu, F.-C.; Yang, C.-W.; Wei, Y.-H.; Hsu, M.-T.; Tsai, S.-F.;
Tsai, T.-F.: Cisd2 deficiency drives premature aging and causes mitochondria-mediated
defects in mice. Genes Dev. 23: 1183-1194, 2009.
3. El-Shanti, H.; Lidral, A. C.; Jarrah, N.; Druhan, L.; Ajlouni,
K.: Homozygosity mapping identifies an additional locus for Wolfram
syndrome on chromosome 4q. Am. J. Hum. Genet. 66: 1229-1236, 2000.
Note: Erratum: Am. J. Hum. Genet. 66: 1728 only, 2000.
*FIELD* CN
Cassandra L. Kniffin - updated: 7/30/2009
Dorothy S. Reilly - updated: 4/3/2008
Victor A. McKusick - updated: 10/3/2007
*FIELD* CD
Victor A. McKusick: 5/8/2000
*FIELD* ED
wwang: 09/01/2009
wwang: 8/5/2009
ckniffin: 7/30/2009
wwang: 4/3/2008
alopez: 10/5/2007
terry: 10/3/2007
carol: 10/29/2004
terry: 3/24/2004
carol: 3/5/2004
mcapotos: 12/21/2001
carol: 8/17/2001
carol: 8/21/2000
carol: 5/8/2000
*RECORD*
*FIELD* NO
604928
*FIELD* TI
#604928 WOLFRAM SYNDROME 2; WFS2
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read moreWolfram syndrome-2 is caused by mutation in the CISD2 gene (611507),
which encodes an endoplasmic reticulum intermembrane small protein.
CLINICAL FEATURES
Although Wolfram syndrome (222300) is also referred to as DIDMOAD (for
diabetes insipidus, diabetes mellitus, optic atrophy, and deafness),
only insulin-dependent diabetes mellitus and optic atrophy are
considered necessary to make the diagnosis. One form of Wolfram syndrome
is caused by mutation in the WFS1 gene (606201) on chromosome 4p16.1. To
pursue the possibility of locus heterogeneity, El-Shanti et al. (2000)
studied 4 consanguineous families containing 16 patients with WFS. These
patients had features in addition to those previously described in
Wolfram syndrome. There was absence of diabetes insipidus in all
affected family members. Several patients had profound upper
gastrointestinal ulceration and bleeding.
MAPPING
With the use of 3 microsatellite markers reported to be linked to the
4p16.1 locus, El-Shanti et al. (2000) excluded linkage in 3 of the 4
families. Two affected individuals in 1 family showed homozygosity for
all 3 markers from the region of linkage on 4p16.1. For the other 3
families, genetic heterogeneity for Wolfram syndrome was verified with
demonstration of linkage to 4q22-q24.
MOLECULAR GENETICS
Amr et al. (2007) identified a single missense mutation in the CISD2
gene (611507), in 3 consanguineous families of Jordanian descent with
Wolfram syndrome studied by El-Shanti et al. (2000). A G-to-C
transversion at nucleotide 109 predicted an amino acid change from
glutamic acid to glutamine (E37Q; 611507.0001). The mutation disrupted
the mRNA splicing by eliminating exon 2, and resulted in the
introduction of a premature stop codon. Like wolframin, the
CISD2-encoded protein, ERIS (endoplasmic reticulum intermembrane small
protein), also localizes to the endoplasmic reticulum.
ANIMAL MODEL
Chen et al. (2009) provided evidence that the Cisd2 gene is involved in
mammalian life span control. In mice, Cisd2 was primarily localized to
the mitochondria and associated with the outer mitochondrial membrane.
Cisd2-null mice showed early senescence and shortened life span compared
to wildtype mice. Features included prominent eyes, protruding ears,
corneal opacities and degeneration, thinner bones and hair, and
decreased muscle mass, which are all consistent with premature aging.
Tissue from mutant mice showed progressive mitochondrial breakdown and
dysfunction accompanied by autophagic cell death, which preceded nerve
and muscle degeneration. Mitochondria isolated from the mutant mice
showed a defect in respiration. Together, the phenotype was suggestive
of premature aging with some features of Wolfram syndrome. The findings
suggested that Wolfram syndrome-2 is in part a mitochondria-mediated
disorder. Chen et al. (2009) also noted that the human CISD2 gene maps
to chromosome 4q22-q24, close to a region implicated in human longevity
(152430).
*FIELD* RF
1. Amr, S.; Heisey, C.; Zhang, M.; Xia, X.-J.; Shows, K. H.; Ajlouni,
K.; Pandya, A.; Satin, L. S.; El-Shanti, H.; Shiang, R.: A homozygous
mutation in a novel zinc-finger protein, ERIS, is responsible for
Wolfram syndrome 2. Am. J. Hum. Genet. 81: 673-683, 2007.
2. Chen, Y.-F.; Kao, C.-H.; Chen, Y.-T.; Wang, C.-H.; Wu, C.-Y.; Tsai,
C.-Y.; Liu, F.-C.; Yang, C.-W.; Wei, Y.-H.; Hsu, M.-T.; Tsai, S.-F.;
Tsai, T.-F.: Cisd2 deficiency drives premature aging and causes mitochondria-mediated
defects in mice. Genes Dev. 23: 1183-1194, 2009.
3. El-Shanti, H.; Lidral, A. C.; Jarrah, N.; Druhan, L.; Ajlouni,
K.: Homozygosity mapping identifies an additional locus for Wolfram
syndrome on chromosome 4q. Am. J. Hum. Genet. 66: 1229-1236, 2000.
Note: Erratum: Am. J. Hum. Genet. 66: 1728 only, 2000.
*FIELD* CN
Cassandra L. Kniffin - updated: 7/30/2009
Dorothy S. Reilly - updated: 4/3/2008
Victor A. McKusick - updated: 10/3/2007
*FIELD* CD
Victor A. McKusick: 5/8/2000
*FIELD* ED
wwang: 09/01/2009
wwang: 8/5/2009
ckniffin: 7/30/2009
wwang: 4/3/2008
alopez: 10/5/2007
terry: 10/3/2007
carol: 10/29/2004
terry: 3/24/2004
carol: 3/5/2004
mcapotos: 12/21/2001
carol: 8/17/2001
carol: 8/21/2000
carol: 5/8/2000
MIM
611507
*RECORD*
*FIELD* NO
611507
*FIELD* TI
*611507 CDGSH IRON SULFUR DOMAIN PROTEIN 2; CISD2
;;MITONEET-RELATED 1; MINER1;;
ZINC FINGER PROTEIN ZCD2; ZCD2;;
read moreENDOPLASMIC RETICULUM INTERMEMBRANE SMALL PROTEIN; ERIS;;
NUTRIENT DEPRIVATION AUTOPHAGY FACTOR 1; NAF1
*FIELD* TX
CLONING
By database analysis using CISD1 (611932) as query, Wiley et al. (2007)
identified CISD2 and CISD3 (611933), which they called MINER1 and
MINER2, respectively. The deduced 135-amino acid CISD2 protein contains
a C-terminal CDGSH domain, which contains a consensus sequence that is
shared by CISD1, CISD2, and CISD3. Immunofluorescence studies localized
CISD2 to the endoplasmic reticulum with staining distributed in a
perinuclear pattern and in a lacy network pattern through the cell.
In a search for the mutation responsible for Wolfram syndrome-2 (WFS2;
604928), which maps to chromosome 4q22-q25, Amr et al. (2007) identified
CISD2, which they called ZCD2. The deduced protein has a calculated
molecular mass of 15.3 kD and contains a predicted transmembrane domain
and a C-terminal CDGSH domain. The protein is highly conserved and has
70% identity and 82% similarity across all vertebrate species studied.
RT-PCR of RNA from a variety of human tissues detected expression in the
majority, including brain and pancreas. No expression was detected in
cartilage, skeletal muscle, or fetal liver.
GENE STRUCTURE
Amr et al. (2007) determined that the CISD2 gene contains 3 exons.
MAPPING
Amr et al. (2007) identified the CISD2 gene within the critical region
for WFS2 on chromosome 4q22-q24, between markers D4S591 and D4S3240.
GENE FUNCTION
By expression of FLAG-tagged CISD2 in mammalian cells, Amr et al. (2007)
showed that CISD2 is localized to the endoplasmic reticulum,
colocalizing with calnexin (114217). Coimmunoprecipitation studies
showed that CISD2 and wolframin (606201) do not interact.
Wiley et al. (2007) noted that purified recombinant CISD2 was red in
color and noted that although the CDGSH domain was initially classified
as a zinc finger domain, its actually contains iron. Wiley et al. (2007)
showed that the CDGSH domain of CISD1 harbors a redox-sensitive 2Fe-2S
cluster and suggested that the CDGSH domain of CISD2 likewise binds
2Fe-2S and has similar biophysical properties. Based on similarity to
CISD1, they suggested that the CISD2 is a member of an iron-containing
family of proteins with CDGSH domains.
MOLECULAR GENETICS
Wolfram syndrome (WFS; 222300) is an autosomal recessive disorder with
severe neurodegeneration whose phenotype includes juvenile-onset
insulin-dependent diabetes mellitus and optic atrophy, sensorineural
deafness, dementia, psychiatric illnesses, renal tract abnormalities,
and bladder atony. One gene for the disorder, WFS1 (606201) on 4p16.3,
encodes a transmembrane protein located in the endoplasmic reticulum and
may play a role in calcium homeostasis. In a search for the mutation
responsible for a form of Wolfram syndrome mapping to 4q22-24 (WFS2;
604928), Amr et al. (2007) screened genes within the candidate region
for mutations and identified a missense mutation in the CISD2 gene
(611507.0001). Although the amino acid was conserved and the mutation
nonsynonymous, the pathogenesis for the disorder was shown to be
aberrant splicing. The mutation disrupted RNA splicing by eliminating
exon 2, and resulted in the introduction of a premature stop codon.
Because dominant mutations associated with low-frequency nonsyndromic
hearing loss, progressive hearing loss, and isolated optic atrophy with
hearing loss had been found in the WFS1 gene, Amr et al. (2007) screened
377 probands with hearing loss for mutation in the WFS2 gene. No
mutations in WFS2 were identified.
Wolframin, the protein encoded by WFS1, localizes to the endoplasmic
reticulum and plays a role in calcium homeostasis. Amr et al. (2007)
showed that the CISD2-encoded protein, ERIS (endoplasmic reticulum
intermembrane small protein) also localizes to the endoplasmic reticulum
but does not interact directly with wolframin. Lymphoblastoid cells from
individuals with WFS2 showed a significantly greater rise in
intracellular calcium when stimulated with thapsigargin compared with
controls, although no difference was observed in resting concentrations
of intracellular calcium.
ANIMAL MODEL
Chen et al. (2009) provided evidence that the Cisd2 gene is involved in
mammalian life span control. In mice, Cisd2 was primarily localized in
the mitochondria and associated with the outer mitochondrial membrane.
Cisd2-null mice showed early senescence and shortened life span compared
to wildtype mice. Features included prominent eyes, protruding ears,
corneal opacities and degeneration, thinner bones and hair, and
decreased muscle mass, which are all consistent with premature aging.
Tissues from mutant mice showed progressive mitochondrial breakdown and
dysfunction accompanied by autophagic cell death, which preceded nerve
and muscle degeneration. Mitochondria isolated from the mutant mice
showed a defect in respiration. Together, the phenotype was suggestive
of premature aging with some features of Wolfram syndrome. The findings
also suggested that Wolfram syndrome-2 is in part a
mitochondria-mediated disorder. Chen et al. (2009) also noted that the
human CISD2 gene maps to chromosome 4q22-q24, close to a region
implicated in human longevity (152430).
Chang et al. (2012) found that Naf1 -/- mice appeared normal at birth,
but by 2 to 3 months, they developed low body weight, ruffled fur,
tremors, lethargy, and general weakness. At 3 months of age, Naf1 -/-
skeletal muscle showed reduced force-generating capacity and a switch to
slow-twitch muscle phenotype. Impaired muscle function was accompanied
by enhanced autophagy, especially in diaphragm. Enlarged mitochondria
were also observed and likely represented an adaptive response to
enhanced autophagy. In culture, primary Naf1 -/- diaphragm myoblasts
showed elevated basal Ca(2+) content.
*FIELD* AV
.0001
WOLFRAM SYNDROME 2
CISD2, GLU37GLN
Amr et al. (2007) identified a mutation in the CISD2 gene in 3
consanguineous families of Jordanian descent with Wolfram syndrome-2
(604928). A G-to-C transversion in nucleotide 109 in exon 2 predicted an
amino acid change from glutamic acid to glutamine (glu37 to gln, E37Q).
Although the amino acid is conserved and the mutation is nonsynonymous,
the pathogenesis for the disorder was aberrant splicing. The mutation
disrupted mRNA splicing by eliminating exon 2, and resulted in the
introduction of a premature stop codon.
*FIELD* RF
1. Amr, S.; Heisey, C.; Zhang, M.; Xia, X.-J.; Shows, K. H.; Ajlouni,
K.; Pandya, A.; Satin, L. S.; El-Shanti, H.; Shiang, R.: A homozygous
mutation in a novel zinc-finger protein, ERIS, is responsible for
Wolfram syndrome 2. Am. J. Hum. Genet. 81: 673-683, 2007.
2. Chang, N. C.; Nguyen, M.; Bourdon, J.; Risse, P.-A.; Martin, J.;
Danialou, G.; Rizzuto, R.; Petrof, B. J.; Shore, G. C.: Bcl-2-associated
autophagy regulator Naf-1 required for maintenance of skeletal muscle. Hum.
Molec. Genet. 21: 2277-2287, 2012.
3. Chen, Y.-F.; Kao, C.-H.; Chen, Y.-T.; Wang, C.-H.; Wu, C.-Y.; Tsai,
C.-Y.; Liu, F.-C.; Yang, C.-W.; Wei, Y.-H.; Hsu, M.-T.; Tsai, S.-F.;
Tsai, T.-F.: Cisd2 deficiency drives premature aging and causes mitochondria-mediated
defects in mice. Genes Dev. 23: 1183-1194, 2009.
4. Wiley, S. E.; Murphy, A. N.; Ross, S. A.; van der Geer, P.; Dixon,
J. E.: MitoNEET is an iron-containing outer mitochondrial membrane
protein that regulates oxidative capacity. Proc. Nat. Acad. Sci. 104:
5318-5323, 2007.
5. Wiley, S. E.; Paddock, M. L.; Abresch, E. C.; Gross, L.; van der
Geer, P.; Nechushtai, R.; Murphy, A. N.; Jennings, P. A.; Dixon, J.
E.: The outer mitochondrial membrane protein mitoNEET contains a
novel redox-active 2Fe-2S cluster. J. Biol. Chem. 282: 23745-23749,
2007.
*FIELD* CN
Patricia A. Hartz - updated: 07/09/2013
Cassandra L. Kniffin - updated: 7/30/2009
Dorothy S. Reilly - updated: 4/3/2008
*FIELD* CD
Victor A. McKusick: 10/5/2007
*FIELD* ED
mgross: 07/09/2013
mgross: 7/9/2013
wwang: 9/1/2009
wwang: 8/5/2009
ckniffin: 7/30/2009
wwang: 4/3/2008
alopez: 10/5/2007
*RECORD*
*FIELD* NO
611507
*FIELD* TI
*611507 CDGSH IRON SULFUR DOMAIN PROTEIN 2; CISD2
;;MITONEET-RELATED 1; MINER1;;
ZINC FINGER PROTEIN ZCD2; ZCD2;;
read moreENDOPLASMIC RETICULUM INTERMEMBRANE SMALL PROTEIN; ERIS;;
NUTRIENT DEPRIVATION AUTOPHAGY FACTOR 1; NAF1
*FIELD* TX
CLONING
By database analysis using CISD1 (611932) as query, Wiley et al. (2007)
identified CISD2 and CISD3 (611933), which they called MINER1 and
MINER2, respectively. The deduced 135-amino acid CISD2 protein contains
a C-terminal CDGSH domain, which contains a consensus sequence that is
shared by CISD1, CISD2, and CISD3. Immunofluorescence studies localized
CISD2 to the endoplasmic reticulum with staining distributed in a
perinuclear pattern and in a lacy network pattern through the cell.
In a search for the mutation responsible for Wolfram syndrome-2 (WFS2;
604928), which maps to chromosome 4q22-q25, Amr et al. (2007) identified
CISD2, which they called ZCD2. The deduced protein has a calculated
molecular mass of 15.3 kD and contains a predicted transmembrane domain
and a C-terminal CDGSH domain. The protein is highly conserved and has
70% identity and 82% similarity across all vertebrate species studied.
RT-PCR of RNA from a variety of human tissues detected expression in the
majority, including brain and pancreas. No expression was detected in
cartilage, skeletal muscle, or fetal liver.
GENE STRUCTURE
Amr et al. (2007) determined that the CISD2 gene contains 3 exons.
MAPPING
Amr et al. (2007) identified the CISD2 gene within the critical region
for WFS2 on chromosome 4q22-q24, between markers D4S591 and D4S3240.
GENE FUNCTION
By expression of FLAG-tagged CISD2 in mammalian cells, Amr et al. (2007)
showed that CISD2 is localized to the endoplasmic reticulum,
colocalizing with calnexin (114217). Coimmunoprecipitation studies
showed that CISD2 and wolframin (606201) do not interact.
Wiley et al. (2007) noted that purified recombinant CISD2 was red in
color and noted that although the CDGSH domain was initially classified
as a zinc finger domain, its actually contains iron. Wiley et al. (2007)
showed that the CDGSH domain of CISD1 harbors a redox-sensitive 2Fe-2S
cluster and suggested that the CDGSH domain of CISD2 likewise binds
2Fe-2S and has similar biophysical properties. Based on similarity to
CISD1, they suggested that the CISD2 is a member of an iron-containing
family of proteins with CDGSH domains.
MOLECULAR GENETICS
Wolfram syndrome (WFS; 222300) is an autosomal recessive disorder with
severe neurodegeneration whose phenotype includes juvenile-onset
insulin-dependent diabetes mellitus and optic atrophy, sensorineural
deafness, dementia, psychiatric illnesses, renal tract abnormalities,
and bladder atony. One gene for the disorder, WFS1 (606201) on 4p16.3,
encodes a transmembrane protein located in the endoplasmic reticulum and
may play a role in calcium homeostasis. In a search for the mutation
responsible for a form of Wolfram syndrome mapping to 4q22-24 (WFS2;
604928), Amr et al. (2007) screened genes within the candidate region
for mutations and identified a missense mutation in the CISD2 gene
(611507.0001). Although the amino acid was conserved and the mutation
nonsynonymous, the pathogenesis for the disorder was shown to be
aberrant splicing. The mutation disrupted RNA splicing by eliminating
exon 2, and resulted in the introduction of a premature stop codon.
Because dominant mutations associated with low-frequency nonsyndromic
hearing loss, progressive hearing loss, and isolated optic atrophy with
hearing loss had been found in the WFS1 gene, Amr et al. (2007) screened
377 probands with hearing loss for mutation in the WFS2 gene. No
mutations in WFS2 were identified.
Wolframin, the protein encoded by WFS1, localizes to the endoplasmic
reticulum and plays a role in calcium homeostasis. Amr et al. (2007)
showed that the CISD2-encoded protein, ERIS (endoplasmic reticulum
intermembrane small protein) also localizes to the endoplasmic reticulum
but does not interact directly with wolframin. Lymphoblastoid cells from
individuals with WFS2 showed a significantly greater rise in
intracellular calcium when stimulated with thapsigargin compared with
controls, although no difference was observed in resting concentrations
of intracellular calcium.
ANIMAL MODEL
Chen et al. (2009) provided evidence that the Cisd2 gene is involved in
mammalian life span control. In mice, Cisd2 was primarily localized in
the mitochondria and associated with the outer mitochondrial membrane.
Cisd2-null mice showed early senescence and shortened life span compared
to wildtype mice. Features included prominent eyes, protruding ears,
corneal opacities and degeneration, thinner bones and hair, and
decreased muscle mass, which are all consistent with premature aging.
Tissues from mutant mice showed progressive mitochondrial breakdown and
dysfunction accompanied by autophagic cell death, which preceded nerve
and muscle degeneration. Mitochondria isolated from the mutant mice
showed a defect in respiration. Together, the phenotype was suggestive
of premature aging with some features of Wolfram syndrome. The findings
also suggested that Wolfram syndrome-2 is in part a
mitochondria-mediated disorder. Chen et al. (2009) also noted that the
human CISD2 gene maps to chromosome 4q22-q24, close to a region
implicated in human longevity (152430).
Chang et al. (2012) found that Naf1 -/- mice appeared normal at birth,
but by 2 to 3 months, they developed low body weight, ruffled fur,
tremors, lethargy, and general weakness. At 3 months of age, Naf1 -/-
skeletal muscle showed reduced force-generating capacity and a switch to
slow-twitch muscle phenotype. Impaired muscle function was accompanied
by enhanced autophagy, especially in diaphragm. Enlarged mitochondria
were also observed and likely represented an adaptive response to
enhanced autophagy. In culture, primary Naf1 -/- diaphragm myoblasts
showed elevated basal Ca(2+) content.
*FIELD* AV
.0001
WOLFRAM SYNDROME 2
CISD2, GLU37GLN
Amr et al. (2007) identified a mutation in the CISD2 gene in 3
consanguineous families of Jordanian descent with Wolfram syndrome-2
(604928). A G-to-C transversion in nucleotide 109 in exon 2 predicted an
amino acid change from glutamic acid to glutamine (glu37 to gln, E37Q).
Although the amino acid is conserved and the mutation is nonsynonymous,
the pathogenesis for the disorder was aberrant splicing. The mutation
disrupted mRNA splicing by eliminating exon 2, and resulted in the
introduction of a premature stop codon.
*FIELD* RF
1. Amr, S.; Heisey, C.; Zhang, M.; Xia, X.-J.; Shows, K. H.; Ajlouni,
K.; Pandya, A.; Satin, L. S.; El-Shanti, H.; Shiang, R.: A homozygous
mutation in a novel zinc-finger protein, ERIS, is responsible for
Wolfram syndrome 2. Am. J. Hum. Genet. 81: 673-683, 2007.
2. Chang, N. C.; Nguyen, M.; Bourdon, J.; Risse, P.-A.; Martin, J.;
Danialou, G.; Rizzuto, R.; Petrof, B. J.; Shore, G. C.: Bcl-2-associated
autophagy regulator Naf-1 required for maintenance of skeletal muscle. Hum.
Molec. Genet. 21: 2277-2287, 2012.
3. Chen, Y.-F.; Kao, C.-H.; Chen, Y.-T.; Wang, C.-H.; Wu, C.-Y.; Tsai,
C.-Y.; Liu, F.-C.; Yang, C.-W.; Wei, Y.-H.; Hsu, M.-T.; Tsai, S.-F.;
Tsai, T.-F.: Cisd2 deficiency drives premature aging and causes mitochondria-mediated
defects in mice. Genes Dev. 23: 1183-1194, 2009.
4. Wiley, S. E.; Murphy, A. N.; Ross, S. A.; van der Geer, P.; Dixon,
J. E.: MitoNEET is an iron-containing outer mitochondrial membrane
protein that regulates oxidative capacity. Proc. Nat. Acad. Sci. 104:
5318-5323, 2007.
5. Wiley, S. E.; Paddock, M. L.; Abresch, E. C.; Gross, L.; van der
Geer, P.; Nechushtai, R.; Murphy, A. N.; Jennings, P. A.; Dixon, J.
E.: The outer mitochondrial membrane protein mitoNEET contains a
novel redox-active 2Fe-2S cluster. J. Biol. Chem. 282: 23745-23749,
2007.
*FIELD* CN
Patricia A. Hartz - updated: 07/09/2013
Cassandra L. Kniffin - updated: 7/30/2009
Dorothy S. Reilly - updated: 4/3/2008
*FIELD* CD
Victor A. McKusick: 10/5/2007
*FIELD* ED
mgross: 07/09/2013
mgross: 7/9/2013
wwang: 9/1/2009
wwang: 8/5/2009
ckniffin: 7/30/2009
wwang: 4/3/2008
alopez: 10/5/2007