Full text data of MIB1
MIB1
(DIP1, KIAA1323, ZZANK2)
[Confidence: low (only semi-automatic identification from reviews)]
E3 ubiquitin-protein ligase MIB1; 6.3.2.- (DAPK-interacting protein 1; DIP-1; Mind bomb homolog 1; Zinc finger ZZ type with ankyrin repeat domain protein 2)
E3 ubiquitin-protein ligase MIB1; 6.3.2.- (DAPK-interacting protein 1; DIP-1; Mind bomb homolog 1; Zinc finger ZZ type with ankyrin repeat domain protein 2)
UniProt
Q86YT6
ID MIB1_HUMAN Reviewed; 1006 AA.
AC Q86YT6; B0YJ38; Q2TB37; Q68D01; Q6YI51; Q8NBY0; Q8TCB5; Q8TCL7;
read moreAC Q9P2M3;
DT 05-JUL-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2003, sequence version 1.
DT 22-JAN-2014, entry version 108.
DE RecName: Full=E3 ubiquitin-protein ligase MIB1;
DE EC=6.3.2.-;
DE AltName: Full=DAPK-interacting protein 1;
DE Short=DIP-1;
DE AltName: Full=Mind bomb homolog 1;
DE AltName: Full=Zinc finger ZZ type with ankyrin repeat domain protein 2;
GN Name=MIB1; Synonyms=DIP1, KIAA1323, ZZANK2;
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].
RX PubMed=12530964; DOI=10.1016/S1534-5807(02)00409-4;
RA Itoh M., Kim C.-H., Palardy G., Oda T., Jiang Y.-J., Maust D.,
RA Yeo S.-Y., Lorick K., Wright G.J., Ariza-McNaughton L., Weissman A.M.,
RA Lewis J., Chandrasekharappa S.C., Chitnis A.B.;
RT "Mind bomb is a ubiquitin ligase that is essential for efficient
RT activation of Notch signaling by Delta.";
RL Dev. Cell 4:67-82(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Yoo K.-W., Chitnis A., Kim C.-H.;
RL Submitted (SEP-2002) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NHLBI resequencing and genotyping service (RS&G;);
RL Submitted (FEB-2007) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lung;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 195-1006.
RC TISSUE=Amygdala, and Endometrial tumor;
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 611-1006, AND TISSUE
RP SPECIFICITY.
RC TISSUE=Brain;
RX PubMed=10718198; DOI=10.1093/dnares/7.1.65;
RA Nagase T., Kikuno R., Ishikawa K., Hirosawa M., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. XVI.
RT The complete sequences of 150 new cDNA clones from brain which code
RT for large proteins in vitro.";
RL DNA Res. 7:65-73(2000).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 627-1006.
RC TISSUE=Placenta;
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 [8]
RP POSSIBLE SUBCELLULAR LOCATION.
RX PubMed=15048887; DOI=10.1002/ana.20001;
RA Henshall D.C., Schindler C.K., So N.K., Lan J.-Q., Meller R.,
RA Simon R.P.;
RT "Death-associated protein kinase expression in human temporal lobe
RT epilepsy.";
RL Ann. Neurol. 55:485-494(2004).
RN [9]
RP UBIQUITINATION OF TBK1.
RX PubMed=21903422; DOI=10.1016/j.immuni.2011.06.014;
RA Li S., Wang L., Berman M., Kong Y.Y., Dorf M.E.;
RT "Mapping a dynamic innate immunity protein interaction network
RT regulating type I interferon production.";
RL Immunity 35:426-440(2011).
RN [10]
RP VARIANT HIS-174.
RX PubMed=23033978; DOI=10.1056/NEJMoa1206524;
RA de Ligt J., Willemsen M.H., van Bon B.W., Kleefstra T., Yntema H.G.,
RA Kroes T., Vulto-van Silfhout A.T., Koolen D.A., de Vries P.,
RA Gilissen C., del Rosario M., Hoischen A., Scheffer H., de Vries B.B.,
RA Brunner H.G., Veltman J.A., Vissers L.E.;
RT "Diagnostic exome sequencing in persons with severe intellectual
RT disability.";
RL N. Engl. J. Med. 367:1921-1929(2012).
RN [11]
RP VARIANT LVNC7 PHE-943.
RX PubMed=23314057; DOI=10.1038/nm.3046;
RA Luxan G., Casanova J.C., Martinez-Poveda B., Prados B., D'Amato G.,
RA MacGrogan D., Gonzalez-Rajal A., Dobarro D., Torroja C., Martinez F.,
RA Izquierdo-Garcia J.L., Fernandez-Friera L., Sabater-Molina M.,
RA Kong Y.Y., Pizarro G., Ibanez B., Medrano C., Garcia-Pavia P.,
RA Gimeno J.R., Monserrat L., Jimenez-Borreguero L.J., de la Pompa J.L.;
RT "Mutations in the NOTCH pathway regulator MIB1 cause left ventricular
RT noncompaction cardiomyopathy.";
RL Nat. Med. 19:193-201(2013).
CC -!- FUNCTION: E3 ubiquitin-protein ligase that mediates ubiquitination
CC of Delta receptors, which act as ligands of Notch proteins.
CC Positively regulates the Delta-mediated Notch signaling by
CC ubiquitinating the intracellular domain of Delta, leading to
CC endocytosis of Delta receptors. Probably mediates ubiquitination
CC and subsequent proteasomal degradation of DAPK1, thereby
CC antagonizing anti-apoptotic effects of DAPK1 to promote TNF-
CC induced apoptosis (By similarity). Mediates 'Lys-63'-linked
CC polyubiquitination of TBK1, which probably participates in kinase
CC activation.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- INTERACTION:
CC Q9QYP6:Azi2 (xeno); NbExp=2; IntAct=EBI-2129148, EBI-6115874;
CC Q9UHD2:TBK1; NbExp=2; IntAct=EBI-2129148, EBI-356402;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Cell membrane (By similarity).
CC Note=Localizes to the plasma membrane (By similarity). According
CC to PubMed:15048887, it is mitochondrial, however such localization
CC remains unclear.
CC -!- TISSUE SPECIFICITY: Widely expressed at low level. Expressed at
CC higher level in spinal cord, ovary, whole brain, and all specific
CC brain regions examined.
CC -!- PTM: Ubiquitinated. Possibly via autoubiquitination (By
CC similarity).
CC -!- DISEASE: Left ventricular non-compaction 7 (LVNC7) [MIM:615092]: A
CC disease due to an arrest of myocardial morphogenesis. It is
CC characterized by a hypertrophic left ventricle with deep
CC trabeculations and with poor systolic function, with or without
CC associated left ventricular dilation. In some cases, it is
CC associated with other congenital heart anomalies. Note=The disease
CC is caused by mutations affecting the gene represented in this
CC entry.
CC -!- MISCELLANEOUS: In epilepsy brain tissue, levels of expression are
CC increased in the cytoplasm and microsomal fractions (endoplasmic
CC reticulum).
CC -!- SIMILARITY: Contains 9 ANK repeats.
CC -!- SIMILARITY: Contains 2 MIB/HERC2 domains.
CC -!- SIMILARITY: Contains 3 RING-type zinc fingers.
CC -!- SIMILARITY: Contains 1 ZZ-type zinc finger.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH22403.1; Type=Erroneous initiation;
CC Sequence=AAN18023.1; Type=Frameshift; Positions=3;
CC Sequence=BAC11439.1; Type=Erroneous initiation;
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DR EMBL; AY149908; AAN75493.1; -; mRNA.
DR EMBL; AY147849; AAN18023.1; ALT_FRAME; mRNA.
DR EMBL; EF444995; ACA06016.1; -; Genomic_DNA.
DR EMBL; BC022403; AAH22403.1; ALT_INIT; mRNA.
DR EMBL; BC110581; AAI10582.1; -; mRNA.
DR EMBL; BC110582; AAI10583.1; -; mRNA.
DR EMBL; CR749635; CAH18429.1; -; mRNA.
DR EMBL; AL713705; CAD28502.1; -; mRNA.
DR EMBL; AB037744; BAA92561.1; -; mRNA.
DR EMBL; AK075157; BAC11439.1; ALT_INIT; mRNA.
DR RefSeq; NP_065825.1; NM_020774.3.
DR UniGene; Hs.140903; -.
DR UniGene; Hs.658808; -.
DR ProteinModelPortal; Q86YT6; -.
DR SMR; Q86YT6; 15-70, 154-216, 382-779, 851-908, 953-1003.
DR IntAct; Q86YT6; 13.
DR MINT; MINT-2841371; -.
DR PhosphoSite; Q86YT6; -.
DR DMDM; 68565512; -.
DR PaxDb; Q86YT6; -.
DR PRIDE; Q86YT6; -.
DR Ensembl; ENST00000261537; ENSP00000261537; ENSG00000101752.
DR GeneID; 57534; -.
DR KEGG; hsa:57534; -.
DR UCSC; uc002ktp.3; human.
DR CTD; 57534; -.
DR GeneCards; GC18P019284; -.
DR HGNC; HGNC:21086; MIB1.
DR HPA; HPA019100; -.
DR MIM; 608677; gene.
DR MIM; 615092; phenotype.
DR neXtProt; NX_Q86YT6; -.
DR Orphanet; 54260; Left ventricular noncompaction.
DR PharmGKB; PA134862722; -.
DR eggNOG; COG0666; -.
DR HOVERGEN; HBG068386; -.
DR InParanoid; Q86YT6; -.
DR KO; K10645; -.
DR OMA; HDAISKE; -.
DR OrthoDB; EOG7WHH8P; -.
DR PhylomeDB; Q86YT6; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_116125; Disease.
DR SignaLink; Q86YT6; -.
DR UniPathway; UPA00143; -.
DR GeneWiki; MIB1_(gene); -.
DR GenomeRNAi; 57534; -.
DR NextBio; 63948; -.
DR PRO; PR:Q86YT6; -.
DR ArrayExpress; Q86YT6; -.
DR Bgee; Q86YT6; -.
DR CleanEx; HS_MIB1; -.
DR Genevestigator; Q86YT6; -.
DR GO; GO:0005813; C:centrosome; IDA:UniProtKB.
DR GO; GO:0031410; C:cytoplasmic vesicle; IEA:Ensembl.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0031965; C:nuclear membrane; IDA:HPA.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0004842; F:ubiquitin-protein ligase activity; IEA:InterPro.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0001568; P:blood vessel development; IEA:Ensembl.
DR GO; GO:0001947; P:heart looping; IEA:Ensembl.
DR GO; GO:0001701; P:in utero embryonic development; IEA:Ensembl.
DR GO; GO:0045665; P:negative regulation of neuron differentiation; IEA:Ensembl.
DR GO; GO:0001841; P:neural tube formation; IEA:Ensembl.
DR GO; GO:0007219; P:Notch signaling pathway; TAS:Reactome.
DR GO; GO:0045807; P:positive regulation of endocytosis; IEA:Ensembl.
DR GO; GO:0001756; P:somitogenesis; IEA:Ensembl.
DR Gene3D; 1.25.40.20; -; 4.
DR Gene3D; 3.30.40.10; -; 1.
DR InterPro; IPR002110; Ankyrin_rpt.
DR InterPro; IPR020683; Ankyrin_rpt-contain_dom.
DR InterPro; IPR010606; Mib_Herc2.
DR InterPro; IPR001841; Znf_RING.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR InterPro; IPR000433; Znf_ZZ.
DR Pfam; PF00023; Ank; 1.
DR Pfam; PF12796; Ank_2; 3.
DR Pfam; PF06701; MIB_HERC2; 2.
DR Pfam; PF00569; ZZ; 1.
DR PRINTS; PR01415; ANKYRIN.
DR SMART; SM00248; ANK; 9.
DR SMART; SM00184; RING; 3.
DR SMART; SM00291; ZnF_ZZ; 1.
DR SUPFAM; SSF48403; SSF48403; 1.
DR PROSITE; PS50297; ANK_REP_REGION; 1.
DR PROSITE; PS50088; ANK_REPEAT; 6.
DR PROSITE; PS51416; MIB_HERC2; 2.
DR PROSITE; PS00518; ZF_RING_1; FALSE_NEG.
DR PROSITE; PS50089; ZF_RING_2; 3.
DR PROSITE; PS01357; ZF_ZZ_1; 1.
DR PROSITE; PS50135; ZF_ZZ_2; 1.
PE 1: Evidence at protein level;
KW ANK repeat; Cell membrane; Coiled coil; Complete proteome; Cytoplasm;
KW Disease mutation; Ligase; Membrane; Metal-binding;
KW Notch signaling pathway; Polymorphism; Reference proteome; Repeat;
KW Ubl conjugation; Ubl conjugation pathway; Zinc; Zinc-finger.
FT CHAIN 1 1006 E3 ubiquitin-protein ligase MIB1.
FT /FTId=PRO_0000055943.
FT DOMAIN 6 74 MIB/HERC2 1.
FT DOMAIN 143 221 MIB/HERC2 2.
FT REPEAT 430 460 ANK 1.
FT REPEAT 463 492 ANK 2.
FT REPEAT 496 525 ANK 3.
FT REPEAT 529 558 ANK 4.
FT REPEAT 562 591 ANK 5.
FT REPEAT 595 627 ANK 6.
FT REPEAT 631 661 ANK 7.
FT REPEAT 665 694 ANK 8.
FT REPEAT 698 729 ANK 9.
FT ZN_FING 79 126 ZZ-type.
FT ZN_FING 819 854 RING-type 1.
FT ZN_FING 866 901 RING-type 2.
FT ZN_FING 963 996 RING-type 3.
FT COILED 935 962 Potential.
FT VARIANT 174 174 R -> H (found in a patient with severe
FT mental retardation, psychomotor delay, no
FT speech, sleep disturbances, feeding
FT problems, abnormal breething, deep-set
FT eyes and short philtrum).
FT /FTId=VAR_069385.
FT VARIANT 943 943 V -> F (in LVNC7).
FT /FTId=VAR_069620.
FT CONFLICT 327 327 E -> K (in Ref. 2; AAN18023).
FT CONFLICT 398 398 S -> F (in Ref. 2; AAN18023).
SQ SEQUENCE 1006 AA; 110136 MW; 5D7D0D91AF98FF18 CRC64;
MSNSRNNRVM VEGVGARVVR GPDWKWGKQD GGEGHVGTVR SFESPEEVVV VWDNGTAANY
RCSGAYDLRI LDSAPTGIKH DGTMCDTCRQ QPIIGIRWKC AECTNYDLCT VCYHGDKHHL
RHRFYRITTP GSERVLLESR RKSKKITARG IFAGARVVRG VDWQWEDQDG GNGRRGKVTE
IQDWSASSPH SAAYVLWDNG AKNLYRVGFE GMSDLKCVQD AKGGSFYRDH CPVLGEQNGN
RNPGGLQIGD LVNIDLDLEI VQSLQHGHGG WTDGMFETLT TTGTVCGIDE DHDIVVQYPS
GNRWTFNPAV LTKANIVRSG DAAQGAEGGT SQFQVGDLVQ VCYDLERIKL LQRGHGEWAE
AMLPTLGKVG RVQQIYSDSD LKVEVCGTSW TYNPAAVSKV ASAGSAISNA SGERLSQLLK
KLFETQESGD LNEELVKAAA NGDVAKVEDL LKRPDVDVNG QCAGHTAMQA ASQNGHVDIL
KLLLKQNVDV EAEDKDGDRA VHHAAFGDEG AVIEVLHRGS ADLNARNKRR QTPLHIAVNK
GHLQVVKTLL DFGCHPSLQD SEGDTPLHDA ISKKRDDILA VLLEAGADVT ITNNNGFNAL
HHAALRGNPS AMRVLLSKLP RPWIVDEKKD DGYTALHLAA LNNHVEVAEL LVHQGNANLD
IQNVNQQTAL HLAVERQHTQ IVRLLVRAGA KLDIQDKDGD TPLHEALRHH TLSQLRQLQD
MQDVGKVDAA WEPSKNTLIM GLGTQGAEKK SAASIACFLA ANGADLSIRN KKGQSPLDLC
PDPNLCKALA KCHKEKVSGQ VGSRSPSMIS NDSETLEECM VCSDMKRDTL FGPCGHIATC
SLCSPRVKKC LICKEQVQSR TKIEECVVCS DKKAAVLFQP CGHMCACENC ANLMKKCVQC
RAVVERRVPF IMCCGGKSSE DATDDISSGN IPVLQKDKDN TNVNADVQKL QQQLQDIKEQ
TMCPVCLDRL KNMIFLCGHG TCQLCGDRMS ECPICRKAIE RRILLY
//
ID MIB1_HUMAN Reviewed; 1006 AA.
AC Q86YT6; B0YJ38; Q2TB37; Q68D01; Q6YI51; Q8NBY0; Q8TCB5; Q8TCL7;
read moreAC Q9P2M3;
DT 05-JUL-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2003, sequence version 1.
DT 22-JAN-2014, entry version 108.
DE RecName: Full=E3 ubiquitin-protein ligase MIB1;
DE EC=6.3.2.-;
DE AltName: Full=DAPK-interacting protein 1;
DE Short=DIP-1;
DE AltName: Full=Mind bomb homolog 1;
DE AltName: Full=Zinc finger ZZ type with ankyrin repeat domain protein 2;
GN Name=MIB1; Synonyms=DIP1, KIAA1323, ZZANK2;
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].
RX PubMed=12530964; DOI=10.1016/S1534-5807(02)00409-4;
RA Itoh M., Kim C.-H., Palardy G., Oda T., Jiang Y.-J., Maust D.,
RA Yeo S.-Y., Lorick K., Wright G.J., Ariza-McNaughton L., Weissman A.M.,
RA Lewis J., Chandrasekharappa S.C., Chitnis A.B.;
RT "Mind bomb is a ubiquitin ligase that is essential for efficient
RT activation of Notch signaling by Delta.";
RL Dev. Cell 4:67-82(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Yoo K.-W., Chitnis A., Kim C.-H.;
RL Submitted (SEP-2002) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NHLBI resequencing and genotyping service (RS&G;);
RL Submitted (FEB-2007) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lung;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 195-1006.
RC TISSUE=Amygdala, and Endometrial tumor;
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 611-1006, AND TISSUE
RP SPECIFICITY.
RC TISSUE=Brain;
RX PubMed=10718198; DOI=10.1093/dnares/7.1.65;
RA Nagase T., Kikuno R., Ishikawa K., Hirosawa M., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. XVI.
RT The complete sequences of 150 new cDNA clones from brain which code
RT for large proteins in vitro.";
RL DNA Res. 7:65-73(2000).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 627-1006.
RC TISSUE=Placenta;
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 [8]
RP POSSIBLE SUBCELLULAR LOCATION.
RX PubMed=15048887; DOI=10.1002/ana.20001;
RA Henshall D.C., Schindler C.K., So N.K., Lan J.-Q., Meller R.,
RA Simon R.P.;
RT "Death-associated protein kinase expression in human temporal lobe
RT epilepsy.";
RL Ann. Neurol. 55:485-494(2004).
RN [9]
RP UBIQUITINATION OF TBK1.
RX PubMed=21903422; DOI=10.1016/j.immuni.2011.06.014;
RA Li S., Wang L., Berman M., Kong Y.Y., Dorf M.E.;
RT "Mapping a dynamic innate immunity protein interaction network
RT regulating type I interferon production.";
RL Immunity 35:426-440(2011).
RN [10]
RP VARIANT HIS-174.
RX PubMed=23033978; DOI=10.1056/NEJMoa1206524;
RA de Ligt J., Willemsen M.H., van Bon B.W., Kleefstra T., Yntema H.G.,
RA Kroes T., Vulto-van Silfhout A.T., Koolen D.A., de Vries P.,
RA Gilissen C., del Rosario M., Hoischen A., Scheffer H., de Vries B.B.,
RA Brunner H.G., Veltman J.A., Vissers L.E.;
RT "Diagnostic exome sequencing in persons with severe intellectual
RT disability.";
RL N. Engl. J. Med. 367:1921-1929(2012).
RN [11]
RP VARIANT LVNC7 PHE-943.
RX PubMed=23314057; DOI=10.1038/nm.3046;
RA Luxan G., Casanova J.C., Martinez-Poveda B., Prados B., D'Amato G.,
RA MacGrogan D., Gonzalez-Rajal A., Dobarro D., Torroja C., Martinez F.,
RA Izquierdo-Garcia J.L., Fernandez-Friera L., Sabater-Molina M.,
RA Kong Y.Y., Pizarro G., Ibanez B., Medrano C., Garcia-Pavia P.,
RA Gimeno J.R., Monserrat L., Jimenez-Borreguero L.J., de la Pompa J.L.;
RT "Mutations in the NOTCH pathway regulator MIB1 cause left ventricular
RT noncompaction cardiomyopathy.";
RL Nat. Med. 19:193-201(2013).
CC -!- FUNCTION: E3 ubiquitin-protein ligase that mediates ubiquitination
CC of Delta receptors, which act as ligands of Notch proteins.
CC Positively regulates the Delta-mediated Notch signaling by
CC ubiquitinating the intracellular domain of Delta, leading to
CC endocytosis of Delta receptors. Probably mediates ubiquitination
CC and subsequent proteasomal degradation of DAPK1, thereby
CC antagonizing anti-apoptotic effects of DAPK1 to promote TNF-
CC induced apoptosis (By similarity). Mediates 'Lys-63'-linked
CC polyubiquitination of TBK1, which probably participates in kinase
CC activation.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- INTERACTION:
CC Q9QYP6:Azi2 (xeno); NbExp=2; IntAct=EBI-2129148, EBI-6115874;
CC Q9UHD2:TBK1; NbExp=2; IntAct=EBI-2129148, EBI-356402;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Cell membrane (By similarity).
CC Note=Localizes to the plasma membrane (By similarity). According
CC to PubMed:15048887, it is mitochondrial, however such localization
CC remains unclear.
CC -!- TISSUE SPECIFICITY: Widely expressed at low level. Expressed at
CC higher level in spinal cord, ovary, whole brain, and all specific
CC brain regions examined.
CC -!- PTM: Ubiquitinated. Possibly via autoubiquitination (By
CC similarity).
CC -!- DISEASE: Left ventricular non-compaction 7 (LVNC7) [MIM:615092]: A
CC disease due to an arrest of myocardial morphogenesis. It is
CC characterized by a hypertrophic left ventricle with deep
CC trabeculations and with poor systolic function, with or without
CC associated left ventricular dilation. In some cases, it is
CC associated with other congenital heart anomalies. Note=The disease
CC is caused by mutations affecting the gene represented in this
CC entry.
CC -!- MISCELLANEOUS: In epilepsy brain tissue, levels of expression are
CC increased in the cytoplasm and microsomal fractions (endoplasmic
CC reticulum).
CC -!- SIMILARITY: Contains 9 ANK repeats.
CC -!- SIMILARITY: Contains 2 MIB/HERC2 domains.
CC -!- SIMILARITY: Contains 3 RING-type zinc fingers.
CC -!- SIMILARITY: Contains 1 ZZ-type zinc finger.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH22403.1; Type=Erroneous initiation;
CC Sequence=AAN18023.1; Type=Frameshift; Positions=3;
CC Sequence=BAC11439.1; Type=Erroneous initiation;
CC -----------------------------------------------------------------------
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DR EMBL; AY149908; AAN75493.1; -; mRNA.
DR EMBL; AY147849; AAN18023.1; ALT_FRAME; mRNA.
DR EMBL; EF444995; ACA06016.1; -; Genomic_DNA.
DR EMBL; BC022403; AAH22403.1; ALT_INIT; mRNA.
DR EMBL; BC110581; AAI10582.1; -; mRNA.
DR EMBL; BC110582; AAI10583.1; -; mRNA.
DR EMBL; CR749635; CAH18429.1; -; mRNA.
DR EMBL; AL713705; CAD28502.1; -; mRNA.
DR EMBL; AB037744; BAA92561.1; -; mRNA.
DR EMBL; AK075157; BAC11439.1; ALT_INIT; mRNA.
DR RefSeq; NP_065825.1; NM_020774.3.
DR UniGene; Hs.140903; -.
DR UniGene; Hs.658808; -.
DR ProteinModelPortal; Q86YT6; -.
DR SMR; Q86YT6; 15-70, 154-216, 382-779, 851-908, 953-1003.
DR IntAct; Q86YT6; 13.
DR MINT; MINT-2841371; -.
DR PhosphoSite; Q86YT6; -.
DR DMDM; 68565512; -.
DR PaxDb; Q86YT6; -.
DR PRIDE; Q86YT6; -.
DR Ensembl; ENST00000261537; ENSP00000261537; ENSG00000101752.
DR GeneID; 57534; -.
DR KEGG; hsa:57534; -.
DR UCSC; uc002ktp.3; human.
DR CTD; 57534; -.
DR GeneCards; GC18P019284; -.
DR HGNC; HGNC:21086; MIB1.
DR HPA; HPA019100; -.
DR MIM; 608677; gene.
DR MIM; 615092; phenotype.
DR neXtProt; NX_Q86YT6; -.
DR Orphanet; 54260; Left ventricular noncompaction.
DR PharmGKB; PA134862722; -.
DR eggNOG; COG0666; -.
DR HOVERGEN; HBG068386; -.
DR InParanoid; Q86YT6; -.
DR KO; K10645; -.
DR OMA; HDAISKE; -.
DR OrthoDB; EOG7WHH8P; -.
DR PhylomeDB; Q86YT6; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_116125; Disease.
DR SignaLink; Q86YT6; -.
DR UniPathway; UPA00143; -.
DR GeneWiki; MIB1_(gene); -.
DR GenomeRNAi; 57534; -.
DR NextBio; 63948; -.
DR PRO; PR:Q86YT6; -.
DR ArrayExpress; Q86YT6; -.
DR Bgee; Q86YT6; -.
DR CleanEx; HS_MIB1; -.
DR Genevestigator; Q86YT6; -.
DR GO; GO:0005813; C:centrosome; IDA:UniProtKB.
DR GO; GO:0031410; C:cytoplasmic vesicle; IEA:Ensembl.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0031965; C:nuclear membrane; IDA:HPA.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0004842; F:ubiquitin-protein ligase activity; IEA:InterPro.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0001568; P:blood vessel development; IEA:Ensembl.
DR GO; GO:0001947; P:heart looping; IEA:Ensembl.
DR GO; GO:0001701; P:in utero embryonic development; IEA:Ensembl.
DR GO; GO:0045665; P:negative regulation of neuron differentiation; IEA:Ensembl.
DR GO; GO:0001841; P:neural tube formation; IEA:Ensembl.
DR GO; GO:0007219; P:Notch signaling pathway; TAS:Reactome.
DR GO; GO:0045807; P:positive regulation of endocytosis; IEA:Ensembl.
DR GO; GO:0001756; P:somitogenesis; IEA:Ensembl.
DR Gene3D; 1.25.40.20; -; 4.
DR Gene3D; 3.30.40.10; -; 1.
DR InterPro; IPR002110; Ankyrin_rpt.
DR InterPro; IPR020683; Ankyrin_rpt-contain_dom.
DR InterPro; IPR010606; Mib_Herc2.
DR InterPro; IPR001841; Znf_RING.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR InterPro; IPR000433; Znf_ZZ.
DR Pfam; PF00023; Ank; 1.
DR Pfam; PF12796; Ank_2; 3.
DR Pfam; PF06701; MIB_HERC2; 2.
DR Pfam; PF00569; ZZ; 1.
DR PRINTS; PR01415; ANKYRIN.
DR SMART; SM00248; ANK; 9.
DR SMART; SM00184; RING; 3.
DR SMART; SM00291; ZnF_ZZ; 1.
DR SUPFAM; SSF48403; SSF48403; 1.
DR PROSITE; PS50297; ANK_REP_REGION; 1.
DR PROSITE; PS50088; ANK_REPEAT; 6.
DR PROSITE; PS51416; MIB_HERC2; 2.
DR PROSITE; PS00518; ZF_RING_1; FALSE_NEG.
DR PROSITE; PS50089; ZF_RING_2; 3.
DR PROSITE; PS01357; ZF_ZZ_1; 1.
DR PROSITE; PS50135; ZF_ZZ_2; 1.
PE 1: Evidence at protein level;
KW ANK repeat; Cell membrane; Coiled coil; Complete proteome; Cytoplasm;
KW Disease mutation; Ligase; Membrane; Metal-binding;
KW Notch signaling pathway; Polymorphism; Reference proteome; Repeat;
KW Ubl conjugation; Ubl conjugation pathway; Zinc; Zinc-finger.
FT CHAIN 1 1006 E3 ubiquitin-protein ligase MIB1.
FT /FTId=PRO_0000055943.
FT DOMAIN 6 74 MIB/HERC2 1.
FT DOMAIN 143 221 MIB/HERC2 2.
FT REPEAT 430 460 ANK 1.
FT REPEAT 463 492 ANK 2.
FT REPEAT 496 525 ANK 3.
FT REPEAT 529 558 ANK 4.
FT REPEAT 562 591 ANK 5.
FT REPEAT 595 627 ANK 6.
FT REPEAT 631 661 ANK 7.
FT REPEAT 665 694 ANK 8.
FT REPEAT 698 729 ANK 9.
FT ZN_FING 79 126 ZZ-type.
FT ZN_FING 819 854 RING-type 1.
FT ZN_FING 866 901 RING-type 2.
FT ZN_FING 963 996 RING-type 3.
FT COILED 935 962 Potential.
FT VARIANT 174 174 R -> H (found in a patient with severe
FT mental retardation, psychomotor delay, no
FT speech, sleep disturbances, feeding
FT problems, abnormal breething, deep-set
FT eyes and short philtrum).
FT /FTId=VAR_069385.
FT VARIANT 943 943 V -> F (in LVNC7).
FT /FTId=VAR_069620.
FT CONFLICT 327 327 E -> K (in Ref. 2; AAN18023).
FT CONFLICT 398 398 S -> F (in Ref. 2; AAN18023).
SQ SEQUENCE 1006 AA; 110136 MW; 5D7D0D91AF98FF18 CRC64;
MSNSRNNRVM VEGVGARVVR GPDWKWGKQD GGEGHVGTVR SFESPEEVVV VWDNGTAANY
RCSGAYDLRI LDSAPTGIKH DGTMCDTCRQ QPIIGIRWKC AECTNYDLCT VCYHGDKHHL
RHRFYRITTP GSERVLLESR RKSKKITARG IFAGARVVRG VDWQWEDQDG GNGRRGKVTE
IQDWSASSPH SAAYVLWDNG AKNLYRVGFE GMSDLKCVQD AKGGSFYRDH CPVLGEQNGN
RNPGGLQIGD LVNIDLDLEI VQSLQHGHGG WTDGMFETLT TTGTVCGIDE DHDIVVQYPS
GNRWTFNPAV LTKANIVRSG DAAQGAEGGT SQFQVGDLVQ VCYDLERIKL LQRGHGEWAE
AMLPTLGKVG RVQQIYSDSD LKVEVCGTSW TYNPAAVSKV ASAGSAISNA SGERLSQLLK
KLFETQESGD LNEELVKAAA NGDVAKVEDL LKRPDVDVNG QCAGHTAMQA ASQNGHVDIL
KLLLKQNVDV EAEDKDGDRA VHHAAFGDEG AVIEVLHRGS ADLNARNKRR QTPLHIAVNK
GHLQVVKTLL DFGCHPSLQD SEGDTPLHDA ISKKRDDILA VLLEAGADVT ITNNNGFNAL
HHAALRGNPS AMRVLLSKLP RPWIVDEKKD DGYTALHLAA LNNHVEVAEL LVHQGNANLD
IQNVNQQTAL HLAVERQHTQ IVRLLVRAGA KLDIQDKDGD TPLHEALRHH TLSQLRQLQD
MQDVGKVDAA WEPSKNTLIM GLGTQGAEKK SAASIACFLA ANGADLSIRN KKGQSPLDLC
PDPNLCKALA KCHKEKVSGQ VGSRSPSMIS NDSETLEECM VCSDMKRDTL FGPCGHIATC
SLCSPRVKKC LICKEQVQSR TKIEECVVCS DKKAAVLFQP CGHMCACENC ANLMKKCVQC
RAVVERRVPF IMCCGGKSSE DATDDISSGN IPVLQKDKDN TNVNADVQKL QQQLQDIKEQ
TMCPVCLDRL KNMIFLCGHG TCQLCGDRMS ECPICRKAIE RRILLY
//
MIM
608677
*RECORD*
*FIELD* NO
608677
*FIELD* TI
*608677 MINDBOMB, DROSOPHILA, HOMOLOG OF, 1; MIB1
;;MIB;;
DAPK-INTERACTING PROTEIN 1; DIP1;;
read moreKIAA1323
*FIELD* TX
DESCRIPTION
Notch (see NOTCH1; 190198) signaling is a widely used cell-cell
signaling pathway that plays a critical role in cell fate determination
of various lineages. Notch activation requires the endocytosis of Notch
ligands in the signal-sending cells. MIB1 is an E3 ubiquitin ligases
that regulates endocytosis of Notch ligands (summary by Song et al.,
2008).
CLONING
By sequencing clones obtained from a size-fractionated fetal brain cDNA
library, Nagase et al. (2000) cloned DIP1, which they designated
KIAA1323. The DIP1 transcript contains a 3-prime repeat sequence. RT-PCR
ELISA detected moderate to high DIP1 expression in all tissues examined,
with highest levels in spinal cord, ovary, whole brain, and all specific
brain regions examined.
Jin et al. (2002) cloned mouse Dip1 from a bladder cDNA library. The
deduced 1,006-amino acid protein contains a zinc finger, 9 ankyrin
repeats, 3 RING fingers, and an alpha-helical coiled-coil region between
RING2 and RING3. Northern blot analysis detected a 4.0-kb transcript in
all mouse tissues analyzed. Western blot analysis detected Dip1 at an
apparent molecular mass of about 110 kD in all mouse tissue lysates
examined.
MAPPING
By radiation hybrid analysis, Nagase et al. (2000) mapped the DIP1 gene
to chromosome 18.
Gross (2012) mapped the MIB1 gene to chromosome 18q11.2 based on an
alignment of the MIB1 sequence (GenBank GENBANK BC022403) with the
genomic sequence (GRCh37).
GENE FUNCTION
Jin et al. (2002) found that Dip1 immunoprecipitated with Dapk (600831)
from COS cell lysates; Dip1 interacted with the ankyrin repeats in Dapk.
HeLa cells transiently expressing mouse Dip1 or only the Dip1 RING
finger motifs showed DNA fragmentation characteristic of apoptotic
changes. Overexpression of Dip1 abolished the antiapoptotic effect of
Dapk expression. Dip1 regulated the cellular levels of Dapk through its
E3 ubiquitin ligase activity, which promoted ubiquitination of Dapk in
vitro and in vivo.
In hippocampal tissue from 10 patients with intractable temporal lobe
epilepsy (608096), Henshall et al. (2004) found increased DAPK
expression and phosphorylation compared with controls. In control
brains, DAPK and DIP1 localized within mitochondria, whereas in epilepsy
brain tissue, levels of both were increased in cytoplasmic and
microsomal fractions (endoplasmic reticulum). Coimmunoprecipitation
analysis showed increased DAPK binding to calmodulin (114180), DIP1, and
FADD (602457) in neurons of epilepsy brain tissue compared with
controls. Henshall et al. (2004) suggested that DAPK is a molecular
regulator of neuronal death in epilepsy.
MOLECULAR GENETICS
In 2 Spanish families segregating autosomal dominant left ventricular
noncompaction (LVNC7; 615092), Luxan et al. (2013) identified
heterozygosity for a missense (V943F; 608677.0001) and a nonsense
(R530X; 608677.0002) mutation in the MIB1 gene, respectively, that
segregated fully with disease in each family. Analysis of peripheral
blood samples from affected individuals showed reduced NOTCH1 (190198)
activity and reduced expression of target genes. Functional studies in
cells and zebrafish embryos as well as in silico modeling indicated that
MIB1 functions as a dimer, which is disrupted by the mutations.
ANIMAL MODEL
Barsi et al. (2005) found that homozygous Mib1 deletion in mice resulted
in lethality by embryonic day 10.5 due to severely reduced Notch
signaling. Premature neurons underwent apoptosis soon after
differentiation. Aberrant neurogenesis was a direct consequence of
lowered Hes1 (139605) and Hes5 (607348) expression resulting from the
inability to cleave Notch1 at S3 in order to generate Notch1
intracellular domain. Barsi et al. (2005) concluded that MIB1 is
required for S3 cleavage of the Notch1 receptor.
By inactivating Mib1, but not the E3 ubiquitin ligases Mib2 (611141),
Neur1 (NEURL; 603804), and Neur2 (NEURL2; 608597), Song et al. (2008)
demonstrated that Mib1 regulates T- and marginal zone B (MZB)-cell cell
development in mouse thymus and spleen. Reconstitution of Mib1-deficient
mice with wildtype bone marrow cells revealed that Mib1 regulates T and
MZB development in signaling cells in thymic and splenic
microenvironments. Dll1 (606582) was not endocytosed and instead
accumulated in Mib1-deficient thymic niches. Song et al. (2008)
concluded that MIB1 is an essential E3 ubiquitin ligase for NOTCH
signaling in T- and MZB-cell development in thymic and splenic
microenvironments.
Luxan et al. (2013) generated mice with a conditional Mib1
loss-of-function allele and observed at embryonic day 16.5 that the
mutant mice had a dilated heart with a thin compact myocardium and large
noncompacted trabeculae protruding toward the ventricular lumen;
similarly, newborn mice had large trabeculae in the left and right
ventricles and a thin compact myocardium, and these features persisted
into adulthood. Echocardiography in adult mice revealed prominent
trabeculations and deep intertrabecular recesses in the mutants, with a
noncompacted to compacted myocardium ratio of 2.0; the LVNC phenotype
was confirmed by high-resolution cardiac MRI. Endocardial Notch1
intracellular domain expression was severely reduced, indicating that
Mib1 inactivation in the myocardium affects endocardial Notch1 signaling
activity. Coronary artery development also seemed to be defective in the
mutant mice, as indicated by lost or reduced expression of Hey1
(602953), Hey2 (604674), and Efnb2 (600527) in the vessels of the
compact myocardium.
Using a conditional knockout strategy, Kang et al. (2013) found that
Mib1 had a role in neurogenesis and gliogenesis in developing mouse
spinal cord. Misexpression of Mib1 or expression of a RING domain
deletion mutant of Mib1 in ovo revealed that Mib1 was required for
specification of V2 interneurons in the chicken neural tube.
*FIELD* AV
.0001
LEFT VENTRICULAR NONCOMPACTION 7
MIB1, VAL943PHE
In 6 affected members over 3 generations of a Spanish family with left
ventricular noncompaction (LVNC7; 615092), Luxan et al. (2013)
identified heterozygosity for a 2827G-T transversion in exon 20 of the
MIB1 gene, resulting in a val943-to-phe substitution at a highly
conserved residue within a coiled-coil region separating the 3 RING
finger domains. The mutation was not found in unaffected family members,
in 263 Spanish controls, or in the 1000 Genomes database. However, the
V943F mutation was present in 3 of 5,375 individuals in the National
Heart, Lung, and Blood Institute Grand Opportunity Exome Sequencing
Project database, suggesting that MIB1 mutations may be frequent in
populations with heart, lung, or blood diseases. Western blot analysis
of peripheral blood from the female proband's affected father revealed
an approximately 8% reduction in MIB1 expression compared to control
samples.
.0002
LEFT VENTRICULAR NONCOMPACTION 7
MIB1, ARG530TER
In 6 affected members over 2 generations of a Spanish family with left
ventricular noncompaction (LVNC7; 615092), Luxan et al. (2013)
identified heterozygosity for a 1587C-T transition in exon 11 of the
MIB1 gene, resulting in an arg530-to-ter (R530X) substitution in the
ankyrin repeats region. The mutation was not found in unaffected family
members, in 263 Spanish controls, or in the 1000 Genomes database.
Western blot analysis of peripheral blood from the male proband's
affected father revealed an approximately 20% reduction in MIB1
expression compared to control samples. Analysis by qPCR showed no
amplification of R530X, suggesting that the mutant mRNA is degraded by
nonsense mediated decay.
*FIELD* RF
1. Barsi, J. C.; Rajendra, R.; Wu, J. I.; Artzt, K.: Mind bomb1 is
a ubiquitin ligase essential for mouse embryonic development and Notch
signaling. Mech. Dev. 122: 1106-1117, 2005.
2. Gross, M. B.: Personal Communication. Baltimore, Md. 7/20/2012.
3. Henshall, D. C.; Schindler, C. K.; So, N. K.; Lan, J.-Q.; Meller,
R.; Simon, R. P.: Death-associated protein kinase expression in human
temporal lobe epilepsy. Ann. Neurol. 55: 485-494, 2004.
4. Jin, Y.; Blue, E. K.; Dixon, S.; Shao, Z.; Gallagher, P. J.: A
death-associated protein kinase (DAPK)-interacting protein, DIP-1,
is an E3 ubiquitin ligase that promotes tumor necrosis factor-induced
apoptosis and regulates the cellular levels of DAPK. J. Biol. Chem. 277:
46980-46986, 2002.
5. Kang, K.; Lee, D.; Hong, S.; Park, S.-G.; Song, M.-R.: The E3
ligase mind bomb-1 (Mib1) modulates delta-notch signaling to control
neurogenesis and gliogenesis in the developing spinal cord. J. Biol.
Chem. 288: 2580-2592, 2013.
6. Luxan, G.; Casanova, J. C.; Martinez-Poveda, B.; Prados, B.; D'Amato,
G.; MacGrogan, D.; Gonzalez-Rajal, A.; Dobarro, D.; Torroja, C.; Martinez,
F.; Izquierdo-Garcia, J. L.; Fernandez-Friera, L.; and 10 others
: Mutations in the NOTCH pathway regulator MIB1 cause left ventricular
noncompaction cardiomyopathy. Nature Med. 19: 193-201, 2013.
7. Nagase, T.; Kikuno, R.; Ishikawa, K.; Hirosawa, M.; Ohara, O.:
Prediction of the coding sequences of unidentified human genes. XVI.
The complete sequences of 150 new cDNA clones from brain which code
for large proteins in vitro. DNA Res. 7: 65-73, 2000.
8. Song, R.; Kim, Y.-W.; Koo, B.-K.; Jeong, H.-W.; Yoon, M.-J.; Yoon,
K.-J.; Jun, D.-J.; Im, S.-K.; Shin, J.; Kong, M.-P.; Kim, K.-T.; Yoon,
K.; Kong, Y.-Y.: Mind bomb 1 in the lymphopoietic niches is essential
for T and marginal zone B cell development. J. Exp. Med. 205: 2525-2536,
2008.
*FIELD* CN
Patricia A. Hartz - updated: 11/5/2013
Marla J. F. O'Neill - updated: 2/22/2013
Matthew B. Gross - updated: 7/20/2012
Paul J. Converse - updated: 7/16/2012
Patricia A. Hartz - updated: 12/16/2005
Cassandra L. Kniffin - updated: 6/1/2004
*FIELD* CD
Patricia A. Hartz: 5/21/2004
*FIELD* ED
mgross: 11/06/2013
mcolton: 11/5/2013
carol: 2/22/2013
mgross: 7/20/2012
terry: 7/16/2012
wwang: 12/16/2005
alopez: 7/19/2005
ckniffin: 6/1/2004
mgross: 5/21/2004
*RECORD*
*FIELD* NO
608677
*FIELD* TI
*608677 MINDBOMB, DROSOPHILA, HOMOLOG OF, 1; MIB1
;;MIB;;
DAPK-INTERACTING PROTEIN 1; DIP1;;
read moreKIAA1323
*FIELD* TX
DESCRIPTION
Notch (see NOTCH1; 190198) signaling is a widely used cell-cell
signaling pathway that plays a critical role in cell fate determination
of various lineages. Notch activation requires the endocytosis of Notch
ligands in the signal-sending cells. MIB1 is an E3 ubiquitin ligases
that regulates endocytosis of Notch ligands (summary by Song et al.,
2008).
CLONING
By sequencing clones obtained from a size-fractionated fetal brain cDNA
library, Nagase et al. (2000) cloned DIP1, which they designated
KIAA1323. The DIP1 transcript contains a 3-prime repeat sequence. RT-PCR
ELISA detected moderate to high DIP1 expression in all tissues examined,
with highest levels in spinal cord, ovary, whole brain, and all specific
brain regions examined.
Jin et al. (2002) cloned mouse Dip1 from a bladder cDNA library. The
deduced 1,006-amino acid protein contains a zinc finger, 9 ankyrin
repeats, 3 RING fingers, and an alpha-helical coiled-coil region between
RING2 and RING3. Northern blot analysis detected a 4.0-kb transcript in
all mouse tissues analyzed. Western blot analysis detected Dip1 at an
apparent molecular mass of about 110 kD in all mouse tissue lysates
examined.
MAPPING
By radiation hybrid analysis, Nagase et al. (2000) mapped the DIP1 gene
to chromosome 18.
Gross (2012) mapped the MIB1 gene to chromosome 18q11.2 based on an
alignment of the MIB1 sequence (GenBank GENBANK BC022403) with the
genomic sequence (GRCh37).
GENE FUNCTION
Jin et al. (2002) found that Dip1 immunoprecipitated with Dapk (600831)
from COS cell lysates; Dip1 interacted with the ankyrin repeats in Dapk.
HeLa cells transiently expressing mouse Dip1 or only the Dip1 RING
finger motifs showed DNA fragmentation characteristic of apoptotic
changes. Overexpression of Dip1 abolished the antiapoptotic effect of
Dapk expression. Dip1 regulated the cellular levels of Dapk through its
E3 ubiquitin ligase activity, which promoted ubiquitination of Dapk in
vitro and in vivo.
In hippocampal tissue from 10 patients with intractable temporal lobe
epilepsy (608096), Henshall et al. (2004) found increased DAPK
expression and phosphorylation compared with controls. In control
brains, DAPK and DIP1 localized within mitochondria, whereas in epilepsy
brain tissue, levels of both were increased in cytoplasmic and
microsomal fractions (endoplasmic reticulum). Coimmunoprecipitation
analysis showed increased DAPK binding to calmodulin (114180), DIP1, and
FADD (602457) in neurons of epilepsy brain tissue compared with
controls. Henshall et al. (2004) suggested that DAPK is a molecular
regulator of neuronal death in epilepsy.
MOLECULAR GENETICS
In 2 Spanish families segregating autosomal dominant left ventricular
noncompaction (LVNC7; 615092), Luxan et al. (2013) identified
heterozygosity for a missense (V943F; 608677.0001) and a nonsense
(R530X; 608677.0002) mutation in the MIB1 gene, respectively, that
segregated fully with disease in each family. Analysis of peripheral
blood samples from affected individuals showed reduced NOTCH1 (190198)
activity and reduced expression of target genes. Functional studies in
cells and zebrafish embryos as well as in silico modeling indicated that
MIB1 functions as a dimer, which is disrupted by the mutations.
ANIMAL MODEL
Barsi et al. (2005) found that homozygous Mib1 deletion in mice resulted
in lethality by embryonic day 10.5 due to severely reduced Notch
signaling. Premature neurons underwent apoptosis soon after
differentiation. Aberrant neurogenesis was a direct consequence of
lowered Hes1 (139605) and Hes5 (607348) expression resulting from the
inability to cleave Notch1 at S3 in order to generate Notch1
intracellular domain. Barsi et al. (2005) concluded that MIB1 is
required for S3 cleavage of the Notch1 receptor.
By inactivating Mib1, but not the E3 ubiquitin ligases Mib2 (611141),
Neur1 (NEURL; 603804), and Neur2 (NEURL2; 608597), Song et al. (2008)
demonstrated that Mib1 regulates T- and marginal zone B (MZB)-cell cell
development in mouse thymus and spleen. Reconstitution of Mib1-deficient
mice with wildtype bone marrow cells revealed that Mib1 regulates T and
MZB development in signaling cells in thymic and splenic
microenvironments. Dll1 (606582) was not endocytosed and instead
accumulated in Mib1-deficient thymic niches. Song et al. (2008)
concluded that MIB1 is an essential E3 ubiquitin ligase for NOTCH
signaling in T- and MZB-cell development in thymic and splenic
microenvironments.
Luxan et al. (2013) generated mice with a conditional Mib1
loss-of-function allele and observed at embryonic day 16.5 that the
mutant mice had a dilated heart with a thin compact myocardium and large
noncompacted trabeculae protruding toward the ventricular lumen;
similarly, newborn mice had large trabeculae in the left and right
ventricles and a thin compact myocardium, and these features persisted
into adulthood. Echocardiography in adult mice revealed prominent
trabeculations and deep intertrabecular recesses in the mutants, with a
noncompacted to compacted myocardium ratio of 2.0; the LVNC phenotype
was confirmed by high-resolution cardiac MRI. Endocardial Notch1
intracellular domain expression was severely reduced, indicating that
Mib1 inactivation in the myocardium affects endocardial Notch1 signaling
activity. Coronary artery development also seemed to be defective in the
mutant mice, as indicated by lost or reduced expression of Hey1
(602953), Hey2 (604674), and Efnb2 (600527) in the vessels of the
compact myocardium.
Using a conditional knockout strategy, Kang et al. (2013) found that
Mib1 had a role in neurogenesis and gliogenesis in developing mouse
spinal cord. Misexpression of Mib1 or expression of a RING domain
deletion mutant of Mib1 in ovo revealed that Mib1 was required for
specification of V2 interneurons in the chicken neural tube.
*FIELD* AV
.0001
LEFT VENTRICULAR NONCOMPACTION 7
MIB1, VAL943PHE
In 6 affected members over 3 generations of a Spanish family with left
ventricular noncompaction (LVNC7; 615092), Luxan et al. (2013)
identified heterozygosity for a 2827G-T transversion in exon 20 of the
MIB1 gene, resulting in a val943-to-phe substitution at a highly
conserved residue within a coiled-coil region separating the 3 RING
finger domains. The mutation was not found in unaffected family members,
in 263 Spanish controls, or in the 1000 Genomes database. However, the
V943F mutation was present in 3 of 5,375 individuals in the National
Heart, Lung, and Blood Institute Grand Opportunity Exome Sequencing
Project database, suggesting that MIB1 mutations may be frequent in
populations with heart, lung, or blood diseases. Western blot analysis
of peripheral blood from the female proband's affected father revealed
an approximately 8% reduction in MIB1 expression compared to control
samples.
.0002
LEFT VENTRICULAR NONCOMPACTION 7
MIB1, ARG530TER
In 6 affected members over 2 generations of a Spanish family with left
ventricular noncompaction (LVNC7; 615092), Luxan et al. (2013)
identified heterozygosity for a 1587C-T transition in exon 11 of the
MIB1 gene, resulting in an arg530-to-ter (R530X) substitution in the
ankyrin repeats region. The mutation was not found in unaffected family
members, in 263 Spanish controls, or in the 1000 Genomes database.
Western blot analysis of peripheral blood from the male proband's
affected father revealed an approximately 20% reduction in MIB1
expression compared to control samples. Analysis by qPCR showed no
amplification of R530X, suggesting that the mutant mRNA is degraded by
nonsense mediated decay.
*FIELD* RF
1. Barsi, J. C.; Rajendra, R.; Wu, J. I.; Artzt, K.: Mind bomb1 is
a ubiquitin ligase essential for mouse embryonic development and Notch
signaling. Mech. Dev. 122: 1106-1117, 2005.
2. Gross, M. B.: Personal Communication. Baltimore, Md. 7/20/2012.
3. Henshall, D. C.; Schindler, C. K.; So, N. K.; Lan, J.-Q.; Meller,
R.; Simon, R. P.: Death-associated protein kinase expression in human
temporal lobe epilepsy. Ann. Neurol. 55: 485-494, 2004.
4. Jin, Y.; Blue, E. K.; Dixon, S.; Shao, Z.; Gallagher, P. J.: A
death-associated protein kinase (DAPK)-interacting protein, DIP-1,
is an E3 ubiquitin ligase that promotes tumor necrosis factor-induced
apoptosis and regulates the cellular levels of DAPK. J. Biol. Chem. 277:
46980-46986, 2002.
5. Kang, K.; Lee, D.; Hong, S.; Park, S.-G.; Song, M.-R.: The E3
ligase mind bomb-1 (Mib1) modulates delta-notch signaling to control
neurogenesis and gliogenesis in the developing spinal cord. J. Biol.
Chem. 288: 2580-2592, 2013.
6. Luxan, G.; Casanova, J. C.; Martinez-Poveda, B.; Prados, B.; D'Amato,
G.; MacGrogan, D.; Gonzalez-Rajal, A.; Dobarro, D.; Torroja, C.; Martinez,
F.; Izquierdo-Garcia, J. L.; Fernandez-Friera, L.; and 10 others
: Mutations in the NOTCH pathway regulator MIB1 cause left ventricular
noncompaction cardiomyopathy. Nature Med. 19: 193-201, 2013.
7. Nagase, T.; Kikuno, R.; Ishikawa, K.; Hirosawa, M.; Ohara, O.:
Prediction of the coding sequences of unidentified human genes. XVI.
The complete sequences of 150 new cDNA clones from brain which code
for large proteins in vitro. DNA Res. 7: 65-73, 2000.
8. Song, R.; Kim, Y.-W.; Koo, B.-K.; Jeong, H.-W.; Yoon, M.-J.; Yoon,
K.-J.; Jun, D.-J.; Im, S.-K.; Shin, J.; Kong, M.-P.; Kim, K.-T.; Yoon,
K.; Kong, Y.-Y.: Mind bomb 1 in the lymphopoietic niches is essential
for T and marginal zone B cell development. J. Exp. Med. 205: 2525-2536,
2008.
*FIELD* CN
Patricia A. Hartz - updated: 11/5/2013
Marla J. F. O'Neill - updated: 2/22/2013
Matthew B. Gross - updated: 7/20/2012
Paul J. Converse - updated: 7/16/2012
Patricia A. Hartz - updated: 12/16/2005
Cassandra L. Kniffin - updated: 6/1/2004
*FIELD* CD
Patricia A. Hartz: 5/21/2004
*FIELD* ED
mgross: 11/06/2013
mcolton: 11/5/2013
carol: 2/22/2013
mgross: 7/20/2012
terry: 7/16/2012
wwang: 12/16/2005
alopez: 7/19/2005
ckniffin: 6/1/2004
mgross: 5/21/2004
MIM
615092
*RECORD*
*FIELD* NO
615092
*FIELD* TI
#615092 LEFT VENTRICULAR NONCOMPACTION 7; LVNC7
*FIELD* TX
A number sign (#) is used with this entry because of evidence that left
read moreventricular noncompaction-7 (LVNC7) is caused by heterozygous mutation
in the MIB1 gene (608677) on chromosome 18q11.
For a general phenotypic description and a discussion of genetic
heterogeneity of LVNC, see 604169.
MOLECULAR GENETICS
Luxan et al. (2013) analyzed the MIB1 gene in 100 Spanish probands of
southern European ancestry with left ventricular noncompaction and in 2
probands identified heterozygosity for a missense (V943F; 608677.0001)
and a nonsense (R530X; 608677.0002) mutation, respectively. Each
mutation segregated fully with disease in the respective family and
neither was found in 263 Spanish controls or in the 1000 Genomes
database. However, the V943F mutation was present in 3 of 5,375
individuals in the National Heart, Lung, and Blood Institute Grand
Opportunity Exome Sequencing Project database, suggesting that MIB1
mutations may be frequent in populations with heart, lung, or blood
diseases. Analysis of 12 additional candidate genes implicated in LVNC
revealed no other mutations in either proband.
ANIMAL MODEL
Luxan et al. (2013) generated mice with a conditional Mib1
loss-of-function allele and observed at embryonic day 16.5 that the
mutant mice had a dilated heart with a thin compact myocardium and large
noncompacted trabeculae protruding toward the ventricular lumen;
similarly, newborn mice had large trabeculae in the left and right
ventricles and a thin compact myocardium, and these features persisted
into adulthood. Echocardiography in adult mice revealed prominent
trabeculations and deep intertrabecular recesses in the mutants, with a
noncompacted to compacted myocardium ratio of 2.0; the LVNC phenotype
was confirmed by high-resolution cardiac MRI.
*FIELD* RF
1. Luxan, G.; Casanova, J. C.; Martinez-Poveda, B.; Prados, B.; D'Amato,
G.; MacGrogan, D.; Gonzalez-Rajal, A.; Dobarro, D.; Torroja, C.; Martinez,
F.; Izquierdo-Garcia, J. L.; Fernandez-Friera, L.; and 10 others
: Mutations in the NOTCH pathway regulator MIB1 cause left ventricular
noncompaction cardiomyopathy. Nature Med. 19: 193-201, 2013.
*FIELD* CS
INHERITANCE:
Autosomal dominant
CARDIOVASCULAR:
[Heart];
Left ventricular noncompaction;
Prominent trabeculations
MISCELLANEOUS:
MOLECULAR BASIS:
Caused by mutation in the homolog of Drosophila mindbomb-1 gene (MIB1,
608677.0001)
*FIELD* CD
Marla J. F. O'Neill: 3/1/2013
*FIELD* ED
joanna: 03/01/2013
*FIELD* CD
Marla J. F. O'Neill: 2/22/2013
*FIELD* ED
carol: 02/22/2013
*RECORD*
*FIELD* NO
615092
*FIELD* TI
#615092 LEFT VENTRICULAR NONCOMPACTION 7; LVNC7
*FIELD* TX
A number sign (#) is used with this entry because of evidence that left
read moreventricular noncompaction-7 (LVNC7) is caused by heterozygous mutation
in the MIB1 gene (608677) on chromosome 18q11.
For a general phenotypic description and a discussion of genetic
heterogeneity of LVNC, see 604169.
MOLECULAR GENETICS
Luxan et al. (2013) analyzed the MIB1 gene in 100 Spanish probands of
southern European ancestry with left ventricular noncompaction and in 2
probands identified heterozygosity for a missense (V943F; 608677.0001)
and a nonsense (R530X; 608677.0002) mutation, respectively. Each
mutation segregated fully with disease in the respective family and
neither was found in 263 Spanish controls or in the 1000 Genomes
database. However, the V943F mutation was present in 3 of 5,375
individuals in the National Heart, Lung, and Blood Institute Grand
Opportunity Exome Sequencing Project database, suggesting that MIB1
mutations may be frequent in populations with heart, lung, or blood
diseases. Analysis of 12 additional candidate genes implicated in LVNC
revealed no other mutations in either proband.
ANIMAL MODEL
Luxan et al. (2013) generated mice with a conditional Mib1
loss-of-function allele and observed at embryonic day 16.5 that the
mutant mice had a dilated heart with a thin compact myocardium and large
noncompacted trabeculae protruding toward the ventricular lumen;
similarly, newborn mice had large trabeculae in the left and right
ventricles and a thin compact myocardium, and these features persisted
into adulthood. Echocardiography in adult mice revealed prominent
trabeculations and deep intertrabecular recesses in the mutants, with a
noncompacted to compacted myocardium ratio of 2.0; the LVNC phenotype
was confirmed by high-resolution cardiac MRI.
*FIELD* RF
1. Luxan, G.; Casanova, J. C.; Martinez-Poveda, B.; Prados, B.; D'Amato,
G.; MacGrogan, D.; Gonzalez-Rajal, A.; Dobarro, D.; Torroja, C.; Martinez,
F.; Izquierdo-Garcia, J. L.; Fernandez-Friera, L.; and 10 others
: Mutations in the NOTCH pathway regulator MIB1 cause left ventricular
noncompaction cardiomyopathy. Nature Med. 19: 193-201, 2013.
*FIELD* CS
INHERITANCE:
Autosomal dominant
CARDIOVASCULAR:
[Heart];
Left ventricular noncompaction;
Prominent trabeculations
MISCELLANEOUS:
MOLECULAR BASIS:
Caused by mutation in the homolog of Drosophila mindbomb-1 gene (MIB1,
608677.0001)
*FIELD* CD
Marla J. F. O'Neill: 3/1/2013
*FIELD* ED
joanna: 03/01/2013
*FIELD* CD
Marla J. F. O'Neill: 2/22/2013
*FIELD* ED
carol: 02/22/2013