Full text data of UBR1
UBR1
[Confidence: low (only semi-automatic identification from reviews)]
E3 ubiquitin-protein ligase UBR1; 6.3.2.- (N-recognin-1; Ubiquitin-protein ligase E3-alpha-1; Ubiquitin-protein ligase E3-alpha-I)
E3 ubiquitin-protein ligase UBR1; 6.3.2.- (N-recognin-1; Ubiquitin-protein ligase E3-alpha-1; Ubiquitin-protein ligase E3-alpha-I)
UniProt
Q8IWV7
ID UBR1_HUMAN Reviewed; 1749 AA.
AC Q8IWV7; O60708; O75492; Q14D45; Q68DN9; Q8IWY6; Q96JY4;
DT 16-AUG-2005, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-MAR-2003, sequence version 1.
DT 22-JAN-2014, entry version 95.
DE RecName: Full=E3 ubiquitin-protein ligase UBR1;
DE EC=6.3.2.-;
DE AltName: Full=N-recognin-1;
DE AltName: Full=Ubiquitin-protein ligase E3-alpha-1;
DE AltName: Full=Ubiquitin-protein ligase E3-alpha-I;
GN Name=UBR1;
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] (ISOFORM 1), TISSUE SPECIFICITY, AND
RP FUNCTION.
RX PubMed=15548684; DOI=10.1158/0008-5472.CAN-04-2102;
RA Kwak K.S., Zhou X., Solomon V., Baracos V.E., Davis J., Bannon A.W.,
RA Boyle W.J., Lacey D.L., Han H.Q.;
RT "Regulation of protein catabolism by muscle-specific and cytokine-
RT inducible ubiquitin ligase E3alpha-II during cancer cachexia.";
RL Cancer Res. 64:8193-8198(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
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 [3]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 18-1727 (ISOFORM 1).
RC TISSUE=Erythroid cell;
RX PubMed=12434312; DOI=10.1086/344781;
RA Dgany O., Avidan N., Delaunay J., Krasnov T., Shalmon L., Shalev H.,
RA Eidelitz-Markus T., Kapelushnik J., Cattan D., Pariente A.,
RA Tulliez M., Cretien A., Schischmanoff P.-O., Iolascon A., Fibach E.,
RA Koren A., Roessler J., Le Merrer M., Yaniv I., Zaizov R.,
RA Ben-Asher E., Olender T., Lancet D., Beckmann J.S., Tamary H.;
RT "Congenital dyserythropoietic anemia type I is caused by mutations in
RT codanin-1.";
RL Am. J. Hum. Genet. 71:1467-1474(2002).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 166-1014 (ISOFORM 1).
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 656-1749 (ISOFORM 2).
RC TISSUE=Heart;
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 [GENOMIC DNA / MRNA] OF 702-1034 (ISOFORM 1), AND
RP TISSUE SPECIFICITY.
RX PubMed=9653112; DOI=10.1073/pnas.95.14.7898;
RA Kwon Y.T., Reiss Y., Fried V.A., Hershko A., Yoon J.K., Gonda D.K.,
RA Sangan P., Copeland N.G., Jenkins N.A., Varshavsky A.;
RT "The mouse and human genes encoding the recognition component of the
RT N-end rule pathway.";
RL Proc. Natl. Acad. Sci. U.S.A. 95:7898-7903(1998).
RN [7]
RP INTERACTION WITH RECQL4, AND IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=15317757; DOI=10.1093/hmg/ddh269;
RA Yin J., Kwon Y.T., Varshavsky A., Wang W.;
RT "RECQL4, mutated in the Rothmund-Thomson and RAPADILINO syndromes,
RT interacts with ubiquitin ligases UBR1 and UBR2 of the N-end rule
RT pathway.";
RL Hum. Mol. Genet. 13:2421-2430(2004).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1179, AND MASS
RP SPECTROMETRY.
RC TISSUE=Embryonic kidney;
RX PubMed=17525332; DOI=10.1126/science.1140321;
RA Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III,
RA Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N.,
RA Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J.;
RT "ATM and ATR substrate analysis reveals extensive protein networks
RT responsive to DNA damage.";
RL Science 316:1160-1166(2007).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-21, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [10]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, PHOSPHORYLATION [LARGE
RP SCALE ANALYSIS] AT THR-21, MASS SPECTROMETRY, AND CLEAVAGE OF
RP INITIATOR METHIONINE.
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-21, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [12]
RP FUNCTION.
RX PubMed=20298436; DOI=10.1111/j.1365-2443.2010.01385.x;
RA Kume K., Iizumi Y., Shimada M., Ito Y., Kishi T., Yamaguchi Y.,
RA Handa H.;
RT "Role of N-end rule ubiquitin ligases UBR1 and UBR2 in regulating the
RT leucine-mTOR signaling pathway.";
RL Genes Cells 15:339-349(2010).
RN [13]
RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 98-167 ALONE AND IN COMPLEX
RP WITH N-END RULE PEPTIDE, UBR-TYPE ZINC FINGER, FUNCTION, AND VARIANT
RP JB5 ARG-136.
RX PubMed=20835242; DOI=10.1038/nsmb.1894;
RA Matta-Camacho E., Kozlov G., Li F.F., Gehring K.;
RT "Structural basis of substrate recognition and specificity in the N-
RT end rule pathway.";
RL Nat. Struct. Mol. Biol. 17:1182-1187(2010).
RN [14]
RP VARIANTS JBS ARG-136 AND SER-1279, FUNCTION, DISEASE, TISSUE
RP SPECIFICITY, SUBCELLULAR LOCATION, AND DEVELOPMENTAL STAGE.
RX PubMed=16311597; DOI=10.1038/ng1681;
RA Zenker M., Mayerle J., Lerch M.M., Tagariello A., Zerres K.,
RA Durie P.R., Beier M., Hulskamp G., Guzman C., Rehder H., Beemer F.A.,
RA Hamel B.C.J., Vanlieferinghen P., Gershoni-Baruch R., Vieira M.W.,
RA Dumic M., Auslender R., Gil-da-Silva-Lopes V.L., Steinlicht S.,
RA Rauh M., Shalev S.A., Thiel C., Winterpacht A., Kwon Y.T.,
RA Varshavsky A., Reis A.;
RT "Deficiency of UBR1, a ubiquitin ligase of the N-end rule pathway,
RT causes pancreatic dysfunction, malformations and mental retardation
RT (Johanson-Blizzard syndrome).";
RL Nat. Genet. 37:1345-1350(2005).
CC -!- FUNCTION: E3 ubiquitin-protein ligase which is a component of the
CC N-end rule pathway. Recognizes and binds to proteins bearing
CC specific N-terminal residues that are destabilizing according to
CC the N-end rule, leading to their ubiquitination and subsequent
CC degradation. May be involved in pancreatic homeostasis. Binds
CC leucine and is a negative regulator of the leucine-mTOR signaling
CC pathway, thereby controlling cell growth.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Interacts with RECQL4.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q8IWV7-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8IWV7-2; Sequence=VSP_015164, VSP_015165;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Broadly expressed, with highest levels in
CC skeletal muscle, kidney and pancreas. Present in acinar cells of
CC the pancreas (at protein level).
CC -!- DEVELOPMENTAL STAGE: Expressed in fetal pancreas.
CC -!- DOMAIN: The RING-H2 zinc finger is an atypical RING finger with a
CC His ligand in place of the fourth Cys of the classical motif.
CC -!- DOMAIN: The UBR-type zinc finger forms a pocket that mediates
CC recognition of type 1 N-degrons. It exhibits preference for
CC Arginine in first position, has poor affinity for histidine, and
CC doesn't bind acetylated peptides.
CC -!- DISEASE: Johanson-Blizzard syndrome (JBS) [MIM:243800]: This
CC disorder includes congenital exocrine pancreatic insufficiency,
CC multiple malformations such as nasal wing aplasia, and frequent
CC mental retardation. Pancreas of individuals with JBS do not
CC express UBR1 and show intrauterine-onset destructive pancreatitis.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the UBR1 family.
CC -!- SIMILARITY: Contains 1 RING-type zinc finger.
CC -!- SIMILARITY: Contains 1 UBR-type zinc finger.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAB55380.1; Type=Erroneous initiation;
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DR EMBL; AY061886; AAL32103.1; -; mRNA.
DR EMBL; BC113505; AAI13506.1; -; mRNA.
DR EMBL; BC113507; AAI13508.1; -; mRNA.
DR EMBL; AF525401; AAO14997.1; -; mRNA.
DR EMBL; AK027803; BAB55380.1; ALT_INIT; mRNA.
DR EMBL; CR749326; CAH18181.1; -; mRNA.
DR EMBL; AF061556; AAC39845.1; -; mRNA.
DR EMBL; AH006181; AAC23677.1; -; Genomic_DNA.
DR RefSeq; NP_777576.1; NM_174916.2.
DR UniGene; Hs.591121; -.
DR PDB; 3NY1; X-ray; 2.08 A; A/B=97-168.
DR PDBsum; 3NY1; -.
DR ProteinModelPortal; Q8IWV7; -.
DR SMR; Q8IWV7; 97-167.
DR DIP; DIP-47033N; -.
DR IntAct; Q8IWV7; 29.
DR MINT; MINT-1417571; -.
DR STRING; 9606.ENSP00000290650; -.
DR PhosphoSite; Q8IWV7; -.
DR DMDM; 73622071; -.
DR PaxDb; Q8IWV7; -.
DR PRIDE; Q8IWV7; -.
DR Ensembl; ENST00000290650; ENSP00000290650; ENSG00000159459.
DR Ensembl; ENST00000382177; ENSP00000371612; ENSG00000159459.
DR Ensembl; ENST00000569066; ENSP00000456327; ENSG00000159459.
DR GeneID; 197131; -.
DR KEGG; hsa:197131; -.
DR UCSC; uc001zqq.3; human.
DR CTD; 197131; -.
DR GeneCards; GC15M043235; -.
DR HGNC; HGNC:16808; UBR1.
DR HPA; HPA038838; -.
DR MIM; 243800; phenotype.
DR MIM; 605981; gene.
DR neXtProt; NX_Q8IWV7; -.
DR Orphanet; 2315; Johanson-Blizzard syndrome.
DR PharmGKB; PA38187; -.
DR eggNOG; NOG310244; -.
DR HOVERGEN; HBG080426; -.
DR InParanoid; Q8IWV7; -.
DR KO; K10625; -.
DR OMA; PDEMDPR; -.
DR OrthoDB; EOG7RNJZB; -.
DR PhylomeDB; Q8IWV7; -.
DR Reactome; REACT_6900; Immune System.
DR UniPathway; UPA00143; -.
DR EvolutionaryTrace; Q8IWV7; -.
DR GeneWiki; UBR1; -.
DR GenomeRNAi; 197131; -.
DR NextBio; 89608; -.
DR PRO; PR:Q8IWV7; -.
DR ArrayExpress; Q8IWV7; -.
DR Bgee; Q8IWV7; -.
DR CleanEx; HS_UBR1; -.
DR Genevestigator; Q8IWV7; -.
DR GO; GO:0005829; C:cytosol; IEA:UniProtKB-SubCell.
DR GO; GO:0000502; C:proteasome complex; IEA:Ensembl.
DR GO; GO:0000151; C:ubiquitin ligase complex; IEA:Ensembl.
DR GO; GO:0070728; F:leucine binding; IDA:UniProtKB.
DR GO; GO:0004842; F:ubiquitin-protein ligase activity; IEA:Ensembl.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0071233; P:cellular response to leucine; IDA:UniProtKB.
DR GO; GO:0032007; P:negative regulation of TOR signaling cascade; IMP:UniProtKB.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IEA:Ensembl.
DR Gene3D; 3.30.1390.10; -; 1.
DR Gene3D; 3.30.40.10; -; 2.
DR InterPro; IPR003769; ClpS_core.
DR InterPro; IPR014719; Ribosomal_L7/12_C/ClpS-like.
DR InterPro; IPR003126; Znf_N-recognin.
DR InterPro; IPR013993; Znf_N-recognin_met.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR Pfam; PF02617; ClpS; 1.
DR Pfam; PF02207; zf-UBR; 1.
DR SMART; SM00396; ZnF_UBR1; 1.
DR SUPFAM; SSF54736; SSF54736; 1.
DR PROSITE; PS00518; ZF_RING_1; FALSE_NEG.
DR PROSITE; PS50089; ZF_RING_2; FALSE_NEG.
DR PROSITE; PS51157; ZF_UBR; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Complete proteome;
KW Cytoplasm; Disease mutation; Ligase; Metal-binding; Phosphoprotein;
KW Polymorphism; Reference proteome; Ubl conjugation pathway; Zinc;
KW Zinc-finger.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 1749 E3 ubiquitin-protein ligase UBR1.
FT /FTId=PRO_0000056136.
FT ZN_FING 97 168 UBR-type.
FT ZN_FING 1098 1201 RING-type; atypical.
FT COMPBIAS 864 869 Poly-Pro.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 21 21 Phosphothreonine.
FT MOD_RES 1179 1179 Phosphoserine.
FT VAR_SEQ 795 803 NNETGLENV -> TRCIRPWSL (in isoform 2).
FT /FTId=VSP_015164.
FT VAR_SEQ 804 1749 Missing (in isoform 2).
FT /FTId=VSP_015165.
FT VARIANT 136 136 H -> R (in JBS; prevents proper folding
FT of the UBR-type zinc finger).
FT /FTId=VAR_024741.
FT VARIANT 596 596 K -> M (in dbSNP:rs34568456).
FT /FTId=VAR_034467.
FT VARIANT 899 899 I -> V (in dbSNP:rs35069201).
FT /FTId=VAR_052116.
FT VARIANT 1279 1279 G -> S (in JBS).
FT /FTId=VAR_024742.
FT VARIANT 1548 1548 T -> A (in dbSNP:rs3917223).
FT /FTId=VAR_061822.
FT CONFLICT 201 201 V -> A (in Ref. 4).
FT CONFLICT 900 900 D -> N (in Ref. 6; AAC39845).
FT CONFLICT 973 973 D -> T (in Ref. 3; AAO14997).
FT CONFLICT 993 993 C -> S (in Ref. 6; AAC23677).
FT CONFLICT 1710 1719 LSRERYRKLH -> FLVSGTEAP (in Ref. 3).
FT CONFLICT 1722 1722 W -> R (in Ref. 3).
FT STRAND 108 112
FT TURN 113 115
FT STRAND 116 118
FT HELIX 125 128
FT HELIX 132 135
FT STRAND 138 142
FT STRAND 156 159
FT TURN 164 166
SQ SEQUENCE 1749 AA; 200211 MW; 3AE0E1A749884971 CRC64;
MADEEAGGTE RMEISAELPQ TPQRLASWWD QQVDFYTAFL HHLAQLVPEI YFAEMDPDLE
KQEESVQMSI FTPLEWYLFG EDPDICLEKL KHSGAFQLCG RVFKSGETTY SCRDCAIDPT
CVLCMDCFQD SVHKNHRYKM HTSTGGGFCD CGDTEAWKTG PFCVNHEPGR AGTIKENSRC
PLNEEVIVQA RKIFPSVIKY VVEMTIWEEE KELPPELQIR EKNERYYCVL FNDEHHSYDH
VIYSLQRALD CELAEAQLHT TAIDKEGRRA VKAGAYAACQ EAKEDIKSHS ENVSQHPLHV
EVLHSEIMAH QKFALRLGSW MNKIMSYSSD FRQIFCQACL REEPDSENPC LISRLMLWDA
KLYKGARKIL HELIFSSFFM EMEYKKLFAM EFVKYYKQLQ KEYISDDHDR SISITALSVQ
MFTVPTLARH LIEEQNVISV ITETLLEVLP EYLDRNNKFN FQGYSQDKLG RVYAVICDLK
YILISKPTIW TERLRMQFLE GFRSFLKILT CMQGMEEIRR QVGQHIEVDP DWEAAIAIQM
QLKNILLMFQ EWCACDEELL LVAYKECHKA VMRCSTSFIS SSKTVVQSCG HSLETKSYRV
SEDLVSIHLP LSRTLAGLHV RLSRLGAVSR LHEFVSFEDF QVEVLVEYPL RCLVLVAQVV
AEMWRRNGLS LISQVFYYQD VKCREEMYDK DIIMLQIGAS LMDPNKFLLL VLQRYELAEA
FNKTISTKDQ DLIKQYNTLI EEMLQVLIYI VGERYVPGVG NVTKEEVTMR EIIHLLCIEP
MPHSAIAKNL PENENNETGL ENVINKVATF KKPGVSGHGV YELKDESLKD FNMYFYHYSK
TQHSKAEHMQ KKRRKQENKD EALPPPPPPE FCPAFSKVIN LLNCDIMMYI LRTVFERAID
TDSNLWTEGM LQMAFHILAL GLLEEKQQLQ KAPEEEVTFD FYHKASRLGS SAMNIQMLLE
KLKGIPQLEG QKDMITWILQ MFDTVKRLRE KSCLIVATTS GSESIKNDEI THDKEKAERK
RKAEAARLHR QKIMAQMSAL QKNFIETHKL MYDNTSEMPG KEDSIMEEES TPAVSDYSRI
ALGPKRGPSV TEKEVLTCIL CQEEQEVKIE NNAMVLSACV QKSTALTQHR GKPIELSGEA
LDPLFMDPDL AYGTYTGSCG HVMHAVCWQK YFEAVQLSSQ QRIHVDLFDL ESGEYLCPLC
KSLCNTVIPI IPLQPQKINS ENADALAQLL TLARWIQTVL ARISGYNIRH AKGENPIPIF
FNQGMGDSTL EFHSILSFGV ESSIKYSNSI KEMVILFATT IYRIGLKVPP DERDPRVPML
TWSTCAFTIQ AIENLLGDEG KPLFGALQNR QHNGLKALMQ FAVAQRITCP QVLIQKHLVR
LLSVVLPNIK SEDTPCLLSI DLFHVLVGAV LAFPSLYWDD PVDLQPSSVS SSYNHLYLFH
LITMAHMLQI LLTVDTGLPL AQVQEDSEEA HSASSFFAEI SQYTSGSIGC DIPGWYLWVS
LKNGITPYLR CAALFFHYLL GVTPPEELHT NSAEGEYSAL CSYLSLPTNL FLLFQEYWDT
VRPLLQRWCA DPALLNCLKQ KNTVVRYPRK RNSLIELPDD YSCLLNQASH FRCPRSADDE
RKHPVLCLFC GAILCSQNIC CQEIVNGEEV GACIFHALHC GAGVCIFLKI RECRVVLVEG
KARGCAYPAP YLDEYGETDP GLKRGNPLHL SRERYRKLHL VWQQHCIIEE IARSQETNQM
LFGFNWQLL
//
ID UBR1_HUMAN Reviewed; 1749 AA.
AC Q8IWV7; O60708; O75492; Q14D45; Q68DN9; Q8IWY6; Q96JY4;
DT 16-AUG-2005, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-MAR-2003, sequence version 1.
DT 22-JAN-2014, entry version 95.
DE RecName: Full=E3 ubiquitin-protein ligase UBR1;
DE EC=6.3.2.-;
DE AltName: Full=N-recognin-1;
DE AltName: Full=Ubiquitin-protein ligase E3-alpha-1;
DE AltName: Full=Ubiquitin-protein ligase E3-alpha-I;
GN Name=UBR1;
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] (ISOFORM 1), TISSUE SPECIFICITY, AND
RP FUNCTION.
RX PubMed=15548684; DOI=10.1158/0008-5472.CAN-04-2102;
RA Kwak K.S., Zhou X., Solomon V., Baracos V.E., Davis J., Bannon A.W.,
RA Boyle W.J., Lacey D.L., Han H.Q.;
RT "Regulation of protein catabolism by muscle-specific and cytokine-
RT inducible ubiquitin ligase E3alpha-II during cancer cachexia.";
RL Cancer Res. 64:8193-8198(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
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 [3]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 18-1727 (ISOFORM 1).
RC TISSUE=Erythroid cell;
RX PubMed=12434312; DOI=10.1086/344781;
RA Dgany O., Avidan N., Delaunay J., Krasnov T., Shalmon L., Shalev H.,
RA Eidelitz-Markus T., Kapelushnik J., Cattan D., Pariente A.,
RA Tulliez M., Cretien A., Schischmanoff P.-O., Iolascon A., Fibach E.,
RA Koren A., Roessler J., Le Merrer M., Yaniv I., Zaizov R.,
RA Ben-Asher E., Olender T., Lancet D., Beckmann J.S., Tamary H.;
RT "Congenital dyserythropoietic anemia type I is caused by mutations in
RT codanin-1.";
RL Am. J. Hum. Genet. 71:1467-1474(2002).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 166-1014 (ISOFORM 1).
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 656-1749 (ISOFORM 2).
RC TISSUE=Heart;
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 [GENOMIC DNA / MRNA] OF 702-1034 (ISOFORM 1), AND
RP TISSUE SPECIFICITY.
RX PubMed=9653112; DOI=10.1073/pnas.95.14.7898;
RA Kwon Y.T., Reiss Y., Fried V.A., Hershko A., Yoon J.K., Gonda D.K.,
RA Sangan P., Copeland N.G., Jenkins N.A., Varshavsky A.;
RT "The mouse and human genes encoding the recognition component of the
RT N-end rule pathway.";
RL Proc. Natl. Acad. Sci. U.S.A. 95:7898-7903(1998).
RN [7]
RP INTERACTION WITH RECQL4, AND IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=15317757; DOI=10.1093/hmg/ddh269;
RA Yin J., Kwon Y.T., Varshavsky A., Wang W.;
RT "RECQL4, mutated in the Rothmund-Thomson and RAPADILINO syndromes,
RT interacts with ubiquitin ligases UBR1 and UBR2 of the N-end rule
RT pathway.";
RL Hum. Mol. Genet. 13:2421-2430(2004).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1179, AND MASS
RP SPECTROMETRY.
RC TISSUE=Embryonic kidney;
RX PubMed=17525332; DOI=10.1126/science.1140321;
RA Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III,
RA Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N.,
RA Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J.;
RT "ATM and ATR substrate analysis reveals extensive protein networks
RT responsive to DNA damage.";
RL Science 316:1160-1166(2007).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-21, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [10]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, PHOSPHORYLATION [LARGE
RP SCALE ANALYSIS] AT THR-21, MASS SPECTROMETRY, AND CLEAVAGE OF
RP INITIATOR METHIONINE.
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-21, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [12]
RP FUNCTION.
RX PubMed=20298436; DOI=10.1111/j.1365-2443.2010.01385.x;
RA Kume K., Iizumi Y., Shimada M., Ito Y., Kishi T., Yamaguchi Y.,
RA Handa H.;
RT "Role of N-end rule ubiquitin ligases UBR1 and UBR2 in regulating the
RT leucine-mTOR signaling pathway.";
RL Genes Cells 15:339-349(2010).
RN [13]
RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 98-167 ALONE AND IN COMPLEX
RP WITH N-END RULE PEPTIDE, UBR-TYPE ZINC FINGER, FUNCTION, AND VARIANT
RP JB5 ARG-136.
RX PubMed=20835242; DOI=10.1038/nsmb.1894;
RA Matta-Camacho E., Kozlov G., Li F.F., Gehring K.;
RT "Structural basis of substrate recognition and specificity in the N-
RT end rule pathway.";
RL Nat. Struct. Mol. Biol. 17:1182-1187(2010).
RN [14]
RP VARIANTS JBS ARG-136 AND SER-1279, FUNCTION, DISEASE, TISSUE
RP SPECIFICITY, SUBCELLULAR LOCATION, AND DEVELOPMENTAL STAGE.
RX PubMed=16311597; DOI=10.1038/ng1681;
RA Zenker M., Mayerle J., Lerch M.M., Tagariello A., Zerres K.,
RA Durie P.R., Beier M., Hulskamp G., Guzman C., Rehder H., Beemer F.A.,
RA Hamel B.C.J., Vanlieferinghen P., Gershoni-Baruch R., Vieira M.W.,
RA Dumic M., Auslender R., Gil-da-Silva-Lopes V.L., Steinlicht S.,
RA Rauh M., Shalev S.A., Thiel C., Winterpacht A., Kwon Y.T.,
RA Varshavsky A., Reis A.;
RT "Deficiency of UBR1, a ubiquitin ligase of the N-end rule pathway,
RT causes pancreatic dysfunction, malformations and mental retardation
RT (Johanson-Blizzard syndrome).";
RL Nat. Genet. 37:1345-1350(2005).
CC -!- FUNCTION: E3 ubiquitin-protein ligase which is a component of the
CC N-end rule pathway. Recognizes and binds to proteins bearing
CC specific N-terminal residues that are destabilizing according to
CC the N-end rule, leading to their ubiquitination and subsequent
CC degradation. May be involved in pancreatic homeostasis. Binds
CC leucine and is a negative regulator of the leucine-mTOR signaling
CC pathway, thereby controlling cell growth.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Interacts with RECQL4.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q8IWV7-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8IWV7-2; Sequence=VSP_015164, VSP_015165;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Broadly expressed, with highest levels in
CC skeletal muscle, kidney and pancreas. Present in acinar cells of
CC the pancreas (at protein level).
CC -!- DEVELOPMENTAL STAGE: Expressed in fetal pancreas.
CC -!- DOMAIN: The RING-H2 zinc finger is an atypical RING finger with a
CC His ligand in place of the fourth Cys of the classical motif.
CC -!- DOMAIN: The UBR-type zinc finger forms a pocket that mediates
CC recognition of type 1 N-degrons. It exhibits preference for
CC Arginine in first position, has poor affinity for histidine, and
CC doesn't bind acetylated peptides.
CC -!- DISEASE: Johanson-Blizzard syndrome (JBS) [MIM:243800]: This
CC disorder includes congenital exocrine pancreatic insufficiency,
CC multiple malformations such as nasal wing aplasia, and frequent
CC mental retardation. Pancreas of individuals with JBS do not
CC express UBR1 and show intrauterine-onset destructive pancreatitis.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the UBR1 family.
CC -!- SIMILARITY: Contains 1 RING-type zinc finger.
CC -!- SIMILARITY: Contains 1 UBR-type zinc finger.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAB55380.1; Type=Erroneous initiation;
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DR EMBL; AY061886; AAL32103.1; -; mRNA.
DR EMBL; BC113505; AAI13506.1; -; mRNA.
DR EMBL; BC113507; AAI13508.1; -; mRNA.
DR EMBL; AF525401; AAO14997.1; -; mRNA.
DR EMBL; AK027803; BAB55380.1; ALT_INIT; mRNA.
DR EMBL; CR749326; CAH18181.1; -; mRNA.
DR EMBL; AF061556; AAC39845.1; -; mRNA.
DR EMBL; AH006181; AAC23677.1; -; Genomic_DNA.
DR RefSeq; NP_777576.1; NM_174916.2.
DR UniGene; Hs.591121; -.
DR PDB; 3NY1; X-ray; 2.08 A; A/B=97-168.
DR PDBsum; 3NY1; -.
DR ProteinModelPortal; Q8IWV7; -.
DR SMR; Q8IWV7; 97-167.
DR DIP; DIP-47033N; -.
DR IntAct; Q8IWV7; 29.
DR MINT; MINT-1417571; -.
DR STRING; 9606.ENSP00000290650; -.
DR PhosphoSite; Q8IWV7; -.
DR DMDM; 73622071; -.
DR PaxDb; Q8IWV7; -.
DR PRIDE; Q8IWV7; -.
DR Ensembl; ENST00000290650; ENSP00000290650; ENSG00000159459.
DR Ensembl; ENST00000382177; ENSP00000371612; ENSG00000159459.
DR Ensembl; ENST00000569066; ENSP00000456327; ENSG00000159459.
DR GeneID; 197131; -.
DR KEGG; hsa:197131; -.
DR UCSC; uc001zqq.3; human.
DR CTD; 197131; -.
DR GeneCards; GC15M043235; -.
DR HGNC; HGNC:16808; UBR1.
DR HPA; HPA038838; -.
DR MIM; 243800; phenotype.
DR MIM; 605981; gene.
DR neXtProt; NX_Q8IWV7; -.
DR Orphanet; 2315; Johanson-Blizzard syndrome.
DR PharmGKB; PA38187; -.
DR eggNOG; NOG310244; -.
DR HOVERGEN; HBG080426; -.
DR InParanoid; Q8IWV7; -.
DR KO; K10625; -.
DR OMA; PDEMDPR; -.
DR OrthoDB; EOG7RNJZB; -.
DR PhylomeDB; Q8IWV7; -.
DR Reactome; REACT_6900; Immune System.
DR UniPathway; UPA00143; -.
DR EvolutionaryTrace; Q8IWV7; -.
DR GeneWiki; UBR1; -.
DR GenomeRNAi; 197131; -.
DR NextBio; 89608; -.
DR PRO; PR:Q8IWV7; -.
DR ArrayExpress; Q8IWV7; -.
DR Bgee; Q8IWV7; -.
DR CleanEx; HS_UBR1; -.
DR Genevestigator; Q8IWV7; -.
DR GO; GO:0005829; C:cytosol; IEA:UniProtKB-SubCell.
DR GO; GO:0000502; C:proteasome complex; IEA:Ensembl.
DR GO; GO:0000151; C:ubiquitin ligase complex; IEA:Ensembl.
DR GO; GO:0070728; F:leucine binding; IDA:UniProtKB.
DR GO; GO:0004842; F:ubiquitin-protein ligase activity; IEA:Ensembl.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0071233; P:cellular response to leucine; IDA:UniProtKB.
DR GO; GO:0032007; P:negative regulation of TOR signaling cascade; IMP:UniProtKB.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IEA:Ensembl.
DR Gene3D; 3.30.1390.10; -; 1.
DR Gene3D; 3.30.40.10; -; 2.
DR InterPro; IPR003769; ClpS_core.
DR InterPro; IPR014719; Ribosomal_L7/12_C/ClpS-like.
DR InterPro; IPR003126; Znf_N-recognin.
DR InterPro; IPR013993; Znf_N-recognin_met.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR Pfam; PF02617; ClpS; 1.
DR Pfam; PF02207; zf-UBR; 1.
DR SMART; SM00396; ZnF_UBR1; 1.
DR SUPFAM; SSF54736; SSF54736; 1.
DR PROSITE; PS00518; ZF_RING_1; FALSE_NEG.
DR PROSITE; PS50089; ZF_RING_2; FALSE_NEG.
DR PROSITE; PS51157; ZF_UBR; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Complete proteome;
KW Cytoplasm; Disease mutation; Ligase; Metal-binding; Phosphoprotein;
KW Polymorphism; Reference proteome; Ubl conjugation pathway; Zinc;
KW Zinc-finger.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 1749 E3 ubiquitin-protein ligase UBR1.
FT /FTId=PRO_0000056136.
FT ZN_FING 97 168 UBR-type.
FT ZN_FING 1098 1201 RING-type; atypical.
FT COMPBIAS 864 869 Poly-Pro.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 21 21 Phosphothreonine.
FT MOD_RES 1179 1179 Phosphoserine.
FT VAR_SEQ 795 803 NNETGLENV -> TRCIRPWSL (in isoform 2).
FT /FTId=VSP_015164.
FT VAR_SEQ 804 1749 Missing (in isoform 2).
FT /FTId=VSP_015165.
FT VARIANT 136 136 H -> R (in JBS; prevents proper folding
FT of the UBR-type zinc finger).
FT /FTId=VAR_024741.
FT VARIANT 596 596 K -> M (in dbSNP:rs34568456).
FT /FTId=VAR_034467.
FT VARIANT 899 899 I -> V (in dbSNP:rs35069201).
FT /FTId=VAR_052116.
FT VARIANT 1279 1279 G -> S (in JBS).
FT /FTId=VAR_024742.
FT VARIANT 1548 1548 T -> A (in dbSNP:rs3917223).
FT /FTId=VAR_061822.
FT CONFLICT 201 201 V -> A (in Ref. 4).
FT CONFLICT 900 900 D -> N (in Ref. 6; AAC39845).
FT CONFLICT 973 973 D -> T (in Ref. 3; AAO14997).
FT CONFLICT 993 993 C -> S (in Ref. 6; AAC23677).
FT CONFLICT 1710 1719 LSRERYRKLH -> FLVSGTEAP (in Ref. 3).
FT CONFLICT 1722 1722 W -> R (in Ref. 3).
FT STRAND 108 112
FT TURN 113 115
FT STRAND 116 118
FT HELIX 125 128
FT HELIX 132 135
FT STRAND 138 142
FT STRAND 156 159
FT TURN 164 166
SQ SEQUENCE 1749 AA; 200211 MW; 3AE0E1A749884971 CRC64;
MADEEAGGTE RMEISAELPQ TPQRLASWWD QQVDFYTAFL HHLAQLVPEI YFAEMDPDLE
KQEESVQMSI FTPLEWYLFG EDPDICLEKL KHSGAFQLCG RVFKSGETTY SCRDCAIDPT
CVLCMDCFQD SVHKNHRYKM HTSTGGGFCD CGDTEAWKTG PFCVNHEPGR AGTIKENSRC
PLNEEVIVQA RKIFPSVIKY VVEMTIWEEE KELPPELQIR EKNERYYCVL FNDEHHSYDH
VIYSLQRALD CELAEAQLHT TAIDKEGRRA VKAGAYAACQ EAKEDIKSHS ENVSQHPLHV
EVLHSEIMAH QKFALRLGSW MNKIMSYSSD FRQIFCQACL REEPDSENPC LISRLMLWDA
KLYKGARKIL HELIFSSFFM EMEYKKLFAM EFVKYYKQLQ KEYISDDHDR SISITALSVQ
MFTVPTLARH LIEEQNVISV ITETLLEVLP EYLDRNNKFN FQGYSQDKLG RVYAVICDLK
YILISKPTIW TERLRMQFLE GFRSFLKILT CMQGMEEIRR QVGQHIEVDP DWEAAIAIQM
QLKNILLMFQ EWCACDEELL LVAYKECHKA VMRCSTSFIS SSKTVVQSCG HSLETKSYRV
SEDLVSIHLP LSRTLAGLHV RLSRLGAVSR LHEFVSFEDF QVEVLVEYPL RCLVLVAQVV
AEMWRRNGLS LISQVFYYQD VKCREEMYDK DIIMLQIGAS LMDPNKFLLL VLQRYELAEA
FNKTISTKDQ DLIKQYNTLI EEMLQVLIYI VGERYVPGVG NVTKEEVTMR EIIHLLCIEP
MPHSAIAKNL PENENNETGL ENVINKVATF KKPGVSGHGV YELKDESLKD FNMYFYHYSK
TQHSKAEHMQ KKRRKQENKD EALPPPPPPE FCPAFSKVIN LLNCDIMMYI LRTVFERAID
TDSNLWTEGM LQMAFHILAL GLLEEKQQLQ KAPEEEVTFD FYHKASRLGS SAMNIQMLLE
KLKGIPQLEG QKDMITWILQ MFDTVKRLRE KSCLIVATTS GSESIKNDEI THDKEKAERK
RKAEAARLHR QKIMAQMSAL QKNFIETHKL MYDNTSEMPG KEDSIMEEES TPAVSDYSRI
ALGPKRGPSV TEKEVLTCIL CQEEQEVKIE NNAMVLSACV QKSTALTQHR GKPIELSGEA
LDPLFMDPDL AYGTYTGSCG HVMHAVCWQK YFEAVQLSSQ QRIHVDLFDL ESGEYLCPLC
KSLCNTVIPI IPLQPQKINS ENADALAQLL TLARWIQTVL ARISGYNIRH AKGENPIPIF
FNQGMGDSTL EFHSILSFGV ESSIKYSNSI KEMVILFATT IYRIGLKVPP DERDPRVPML
TWSTCAFTIQ AIENLLGDEG KPLFGALQNR QHNGLKALMQ FAVAQRITCP QVLIQKHLVR
LLSVVLPNIK SEDTPCLLSI DLFHVLVGAV LAFPSLYWDD PVDLQPSSVS SSYNHLYLFH
LITMAHMLQI LLTVDTGLPL AQVQEDSEEA HSASSFFAEI SQYTSGSIGC DIPGWYLWVS
LKNGITPYLR CAALFFHYLL GVTPPEELHT NSAEGEYSAL CSYLSLPTNL FLLFQEYWDT
VRPLLQRWCA DPALLNCLKQ KNTVVRYPRK RNSLIELPDD YSCLLNQASH FRCPRSADDE
RKHPVLCLFC GAILCSQNIC CQEIVNGEEV GACIFHALHC GAGVCIFLKI RECRVVLVEG
KARGCAYPAP YLDEYGETDP GLKRGNPLHL SRERYRKLHL VWQQHCIIEE IARSQETNQM
LFGFNWQLL
//
MIM
243800
*RECORD*
*FIELD* NO
243800
*FIELD* TI
#243800 JOHANSON-BLIZZARD SYNDROME; JBS
;;NASAL ALAR HYPOPLASIA, HYPOTHYROIDISM, PANCREATIC ACHYLIA, AND CONGENITAL
read moreDEAFNESS
*FIELD* TX
A number sign (#) is used with this entry because the Johanson-Blizzard
syndrome (JBS) is caused by homozygous or compound heterozygous mutation
in the UBR1 gene (605981) on chromosome 15q.
DESCRIPTION
Johanson-Blizzard syndrome is an autosomal recessive disorder
characterized by poor growth, mental retardation, and variable
dysmorphic features, including aplasia or hypoplasia of the nasal alae,
abnormal hair patterns or scalp defects, and oligodontia. Other features
include hypothyroidism, sensorineural hearing loss, imperforate anus,
and pancreatic exocrine insufficiency (summary by Al-Dosari et al.,
2008).
CLINICAL FEATURES
Johanson and Blizzard (1971) and Park et al. (1972) described this
syndrome in 3 unrelated girls; features included aplasia or hypoplasia
of the nasal alae, congenital deafness, hypothyroidism, postnatal growth
retardation, malabsorption, mental retardation, midline ectodermal scalp
defects, and absent permanent teeth. Park et al. (1972) described
urogenital abnormalities, including double vagina and double uterus.
The male proband of Mardini et al. (1978) had aplasia of the alae nasi,
scalp defects over the anterior and posterior fontanels, and imperforate
anus. Affected brothers were reported by Day and Israel (1978). Flatz et
al. (1979) described this disorder in 2 sisters. Daentl et al. (1979)
reported a case in a male who died at the age of 8 years from
complications of pancreatic exocrine insufficiency. Autopsy showed a
small thyroid filled with colloid, almost complete replacement of the
pancreas with fat, and abnormal gyral formation and cortical neuronal
organization in the brain.
Motohashi et al. (1981) reported 2 families; in 1, 2 children (earlier
reported by Day and Israel, 1978) were affected and in the second, in
addition to the 13-month-old proband, 2 affected sibs had died
perinatally. Moeschler and Lubinsky (1985) described affected brother
and sister. Reichart et al. (1979) and Helin and Jodal (1981) also
reported affected sibs. Normal or near-normal intelligence often seems
the case.
In a review of JBS by Hurst and Baraitser (1989), it was indicated that
11 of 22 reported children had anorectal abnormalities, most often
imperforate anus. Gould et al. (1989) described a family with 2 affected
sibs and possibly a third who had died shortly after birth. One of the 2
sibs reported in detail (surprisingly, the sex was not given) died 3
days after birth, colostomy having been performed at age 36 hours for
imperforate anus. Autopsy showed, in addition to hypoplasia of alae nasi
and frontal and occipital scalp defects, pancreatic ducts and islets
surrounded by connective tissue and a total absence of acini.
Morphologic changes suggested dysplasia leading to developmental
failure, although early acinar destruction could not be ruled out. The
second sib, a male born 3 years later, also had the same facies and
imperforate anus which was successfully treated surgically. He was
treated for pancreatic insufficiency and hypothyroidism, and at age of
10 years performed satisfactorily in a school for the hearing impaired.
In the case of the autopsied sib, the thyroid was grossly and
microscopically normal with abundant scalloping of colloid.
Gershoni-Baruch et al. (1990) described 2 patients. They stated that the
girls reported as cases of trypsinogen deficiency (see 276000) by Morris
and Fisher (1967) and Townes (1969) had in fact this syndrome, as did a
patient with the XXY Klinefelter syndrome reported by Grand et al.
(1966), and 2 sibs with hypoplasia of the exocrine pancreas, 1 of whom
had imperforate anus, reported by Lumb and Beautyman (1952). In all,
they found 26 previously reported cases. They stated that imperforate
anus had been reported in 9 patients with JBS; 6 were females and 4 had
rectovaginal fistula. Nagashima et al. (1993) described diabetes
mellitus, first detected at age 11 years, in a girl with
Johanson-Blizzard syndrome.
Vanlieferinghen et al. (2001) described a case of Johanson-Blizzard
syndrome in a neonate. Clinical features included intrauterine growth
retardation, aplasia of the nasal alae, midline scalp defect, total
situs inversus, imperforate anus, malrotation of the small intestine,
pancreatic insufficiency, deafness, and lethal congenital heart defects
with dextrocardia. The features were confirmed at autopsy.
Vanlieferinghen et al. (2003) described the prenatal ultrasonographic
diagnosis of a recurrence of Johanson-Blizzard syndrome in a subsequent
pregnancy in this family. The pregnancy was terminated at 21 weeks'
gestation. The colon was dilated at 13 weeks. At 17 weeks, dilatation of
the bowel was increased, the nose was very small, and the nasal alae
were not visualized. Examination of the fetus showed a small beaked
nose, midline occipital scalp defect, and monstrous abdominal distention
with imperforate anus. Autopsy showed anorectal atresia with
sigmoidovesical fistula. Bilateral ureteral dilatation with
hydronephrosis and polycystic dysplasia of the kidneys were also
present.
Elting et al. (2008) reported 2 unrelated girls with a mild form of
Johanson-Blizzard syndrome, born of Turkish and Iranian consanguineous
parents, respectively. In addition to the mild but classic features of
the disorder, 1 girl had dilated cardiomyopathy, whereas the other had a
small atrial septal defect. Neither had significant mental impairment.
Molecular genetic analysis revealed that both girls had the same
homozygous mutation in the UBR1 gene (605981.0004).
Al-Dosari et al. (2008) reported a male infant, born of consanguineous
Saudi Arabian parents, with JBS. He showed intrauterine growth
retardation and was noted to have imperforate anus, aplasia of the alae
nasi, long philtrum, downturned mouth corners, upslanting palpebral
fissures, and an unusual hair pattern on the scalp. He also had
hypothyroidism, 2 cafe-au-lait spots, sensorineural hearing loss, and
hepatomegaly with hyperbilirubinemia and elevated liver enzymes. Liver
biopsy showed giant cell hepatocytes, cholestasis, and decreased number
of bile ducts. The liver disease progressed to advanced fibrosis with
portal hypertension. The patient did not have pancreatic insufficiency.
Family history revealed 3 prior abortions in the mother. Al-Dosari et
al. (2008) noted that liver involvement had not previously been reported
in this disorder, but could not rule out that it was unrelated. However,
genetic analysis excluded a mutation in the MRD3 gene (ABCB4; 171060) as
a cause of the liver failure. Liver sections from Ubr1-null mice did not
differ from those of wildtype mice.
INHERITANCE
The possibility of X-linked dominance lethal in the male was raised by
Konigsmark and Gorlin (1976) since most patients had been female and the
syndrome may have been observed in an XXY male. Autosomal recessive
inheritance appeared to have been clinched, however, by the inbred Saudi
Arabian pedigree with 3 affected members (1 male and 2 females) reported
by Mardini et al. (1978). Parental consanguinity was reported also by
Schussheim et al. (1976).
PATHOGENESIS
Using antibody to UBR1 (605981) and either immunofluorescence microscopy
with pancreatic tissue sections or immunoblotting with extracts from
cells in culture, Zenker et al. (2005) observed no UBR1 protein in
individuals with JBS from different families. By contrast, UBR1 was
readily detectable in control pancreas, where it was present largely in
the cytosol of acinar cells. Control immunostaining for trypsinogen
(276000) as a specific marker for acinar cells showed no substantial
differences between pancreas from controls and individuals with JBS,
indicating that there was no primary defect of zymogen synthesis in JBS.
Zenker et al. (2005) examined the pancreatic pathology and cell biology
in autopsy specimens from 2 fetuses (21 and 34 weeks' gestation,
respectively) and also in a newborn baby with JBS. The pancreas of
individuals with JBS showed acinar tissue loss that increased with
gestational age and was accompanied by inflammatory infiltrates, most
prominent in the near-term fetus. Using the TUNEL assay for apoptotic
cells, they found no evidence of increased apoptosis in acinar cells of
individuals with JBS. Taken together, these findings suggested that the
main pancreatic defect in individuals with JBS is not perturbed acinar
development in early embryogenesis, but rather gradual destruction of
previously formed acinar cells in maturing fetuses, a process that
resembles pancreatitis of intrauterine onset.
MAPPING
To identify the locus mutated in JBS, Zenker et al. (2005) performed a
genomewide linkage scan using a panel of microsatellite markers with an
average distance of 10 cM in 7 kindreds with the disorder. They
identified a region of homozygosity on 15q shared by individuals
originating from all consanguineous families. They further analyzed this
region by typing additional microsatellite markers from the draft human
genome sequence and refined the candidate region to a 7.5-cM interval.
The maximum 2-point lod score was 4.8 for theta = 0.0 at D15S968.
MOLECULAR GENETICS
Zenker et al. (2005) prioritized genes within the JBS candidate region
on chromosome 15q for mutational screening on the basis of putative
function and expression data but identified no obvious candidate. By
high-throughput sequencing of DNA from individuals with JBS, they
eventually detected mutations in the UBR1 gene (e.g.,
605981.0001-605981.0003). In affected individuals from 12 of 13 families
included in the study, the variations likely to be causal mutations were
identified in both alleles of UBR1, whereas in 1 family, only the
paternally inherited mutation was found. Most disease-associated UBR1
alleles (12 of 14) were mutations that predicted premature translational
stop codons. Two missense mutations in UBR1 caused substitutions of
residues that are conserved among UBR1 proteins of different species.
In a male infant with JBS, who was born of consanguineous Saudi Arabian
parents, Al-Dosari et al. (2008) identified a homozygous splice site
mutation in the UBR1 gene (605981.0005).
*FIELD* SA
Baraitser and Hodgson (1982); Moeschler et al. (1987); Zerres and
Holtgrave (1986)
*FIELD* RF
1. Al-Dosari, M. S.; Al-Muhsen, S.; Al-Jazaeri, A.; Mayerle, J.; Zenker,
M.; Alkuraya, F. S.: Johanson-Blizzard syndrome: report of a novel
mutation and severe liver involvement. Am. J. Med. Genet. 146A:
1875-1879, 2008.
2. Baraitser, M.; Hodgson, S. V.: The Johanson-Blizzard syndrome. J.
Med. Genet. 19: 302-303, 1982.
3. Daentl, D. L.; Frias, J. L.; Gilbert, E. F.; Opitz, J. M.: The
Johanson-Blizzard syndrome: case report and autopsy findings. Am.
J. Med. Genet. 3: 129-135, 1979.
4. Day, D. W.; Israel, J. N.: Johanson-Blizzard syndrome. Birth
Defects Orig. Art. Ser. XIV(6B): 275-287, 1978.
5. Elting, M.; Kariminejad, A.; de Sonnaville, M.-L.; Ottenkamp, J.;
Bauhuber, S.; Bozorgmehr, B.; Zenker, M.; Cobben, J. M.: Johanson-Blizzard
syndrome caused by identical UBR1 mutations in two unrelated girls,
one with a cardiomyopathy. Am. J. Med. Genet. 146A: 3058-3061, 2008.
6. Flatz, S.; Reichart, P.; Burdelski, M.: Personal Communication. Hanover,
N. H. 1/30/1979.
7. Gershoni-Baruch, R.; Lerner, A.; Braun, J.; Katzir, Y.; Iancu,
T. C.; Benderly, A.: Johanson-Blizzard syndrome: clinical spectrum
and further delineation of the syndrome. Am. J. Med. Genet. 35:
546-551, 1990.
8. Gould, N. S.; Paton, J. B.; Bennett, A. R.: Johanson-Blizzard
syndrome: clinical and pathological findings in 2 sibs. Am. J. Med.
Genet. 33: 194-199, 1989.
9. Grand, R. J.; Rosen, S. W.; DiSant'Agnese, P. A.; Kirkham, W. R.
: Unusual case of XXY Klinefelter's syndrome with pancreatic insufficiency,
hypothyroidism, deafness, chronic lung disease, dwarfism and microcephaly. Am.
J. Med. 4: 478-485, 1966.
10. Helin, I.; Jodal, U.: A syndrome of congenital hypoplasia of
the alae nasi, situs inversus, and severe hypoproteinemia in two siblings. J.
Pediat. 99: 932-934, 1981.
11. Hurst, J. A.; Baraitser, M.: Johanson-Blizzard syndrome. J.
Med. Genet. 26: 45-48, 1989.
12. Johanson, A. J.; Blizzard, R. M.: A syndrome of congenital aplasia
of the alae nasi, deafness, hypothyroidism, dwarfism, absent permanent
teeth, and malabsorption. J. Pediat. 79: 982-987, 1971.
13. Konigsmark, B. W.; Gorlin, R. J.: Genetic and Metabolic Deafness.
Philadelphia: W. B. Saunders (pub.) 1976. Pp. 339-341.
14. Lumb, G.; Beautyman, W.: Hypoplasia of the exocrine tissue of
the pancreas. J. Path. Bact. 54: 679-685, 1952.
15. Mardini, M. K.; Ghandour, M.; Sakati, N. A.; Nyhan, W. L.: Johanson-Blizzard
syndrome in a large inbred kindred with three involved members. Clin.
Genet. 14: 247-250, 1978.
16. Moeschler, J. B.; Lubinsky, M. S.: Johanson-Blizzard syndrome
with normal intelligence. Am. J. Med. Genet. 22: 69-73, 1985.
17. Moeschler, J. B.; Polak, M. J.; Jenkins, J. J., III; Amato, R.
S. S.: The Johanson-Blizzard syndrome: a second report of full autopsy
findings. Am. J. Med. Genet. 26: 133-138, 1987.
18. Morris, M. D.; Fisher, D. A.: Trypsinogen deficiency disease. Am.
J. Dis. Child. 114: 203-208, 1967.
19. Motohashi, N.; Pruzansky, S.; Day, D.: Roentgencephalometric
analysis of craniofacial growth in the Johanson-Blizzard syndrome. J.
Craniofac. Genet. Dev. Biol. 1: 57-72, 1981.
20. Nagashima, K.; Yagi, H.; Kuroume, T.: A case of Johanson-Blizzard
syndrome complicated by diabetes mellitus. Clin. Genet. 43: 98-100,
1993.
21. Park, I. J.; Johanson, A. J.; Jones, H. W., Jr.; Blizzard, R.
M.: Special female hermaphroditism associated with multiple disorders. Obstet.
Gynec. 39: 100-106, 1972.
22. Reichart, P.; Flatz, S.; Burdelski, R.: Ektodermale Dysplasie
und exokrine Pancreasinsuffizienz--ein erblich bedingtes Syndrom. Dtsch.
Zahnaerztl. Z. 34: 263-265, 1979.
23. Schussheim, A.; Choi, S. J.; Silverberg, M.: Exocrine pancreatic
insufficiency with congenital anomalies. J. Pediat. 89: 782-784,
1976.
24. Townes, P. L.: Proteolytic and lipolytic deficiency of the exocrine
pancreas. J. Pediat. 75: 221-228, 1969.
25. Vanlieferinghen, P.; Borderon, C.; Francannet, C.; Gembara, P.;
Dechelotte, P.: Johanson-Blizzard syndrome: a new case with autopsy
findings. Genet. Counsel. 12: 245-250, 2001.
26. Vanlieferinghen, P.; Gallot, D.; Francannet, C. H.; Meyer, F.;
Dechelotte, P.: Prenatal ultrasonographic diagnosis of a recurrent
case of Johanson-Blizzard syndrome. Genet. Counsel. 14: 105-107,
2003.
27. Zenker, M.; Mayerle, J.; Lerch, M. M.; Tagariello, A.; Zerres,
K.; Durie, P. R.; Beier, M.; Hulskamp, G.; Guzman, C.; Rehder, H.;
Beemer, F. A.; Hamel, B.; and 14 others: Deficiency of UBR1, a
ubiquitin ligase of the N-end rule pathway, causes pancreatic dysfunction,
malformations and mental retardation (Johanson-Blizzard syndrome). Nature
Genet. 37: 1345-1350, 2005. Note: Erratum: Nature Genet. 38: 265
only, 2006.
28. Zerres, K.; Holtgrave, E.-A.: The Johanson-Blizzard syndrome:
report of a new case with special reference to the dentition and review
of the literature. Clin. Genet. 30: 177-183, 1986.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature;
[Weight];
Low birth weight;
[Other];
Failure to thrive
HEAD AND NECK:
[Head];
Microcephaly;
Midline skin dimples over anterior/posterior fontanelles;
[Ears];
Hearing loss, sensorineural;
Cystic dilatation of cochlea and vestibulum;
[Eyes];
Strabismus;
Cutaneolacrimal fistulae;
Lacrimal puncta aplasia;
[Nose];
Hypoplastic alae nasi;
Beaked nose;
[Teeth];
Hypoplastic deciduous teeth;
Absent permanent teeth
CARDIOVASCULAR:
[Heart];
Atrial septal defect;
Ventricular septal defect;
Dilated cardiomyopathy (rare);
Situs inversus
CHEST:
[Breasts];
Small nipples;
Absent areolae
ABDOMEN:
[Liver];
Liver failure (1 patient);
Giant cell hepatocytes (1 patient);
Cholestasis (1 patient);
Fibrosis (1 patient);
[Pancreas];
Exocrine pancreatic insufficiency;
[Gastrointestinal];
Imperforate anus;
Anteriorly placed anus
GENITOURINARY:
[External genitalia, male];
Micropenis;
Hypospadias;
[External genitalia, female];
Clitoromegaly;
[Internal genitalia, male];
Cryptorchidism;
[Internal genitalia, female];
Double vagina;
Septate vagina;
Urethrovaginal fistulae;
[Kidneys];
Hydronephrosis;
Calicectasis
SKELETAL:
Delayed bone age;
Joint laxity;
[Hands];
Fifth finger clinodactyly;
Transverse palmar crease
SKIN, NAILS, HAIR:
[Skin];
Cafe-au-lait spots;
Scalp aplasia cutis congenita;
Transverse palmar crease;
[Hair];
Blonde, sparse scalp hair;
Frontal upsweep;
Extension of lateral hairline onto forehead;
'Unruly' scalp hair
MUSCLE, SOFT TISSUE:
Anasarca;
Edema (hands and feet)
NEUROLOGIC:
[Central nervous system];
Mental retardation (2/3 patients);
Hypotonia
ENDOCRINE FEATURES:
Hypothyroidism (30% patients);
Diabetes mellitus
LABORATORY ABNORMALITIES:
Low total serum protein;
Hypocalcemia
MISCELLANEOUS:
Death in childhood secondary to malabsorption;
Incidence of 1 in 250,000 births
MOLECULAR BASIS:
Caused by mutation in the ubiquitin-protein ligase E3 component N-recognin
1 gene (UBR1, 605981.0001)
*FIELD* CN
Cassandra L. Kniffin - updated: 6/18/2012
Cassandra L. Kniffin - updated: 12/29/2008
Kelly A. Przylepa - revised: 4/4/2003
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 07/05/2012
ckniffin: 6/18/2012
joanna: 5/1/2009
ckniffin: 12/29/2008
alopez: 12/6/2005
joanna: 3/30/2004
joanna: 4/4/2003
*FIELD* CN
Cassandra L. Kniffin - updated: 6/18/2012
Cassandra L. Kniffin - updated: 12/29/2008
Victor A. McKusick - updated: 12/1/2005
Victor A. McKusick - updated: 7/14/2003
Victor A. McKusick - updated: 1/10/2002
*FIELD* CD
Victor A. McKusick: 6/3/1986
*FIELD* ED
carol: 06/19/2012
ckniffin: 6/18/2012
wwang: 1/6/2009
ckniffin: 12/29/2008
alopez: 2/3/2006
alopez: 12/6/2005
terry: 12/1/2005
carol: 11/18/2004
mgross: 3/17/2004
carol: 7/15/2003
terry: 7/14/2003
cwells: 1/25/2002
cwells: 1/15/2002
terry: 1/10/2002
joanna: 8/12/1997
terry: 5/7/1994
pfoster: 4/25/1994
carol: 3/15/1994
mimadm: 2/19/1994
carol: 12/22/1993
carol: 4/1/1992
*RECORD*
*FIELD* NO
243800
*FIELD* TI
#243800 JOHANSON-BLIZZARD SYNDROME; JBS
;;NASAL ALAR HYPOPLASIA, HYPOTHYROIDISM, PANCREATIC ACHYLIA, AND CONGENITAL
read moreDEAFNESS
*FIELD* TX
A number sign (#) is used with this entry because the Johanson-Blizzard
syndrome (JBS) is caused by homozygous or compound heterozygous mutation
in the UBR1 gene (605981) on chromosome 15q.
DESCRIPTION
Johanson-Blizzard syndrome is an autosomal recessive disorder
characterized by poor growth, mental retardation, and variable
dysmorphic features, including aplasia or hypoplasia of the nasal alae,
abnormal hair patterns or scalp defects, and oligodontia. Other features
include hypothyroidism, sensorineural hearing loss, imperforate anus,
and pancreatic exocrine insufficiency (summary by Al-Dosari et al.,
2008).
CLINICAL FEATURES
Johanson and Blizzard (1971) and Park et al. (1972) described this
syndrome in 3 unrelated girls; features included aplasia or hypoplasia
of the nasal alae, congenital deafness, hypothyroidism, postnatal growth
retardation, malabsorption, mental retardation, midline ectodermal scalp
defects, and absent permanent teeth. Park et al. (1972) described
urogenital abnormalities, including double vagina and double uterus.
The male proband of Mardini et al. (1978) had aplasia of the alae nasi,
scalp defects over the anterior and posterior fontanels, and imperforate
anus. Affected brothers were reported by Day and Israel (1978). Flatz et
al. (1979) described this disorder in 2 sisters. Daentl et al. (1979)
reported a case in a male who died at the age of 8 years from
complications of pancreatic exocrine insufficiency. Autopsy showed a
small thyroid filled with colloid, almost complete replacement of the
pancreas with fat, and abnormal gyral formation and cortical neuronal
organization in the brain.
Motohashi et al. (1981) reported 2 families; in 1, 2 children (earlier
reported by Day and Israel, 1978) were affected and in the second, in
addition to the 13-month-old proband, 2 affected sibs had died
perinatally. Moeschler and Lubinsky (1985) described affected brother
and sister. Reichart et al. (1979) and Helin and Jodal (1981) also
reported affected sibs. Normal or near-normal intelligence often seems
the case.
In a review of JBS by Hurst and Baraitser (1989), it was indicated that
11 of 22 reported children had anorectal abnormalities, most often
imperforate anus. Gould et al. (1989) described a family with 2 affected
sibs and possibly a third who had died shortly after birth. One of the 2
sibs reported in detail (surprisingly, the sex was not given) died 3
days after birth, colostomy having been performed at age 36 hours for
imperforate anus. Autopsy showed, in addition to hypoplasia of alae nasi
and frontal and occipital scalp defects, pancreatic ducts and islets
surrounded by connective tissue and a total absence of acini.
Morphologic changes suggested dysplasia leading to developmental
failure, although early acinar destruction could not be ruled out. The
second sib, a male born 3 years later, also had the same facies and
imperforate anus which was successfully treated surgically. He was
treated for pancreatic insufficiency and hypothyroidism, and at age of
10 years performed satisfactorily in a school for the hearing impaired.
In the case of the autopsied sib, the thyroid was grossly and
microscopically normal with abundant scalloping of colloid.
Gershoni-Baruch et al. (1990) described 2 patients. They stated that the
girls reported as cases of trypsinogen deficiency (see 276000) by Morris
and Fisher (1967) and Townes (1969) had in fact this syndrome, as did a
patient with the XXY Klinefelter syndrome reported by Grand et al.
(1966), and 2 sibs with hypoplasia of the exocrine pancreas, 1 of whom
had imperforate anus, reported by Lumb and Beautyman (1952). In all,
they found 26 previously reported cases. They stated that imperforate
anus had been reported in 9 patients with JBS; 6 were females and 4 had
rectovaginal fistula. Nagashima et al. (1993) described diabetes
mellitus, first detected at age 11 years, in a girl with
Johanson-Blizzard syndrome.
Vanlieferinghen et al. (2001) described a case of Johanson-Blizzard
syndrome in a neonate. Clinical features included intrauterine growth
retardation, aplasia of the nasal alae, midline scalp defect, total
situs inversus, imperforate anus, malrotation of the small intestine,
pancreatic insufficiency, deafness, and lethal congenital heart defects
with dextrocardia. The features were confirmed at autopsy.
Vanlieferinghen et al. (2003) described the prenatal ultrasonographic
diagnosis of a recurrence of Johanson-Blizzard syndrome in a subsequent
pregnancy in this family. The pregnancy was terminated at 21 weeks'
gestation. The colon was dilated at 13 weeks. At 17 weeks, dilatation of
the bowel was increased, the nose was very small, and the nasal alae
were not visualized. Examination of the fetus showed a small beaked
nose, midline occipital scalp defect, and monstrous abdominal distention
with imperforate anus. Autopsy showed anorectal atresia with
sigmoidovesical fistula. Bilateral ureteral dilatation with
hydronephrosis and polycystic dysplasia of the kidneys were also
present.
Elting et al. (2008) reported 2 unrelated girls with a mild form of
Johanson-Blizzard syndrome, born of Turkish and Iranian consanguineous
parents, respectively. In addition to the mild but classic features of
the disorder, 1 girl had dilated cardiomyopathy, whereas the other had a
small atrial septal defect. Neither had significant mental impairment.
Molecular genetic analysis revealed that both girls had the same
homozygous mutation in the UBR1 gene (605981.0004).
Al-Dosari et al. (2008) reported a male infant, born of consanguineous
Saudi Arabian parents, with JBS. He showed intrauterine growth
retardation and was noted to have imperforate anus, aplasia of the alae
nasi, long philtrum, downturned mouth corners, upslanting palpebral
fissures, and an unusual hair pattern on the scalp. He also had
hypothyroidism, 2 cafe-au-lait spots, sensorineural hearing loss, and
hepatomegaly with hyperbilirubinemia and elevated liver enzymes. Liver
biopsy showed giant cell hepatocytes, cholestasis, and decreased number
of bile ducts. The liver disease progressed to advanced fibrosis with
portal hypertension. The patient did not have pancreatic insufficiency.
Family history revealed 3 prior abortions in the mother. Al-Dosari et
al. (2008) noted that liver involvement had not previously been reported
in this disorder, but could not rule out that it was unrelated. However,
genetic analysis excluded a mutation in the MRD3 gene (ABCB4; 171060) as
a cause of the liver failure. Liver sections from Ubr1-null mice did not
differ from those of wildtype mice.
INHERITANCE
The possibility of X-linked dominance lethal in the male was raised by
Konigsmark and Gorlin (1976) since most patients had been female and the
syndrome may have been observed in an XXY male. Autosomal recessive
inheritance appeared to have been clinched, however, by the inbred Saudi
Arabian pedigree with 3 affected members (1 male and 2 females) reported
by Mardini et al. (1978). Parental consanguinity was reported also by
Schussheim et al. (1976).
PATHOGENESIS
Using antibody to UBR1 (605981) and either immunofluorescence microscopy
with pancreatic tissue sections or immunoblotting with extracts from
cells in culture, Zenker et al. (2005) observed no UBR1 protein in
individuals with JBS from different families. By contrast, UBR1 was
readily detectable in control pancreas, where it was present largely in
the cytosol of acinar cells. Control immunostaining for trypsinogen
(276000) as a specific marker for acinar cells showed no substantial
differences between pancreas from controls and individuals with JBS,
indicating that there was no primary defect of zymogen synthesis in JBS.
Zenker et al. (2005) examined the pancreatic pathology and cell biology
in autopsy specimens from 2 fetuses (21 and 34 weeks' gestation,
respectively) and also in a newborn baby with JBS. The pancreas of
individuals with JBS showed acinar tissue loss that increased with
gestational age and was accompanied by inflammatory infiltrates, most
prominent in the near-term fetus. Using the TUNEL assay for apoptotic
cells, they found no evidence of increased apoptosis in acinar cells of
individuals with JBS. Taken together, these findings suggested that the
main pancreatic defect in individuals with JBS is not perturbed acinar
development in early embryogenesis, but rather gradual destruction of
previously formed acinar cells in maturing fetuses, a process that
resembles pancreatitis of intrauterine onset.
MAPPING
To identify the locus mutated in JBS, Zenker et al. (2005) performed a
genomewide linkage scan using a panel of microsatellite markers with an
average distance of 10 cM in 7 kindreds with the disorder. They
identified a region of homozygosity on 15q shared by individuals
originating from all consanguineous families. They further analyzed this
region by typing additional microsatellite markers from the draft human
genome sequence and refined the candidate region to a 7.5-cM interval.
The maximum 2-point lod score was 4.8 for theta = 0.0 at D15S968.
MOLECULAR GENETICS
Zenker et al. (2005) prioritized genes within the JBS candidate region
on chromosome 15q for mutational screening on the basis of putative
function and expression data but identified no obvious candidate. By
high-throughput sequencing of DNA from individuals with JBS, they
eventually detected mutations in the UBR1 gene (e.g.,
605981.0001-605981.0003). In affected individuals from 12 of 13 families
included in the study, the variations likely to be causal mutations were
identified in both alleles of UBR1, whereas in 1 family, only the
paternally inherited mutation was found. Most disease-associated UBR1
alleles (12 of 14) were mutations that predicted premature translational
stop codons. Two missense mutations in UBR1 caused substitutions of
residues that are conserved among UBR1 proteins of different species.
In a male infant with JBS, who was born of consanguineous Saudi Arabian
parents, Al-Dosari et al. (2008) identified a homozygous splice site
mutation in the UBR1 gene (605981.0005).
*FIELD* SA
Baraitser and Hodgson (1982); Moeschler et al. (1987); Zerres and
Holtgrave (1986)
*FIELD* RF
1. Al-Dosari, M. S.; Al-Muhsen, S.; Al-Jazaeri, A.; Mayerle, J.; Zenker,
M.; Alkuraya, F. S.: Johanson-Blizzard syndrome: report of a novel
mutation and severe liver involvement. Am. J. Med. Genet. 146A:
1875-1879, 2008.
2. Baraitser, M.; Hodgson, S. V.: The Johanson-Blizzard syndrome. J.
Med. Genet. 19: 302-303, 1982.
3. Daentl, D. L.; Frias, J. L.; Gilbert, E. F.; Opitz, J. M.: The
Johanson-Blizzard syndrome: case report and autopsy findings. Am.
J. Med. Genet. 3: 129-135, 1979.
4. Day, D. W.; Israel, J. N.: Johanson-Blizzard syndrome. Birth
Defects Orig. Art. Ser. XIV(6B): 275-287, 1978.
5. Elting, M.; Kariminejad, A.; de Sonnaville, M.-L.; Ottenkamp, J.;
Bauhuber, S.; Bozorgmehr, B.; Zenker, M.; Cobben, J. M.: Johanson-Blizzard
syndrome caused by identical UBR1 mutations in two unrelated girls,
one with a cardiomyopathy. Am. J. Med. Genet. 146A: 3058-3061, 2008.
6. Flatz, S.; Reichart, P.; Burdelski, M.: Personal Communication. Hanover,
N. H. 1/30/1979.
7. Gershoni-Baruch, R.; Lerner, A.; Braun, J.; Katzir, Y.; Iancu,
T. C.; Benderly, A.: Johanson-Blizzard syndrome: clinical spectrum
and further delineation of the syndrome. Am. J. Med. Genet. 35:
546-551, 1990.
8. Gould, N. S.; Paton, J. B.; Bennett, A. R.: Johanson-Blizzard
syndrome: clinical and pathological findings in 2 sibs. Am. J. Med.
Genet. 33: 194-199, 1989.
9. Grand, R. J.; Rosen, S. W.; DiSant'Agnese, P. A.; Kirkham, W. R.
: Unusual case of XXY Klinefelter's syndrome with pancreatic insufficiency,
hypothyroidism, deafness, chronic lung disease, dwarfism and microcephaly. Am.
J. Med. 4: 478-485, 1966.
10. Helin, I.; Jodal, U.: A syndrome of congenital hypoplasia of
the alae nasi, situs inversus, and severe hypoproteinemia in two siblings. J.
Pediat. 99: 932-934, 1981.
11. Hurst, J. A.; Baraitser, M.: Johanson-Blizzard syndrome. J.
Med. Genet. 26: 45-48, 1989.
12. Johanson, A. J.; Blizzard, R. M.: A syndrome of congenital aplasia
of the alae nasi, deafness, hypothyroidism, dwarfism, absent permanent
teeth, and malabsorption. J. Pediat. 79: 982-987, 1971.
13. Konigsmark, B. W.; Gorlin, R. J.: Genetic and Metabolic Deafness.
Philadelphia: W. B. Saunders (pub.) 1976. Pp. 339-341.
14. Lumb, G.; Beautyman, W.: Hypoplasia of the exocrine tissue of
the pancreas. J. Path. Bact. 54: 679-685, 1952.
15. Mardini, M. K.; Ghandour, M.; Sakati, N. A.; Nyhan, W. L.: Johanson-Blizzard
syndrome in a large inbred kindred with three involved members. Clin.
Genet. 14: 247-250, 1978.
16. Moeschler, J. B.; Lubinsky, M. S.: Johanson-Blizzard syndrome
with normal intelligence. Am. J. Med. Genet. 22: 69-73, 1985.
17. Moeschler, J. B.; Polak, M. J.; Jenkins, J. J., III; Amato, R.
S. S.: The Johanson-Blizzard syndrome: a second report of full autopsy
findings. Am. J. Med. Genet. 26: 133-138, 1987.
18. Morris, M. D.; Fisher, D. A.: Trypsinogen deficiency disease. Am.
J. Dis. Child. 114: 203-208, 1967.
19. Motohashi, N.; Pruzansky, S.; Day, D.: Roentgencephalometric
analysis of craniofacial growth in the Johanson-Blizzard syndrome. J.
Craniofac. Genet. Dev. Biol. 1: 57-72, 1981.
20. Nagashima, K.; Yagi, H.; Kuroume, T.: A case of Johanson-Blizzard
syndrome complicated by diabetes mellitus. Clin. Genet. 43: 98-100,
1993.
21. Park, I. J.; Johanson, A. J.; Jones, H. W., Jr.; Blizzard, R.
M.: Special female hermaphroditism associated with multiple disorders. Obstet.
Gynec. 39: 100-106, 1972.
22. Reichart, P.; Flatz, S.; Burdelski, R.: Ektodermale Dysplasie
und exokrine Pancreasinsuffizienz--ein erblich bedingtes Syndrom. Dtsch.
Zahnaerztl. Z. 34: 263-265, 1979.
23. Schussheim, A.; Choi, S. J.; Silverberg, M.: Exocrine pancreatic
insufficiency with congenital anomalies. J. Pediat. 89: 782-784,
1976.
24. Townes, P. L.: Proteolytic and lipolytic deficiency of the exocrine
pancreas. J. Pediat. 75: 221-228, 1969.
25. Vanlieferinghen, P.; Borderon, C.; Francannet, C.; Gembara, P.;
Dechelotte, P.: Johanson-Blizzard syndrome: a new case with autopsy
findings. Genet. Counsel. 12: 245-250, 2001.
26. Vanlieferinghen, P.; Gallot, D.; Francannet, C. H.; Meyer, F.;
Dechelotte, P.: Prenatal ultrasonographic diagnosis of a recurrent
case of Johanson-Blizzard syndrome. Genet. Counsel. 14: 105-107,
2003.
27. Zenker, M.; Mayerle, J.; Lerch, M. M.; Tagariello, A.; Zerres,
K.; Durie, P. R.; Beier, M.; Hulskamp, G.; Guzman, C.; Rehder, H.;
Beemer, F. A.; Hamel, B.; and 14 others: Deficiency of UBR1, a
ubiquitin ligase of the N-end rule pathway, causes pancreatic dysfunction,
malformations and mental retardation (Johanson-Blizzard syndrome). Nature
Genet. 37: 1345-1350, 2005. Note: Erratum: Nature Genet. 38: 265
only, 2006.
28. Zerres, K.; Holtgrave, E.-A.: The Johanson-Blizzard syndrome:
report of a new case with special reference to the dentition and review
of the literature. Clin. Genet. 30: 177-183, 1986.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature;
[Weight];
Low birth weight;
[Other];
Failure to thrive
HEAD AND NECK:
[Head];
Microcephaly;
Midline skin dimples over anterior/posterior fontanelles;
[Ears];
Hearing loss, sensorineural;
Cystic dilatation of cochlea and vestibulum;
[Eyes];
Strabismus;
Cutaneolacrimal fistulae;
Lacrimal puncta aplasia;
[Nose];
Hypoplastic alae nasi;
Beaked nose;
[Teeth];
Hypoplastic deciduous teeth;
Absent permanent teeth
CARDIOVASCULAR:
[Heart];
Atrial septal defect;
Ventricular septal defect;
Dilated cardiomyopathy (rare);
Situs inversus
CHEST:
[Breasts];
Small nipples;
Absent areolae
ABDOMEN:
[Liver];
Liver failure (1 patient);
Giant cell hepatocytes (1 patient);
Cholestasis (1 patient);
Fibrosis (1 patient);
[Pancreas];
Exocrine pancreatic insufficiency;
[Gastrointestinal];
Imperforate anus;
Anteriorly placed anus
GENITOURINARY:
[External genitalia, male];
Micropenis;
Hypospadias;
[External genitalia, female];
Clitoromegaly;
[Internal genitalia, male];
Cryptorchidism;
[Internal genitalia, female];
Double vagina;
Septate vagina;
Urethrovaginal fistulae;
[Kidneys];
Hydronephrosis;
Calicectasis
SKELETAL:
Delayed bone age;
Joint laxity;
[Hands];
Fifth finger clinodactyly;
Transverse palmar crease
SKIN, NAILS, HAIR:
[Skin];
Cafe-au-lait spots;
Scalp aplasia cutis congenita;
Transverse palmar crease;
[Hair];
Blonde, sparse scalp hair;
Frontal upsweep;
Extension of lateral hairline onto forehead;
'Unruly' scalp hair
MUSCLE, SOFT TISSUE:
Anasarca;
Edema (hands and feet)
NEUROLOGIC:
[Central nervous system];
Mental retardation (2/3 patients);
Hypotonia
ENDOCRINE FEATURES:
Hypothyroidism (30% patients);
Diabetes mellitus
LABORATORY ABNORMALITIES:
Low total serum protein;
Hypocalcemia
MISCELLANEOUS:
Death in childhood secondary to malabsorption;
Incidence of 1 in 250,000 births
MOLECULAR BASIS:
Caused by mutation in the ubiquitin-protein ligase E3 component N-recognin
1 gene (UBR1, 605981.0001)
*FIELD* CN
Cassandra L. Kniffin - updated: 6/18/2012
Cassandra L. Kniffin - updated: 12/29/2008
Kelly A. Przylepa - revised: 4/4/2003
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 07/05/2012
ckniffin: 6/18/2012
joanna: 5/1/2009
ckniffin: 12/29/2008
alopez: 12/6/2005
joanna: 3/30/2004
joanna: 4/4/2003
*FIELD* CN
Cassandra L. Kniffin - updated: 6/18/2012
Cassandra L. Kniffin - updated: 12/29/2008
Victor A. McKusick - updated: 12/1/2005
Victor A. McKusick - updated: 7/14/2003
Victor A. McKusick - updated: 1/10/2002
*FIELD* CD
Victor A. McKusick: 6/3/1986
*FIELD* ED
carol: 06/19/2012
ckniffin: 6/18/2012
wwang: 1/6/2009
ckniffin: 12/29/2008
alopez: 2/3/2006
alopez: 12/6/2005
terry: 12/1/2005
carol: 11/18/2004
mgross: 3/17/2004
carol: 7/15/2003
terry: 7/14/2003
cwells: 1/25/2002
cwells: 1/15/2002
terry: 1/10/2002
joanna: 8/12/1997
terry: 5/7/1994
pfoster: 4/25/1994
carol: 3/15/1994
mimadm: 2/19/1994
carol: 12/22/1993
carol: 4/1/1992
MIM
605981
*RECORD*
*FIELD* NO
605981
*FIELD* TI
*605981 UBIQUITIN-PROTEIN LIGASE E3 COMPONENT N-RECOGNIN 1; UBR1
*FIELD* TX
DESCRIPTION
read more
A number of regulatory circuits involve metabolically unstable proteins.
Short in vivo half-lives are also characteristic of damaged or otherwise
abnormal proteins. Features of proteins that confer metabolic
instability are called degradation signals, or degrons. The essential
component of one degradation signal, called the N-degron, is a
destabilizing N-terminal residue of a protein. The set of amino acids
that are destabilizing in a given cell type yields a rule, called the
N-end rule, which relates the in vivo half-life of a protein to the
identity of its N-terminal residue. Similar but distinct versions of the
N-end rule pathway are present in all organisms that have been examined,
from mammals to fungi and bacteria. The N-end rule pathway is one
proteolytic pathway of the ubiquitin system. The recognition component
of this pathway, called N-recognin or E3, binds to a destabilizing
N-terminal residue of a substrate protein and participates in the
formation of a substrate-linked multiubiquitin chain (summary by Kwon et
al., 1998).
CLONING
Kwon et al. (1998) isolated full-length mouse Ubr1 cDNAs and partial
human UBR1 cDNAs, which encode an N-recognin called E3-alpha. The mouse
Ubr1 protein is a 1,757-residue, 200-kD protein that contains regions
with sequence similarity to the 225-kD UBR1 protein of S. cerevisiae.
There are apparent UBR1 homologs in other eukaryotes, thus defining a
distinct family of proteins, the UBR family. The residues essential for
substrate recognition by the yeast UBR1 protein are conserved in the
mouse Ubr1 protein. Regions of similarity among the UBR family members
include a putative zinc finger and RING-H2 finger, another zinc-binding
domain. Northern blot analysis detected ubiquitous expression in human
and adult mouse tissues, with highest levels in skeletal muscle and
heart. In mouse embryos, in situ hybridization showed that Ubr1
expression is highest in the branchial arches and in the tail and limb
buds. The authors suggested that the cloning of UBR1 makes possible the
construction of Ubr1-lacking mouse strains, a prerequisite for the
functional understanding of the mammalian N-end rule pathway.
GENE STRUCTURE
Zenker et al. (2005) stated that the UBR1 gene, which encodes one of the
E3 ubiquitin ligases of the N-end rule pathway, spans approximately 161
kb and contains 47 exons. The mouse Ubr1 gene spans approximately 120 kb
of genomic DNA and contains approximately 50 exons (Kwon et al., 1998).
MAPPING
By interspecific backcross analysis, Kwon et al. (1998) mapped the mouse
Ubr1 gene to the middle of chromosome 2. They mapped the human UBR1 gene
to 15q15-q21.1, which shows homology of synteny with mouse chromosome 2.
MOLECULAR GENETICS
Johanson-Blizzard syndrome (JBS; 243800) is an autosomal recessive
disorder that includes congenital exocrine pancreatic insufficiency,
multiple malformations such as nasal wing aplasia, and, frequently,
mental retardation. By homozygosity mapping in 7 kindreds with JBS,
Zenker et al. (2005) mapped the phenotype to 15q14-q21.1. There was no
obvious candidate gene based on putative function and expression data
found in the interval, but by high-throughput direct sequencing of DNA
from individuals with JBS, they eventually detected mutations in the
gene UBR1. In affected individuals from 12 of 13 families included in
the study, the variations likely to be causal mutations were identified
in both alleles of UBR1, whereas in 1 family, only the paternally
inherited mutation was found. Most disease-associated UBR1 alleles (12
of 14) were mutations that predicted premature translational stop
codons. Two missense mutations in UBR1 caused substitutions of residues
that are conserved among UBR1 proteins of different species. One of
these missense mutations, H136R (605981.0001), affected a conserved
motif in the region of UBR1 found to be important for substrate binding
(Tasaki et al., 2005). Two apparently unrelated and nonconsanguineous
families originating from the same district in Costa Rica shared the
same homozygous mutation, Q513X (605981.0003). Haplotype analysis in
these families provided evidence for a common ancestor.
ANIMAL MODEL
To analyze molecular aspects of perturbations in Johanson-Blizzard
syndrome that would be difficult or impossible to address in human
autopsy material, Zenker et al. (2005) used Ubr1 -/- mice. These mice
were viable and fertile and lacked substantial phenotypic abnormalities
other than reduced weight, with disproportionate decreases in skeletal
muscle and adipose tissue (Kwon et al., 2001). Among other findings, the
pancreas of Ubr1 -/- mice was considerably (approximately 100 times)
less responsive to stimulation with the physiologic secretagogue
cholecystokinin (118440). This difference suggested that a signaling
circuit that couples the secretion of pancreatic enzymes to the level of
a secretion-causing compound is controlled by the N-end rule pathway.
Further analysis used an in vivo model of acinar cell stress and
experimental pancreatitis in which supraphysiologic concentrations of
secretagogue resulted in a 'paradoxical' block of pancreatic secretion.
They found that this treatment led to a more severe injury of Ubr1 -/-
pancreas, compared with wildtype, with prominent necrosis in the
deficient pancreas, as indicated by histologic evidence, serum amylase
levels, and other parameters of local pancreatic injury or systemic
inflammatory response. The results suggested that the intact (as
distinguished from Ubr1-deficient) N-end rule pathway contributes to
pancreatic homeostasis and defense against noxious stimuli in pancreatic
acinar cells.
*FIELD* AV
.0001
JOHANSON-BLIZZARD SYNDROME
UBR1, HIS136ARG
In a Dutch patient with Johanson-Blizzard syndrome (JBS; 243800) and
nonconsanguineous parents, Zenker et al. (2005) described compound
heterozygosity for 2 mutations in the UBR1 gene: a 407A-G transition in
exon 3 resulting in a his136-to-arg (H136R) amino acid change, and a
splice donor site mutation, IVS20+2T-C (605981.0002).
.0002
JOHANSON-BLIZZARD SYNDROME
UBR1, IVS20DS, T-C, +2
See 605981.0001 and Zenker et al. (2005).
.0003
JOHANSON-BLIZZARD SYNDROME
UBR1, GLN513TER
Zenker et al. (2005) found that 2 apparently unrelated nonconsanguineous
families originating from the same district in Costa Rica shared the
same homozygous mutation, gln513 to stop (Q513X), as the basis of
Johanson-Blizzard syndrome (JBS; 243800). These were Costa Rican Indian
families. Haplotype analysis provided evidence of a common ancestor. The
amino acid change was caused by a C-to-T transition at nucleotide 1537
in exon 13.
.0004
JOHANSON-BLIZZARD SYNDROME
UBR1, IVS26DS, G-A, +5
In 2 unrelated girls with a mild form of Johanson-Blizzard syndrome
(243800), Elting et al. (2008) identified a homozygous G-to-A transition
in intron 26 of the UBR1 gene. The girls were born of Turkish and
Iranian consanguineous parents, respectively. In addition to the mild
but classic features of the disorder, 1 girl had dilated cardiomyopathy,
whereas the other had a small atrial septal defect. A small amount of
normally spliced mRNA was detected in 1 of the girls, suggesting some
residual normal protein production.
.0005
JOHANSON-BLIZZARD SYNDROME
UBR1, IVS12AS, G-A, -1
In a male infant, born of consanguineous Saudi Arabian parents, with
Johanson-Blizzard syndrome (243800), Al-Dosari et al. (2008) identified
a homozygous G-to-A transition in intron 12 of the UBR1 gene, predicted
to result in the skipping of exon 13, a frameshift, and premature
termination. The mutation was not found in 130 control chromosomes. At
birth, the patient had low birth weight, dysmorphic features with
aplastic alae nasi and unusual hair pattern, imperforate anus, hearing
loss, and hypothyroidism. He also developed severe liver involvement
with cholestasis and fibrosis causing liver failure. He did not have
evidence of pancreatic insufficiency.
*FIELD* RF
1. Al-Dosari, M. S.; Al-Muhsen, S.; Al-Jazaeri, A.; Mayerle, J.; Zenker,
M.; Alkuraya, F. S.: Johanson-Blizzard syndrome: report of a novel
mutation and severe liver involvement. Am. J. Med. Genet. 146A:
1875-1879, 2008.
2. Elting, M.; Kariminejad, A.; de Sonnaville, M.-L.; Ottenkamp, J.;
Bauhuber, S.; Bozorgmehr, B.; Zenker, M.; Cobben, J. M.: Johanson-Blizzard
syndrome caused by identical UBR1 mutations in two unrelated girls,
one with a cardiomyopathy. Am. J. Med. Genet. 146A: 3058-3061, 2008.
3. Kwon, Y. T.; Reiss, Y.; Fried, V. A.; Hershko, A.; Yoon, J. K.;
Gonda, D. K.; Sangan, P.; Copeland, N. G.; Jenkins, N. A.; Varshavsky,
A.: The mouse and human genes encoding the recognition component
of the N-end rule pathway. Proc. Nat. Acad. Sci. 95: 7898-7903,
1998.
4. Kwon, Y. T.; Xia, Z.; Davydov, I. V.; Lecker, S. H.; Varshavsky,
A.: Construction and analysis of mouse strains lacking the ubiquitin
ligase UBR1 (E3alpha) of the N-end rule pathway. Molec. Cell. Biol. 21:
8007-8021, 2001.
5. Tasaki, T.; Mulder, L. C. F.; Iwamatsu, A.; Lee, M. J.; Davydov,
I. V.; Varshavsky, A.; Muesing, M.; Kwon, Y. T.: A family of mammalian
E3 ubiquitin ligases that contain the UBR box motif and recognize
N-degrons. Molec. Cell. Biol. 25: 7120-7136, 2005.
6. Zenker, M.; Mayerle, J.; Lerch, M. M.; Tagariello, A.; Zerres,
K.; Durie, P. R.; Beier, M.; Hulskamp, G.; Guzman, C.; Rehder, H.;
Beemer, F. A.; Hamel, B.; and 14 others: Deficiency of UBR1, a
ubiquitin ligase of the N-end rule pathway, causes pancreatic dysfunction,
malformations and mental retardation (Johanson-Blizzard syndrome). Nature
Genet. 37: 1345-1350, 2005. Note: Erratum: Nature Genet. 38: 265
only, 2006.
*FIELD* CN
Cassandra L. Kniffin - updated: 6/18/2012
Cassandra L. Kniffin - updated: 12/29/2008
Victor A. McKusick - updated: 12/1/2005
*FIELD* CD
Victor A. McKusick: 5/30/2001
*FIELD* ED
carol: 09/10/2013
carol: 6/19/2012
ckniffin: 6/18/2012
terry: 2/29/2012
terry: 1/27/2012
wwang: 1/6/2009
ckniffin: 12/29/2008
wwang: 6/25/2007
terry: 6/21/2007
alopez: 2/3/2006
alopez: 1/18/2006
alopez: 12/6/2005
terry: 12/1/2005
carol: 11/14/2003
joanna: 1/28/2002
mgross: 5/30/2001
*RECORD*
*FIELD* NO
605981
*FIELD* TI
*605981 UBIQUITIN-PROTEIN LIGASE E3 COMPONENT N-RECOGNIN 1; UBR1
*FIELD* TX
DESCRIPTION
read more
A number of regulatory circuits involve metabolically unstable proteins.
Short in vivo half-lives are also characteristic of damaged or otherwise
abnormal proteins. Features of proteins that confer metabolic
instability are called degradation signals, or degrons. The essential
component of one degradation signal, called the N-degron, is a
destabilizing N-terminal residue of a protein. The set of amino acids
that are destabilizing in a given cell type yields a rule, called the
N-end rule, which relates the in vivo half-life of a protein to the
identity of its N-terminal residue. Similar but distinct versions of the
N-end rule pathway are present in all organisms that have been examined,
from mammals to fungi and bacteria. The N-end rule pathway is one
proteolytic pathway of the ubiquitin system. The recognition component
of this pathway, called N-recognin or E3, binds to a destabilizing
N-terminal residue of a substrate protein and participates in the
formation of a substrate-linked multiubiquitin chain (summary by Kwon et
al., 1998).
CLONING
Kwon et al. (1998) isolated full-length mouse Ubr1 cDNAs and partial
human UBR1 cDNAs, which encode an N-recognin called E3-alpha. The mouse
Ubr1 protein is a 1,757-residue, 200-kD protein that contains regions
with sequence similarity to the 225-kD UBR1 protein of S. cerevisiae.
There are apparent UBR1 homologs in other eukaryotes, thus defining a
distinct family of proteins, the UBR family. The residues essential for
substrate recognition by the yeast UBR1 protein are conserved in the
mouse Ubr1 protein. Regions of similarity among the UBR family members
include a putative zinc finger and RING-H2 finger, another zinc-binding
domain. Northern blot analysis detected ubiquitous expression in human
and adult mouse tissues, with highest levels in skeletal muscle and
heart. In mouse embryos, in situ hybridization showed that Ubr1
expression is highest in the branchial arches and in the tail and limb
buds. The authors suggested that the cloning of UBR1 makes possible the
construction of Ubr1-lacking mouse strains, a prerequisite for the
functional understanding of the mammalian N-end rule pathway.
GENE STRUCTURE
Zenker et al. (2005) stated that the UBR1 gene, which encodes one of the
E3 ubiquitin ligases of the N-end rule pathway, spans approximately 161
kb and contains 47 exons. The mouse Ubr1 gene spans approximately 120 kb
of genomic DNA and contains approximately 50 exons (Kwon et al., 1998).
MAPPING
By interspecific backcross analysis, Kwon et al. (1998) mapped the mouse
Ubr1 gene to the middle of chromosome 2. They mapped the human UBR1 gene
to 15q15-q21.1, which shows homology of synteny with mouse chromosome 2.
MOLECULAR GENETICS
Johanson-Blizzard syndrome (JBS; 243800) is an autosomal recessive
disorder that includes congenital exocrine pancreatic insufficiency,
multiple malformations such as nasal wing aplasia, and, frequently,
mental retardation. By homozygosity mapping in 7 kindreds with JBS,
Zenker et al. (2005) mapped the phenotype to 15q14-q21.1. There was no
obvious candidate gene based on putative function and expression data
found in the interval, but by high-throughput direct sequencing of DNA
from individuals with JBS, they eventually detected mutations in the
gene UBR1. In affected individuals from 12 of 13 families included in
the study, the variations likely to be causal mutations were identified
in both alleles of UBR1, whereas in 1 family, only the paternally
inherited mutation was found. Most disease-associated UBR1 alleles (12
of 14) were mutations that predicted premature translational stop
codons. Two missense mutations in UBR1 caused substitutions of residues
that are conserved among UBR1 proteins of different species. One of
these missense mutations, H136R (605981.0001), affected a conserved
motif in the region of UBR1 found to be important for substrate binding
(Tasaki et al., 2005). Two apparently unrelated and nonconsanguineous
families originating from the same district in Costa Rica shared the
same homozygous mutation, Q513X (605981.0003). Haplotype analysis in
these families provided evidence for a common ancestor.
ANIMAL MODEL
To analyze molecular aspects of perturbations in Johanson-Blizzard
syndrome that would be difficult or impossible to address in human
autopsy material, Zenker et al. (2005) used Ubr1 -/- mice. These mice
were viable and fertile and lacked substantial phenotypic abnormalities
other than reduced weight, with disproportionate decreases in skeletal
muscle and adipose tissue (Kwon et al., 2001). Among other findings, the
pancreas of Ubr1 -/- mice was considerably (approximately 100 times)
less responsive to stimulation with the physiologic secretagogue
cholecystokinin (118440). This difference suggested that a signaling
circuit that couples the secretion of pancreatic enzymes to the level of
a secretion-causing compound is controlled by the N-end rule pathway.
Further analysis used an in vivo model of acinar cell stress and
experimental pancreatitis in which supraphysiologic concentrations of
secretagogue resulted in a 'paradoxical' block of pancreatic secretion.
They found that this treatment led to a more severe injury of Ubr1 -/-
pancreas, compared with wildtype, with prominent necrosis in the
deficient pancreas, as indicated by histologic evidence, serum amylase
levels, and other parameters of local pancreatic injury or systemic
inflammatory response. The results suggested that the intact (as
distinguished from Ubr1-deficient) N-end rule pathway contributes to
pancreatic homeostasis and defense against noxious stimuli in pancreatic
acinar cells.
*FIELD* AV
.0001
JOHANSON-BLIZZARD SYNDROME
UBR1, HIS136ARG
In a Dutch patient with Johanson-Blizzard syndrome (JBS; 243800) and
nonconsanguineous parents, Zenker et al. (2005) described compound
heterozygosity for 2 mutations in the UBR1 gene: a 407A-G transition in
exon 3 resulting in a his136-to-arg (H136R) amino acid change, and a
splice donor site mutation, IVS20+2T-C (605981.0002).
.0002
JOHANSON-BLIZZARD SYNDROME
UBR1, IVS20DS, T-C, +2
See 605981.0001 and Zenker et al. (2005).
.0003
JOHANSON-BLIZZARD SYNDROME
UBR1, GLN513TER
Zenker et al. (2005) found that 2 apparently unrelated nonconsanguineous
families originating from the same district in Costa Rica shared the
same homozygous mutation, gln513 to stop (Q513X), as the basis of
Johanson-Blizzard syndrome (JBS; 243800). These were Costa Rican Indian
families. Haplotype analysis provided evidence of a common ancestor. The
amino acid change was caused by a C-to-T transition at nucleotide 1537
in exon 13.
.0004
JOHANSON-BLIZZARD SYNDROME
UBR1, IVS26DS, G-A, +5
In 2 unrelated girls with a mild form of Johanson-Blizzard syndrome
(243800), Elting et al. (2008) identified a homozygous G-to-A transition
in intron 26 of the UBR1 gene. The girls were born of Turkish and
Iranian consanguineous parents, respectively. In addition to the mild
but classic features of the disorder, 1 girl had dilated cardiomyopathy,
whereas the other had a small atrial septal defect. A small amount of
normally spliced mRNA was detected in 1 of the girls, suggesting some
residual normal protein production.
.0005
JOHANSON-BLIZZARD SYNDROME
UBR1, IVS12AS, G-A, -1
In a male infant, born of consanguineous Saudi Arabian parents, with
Johanson-Blizzard syndrome (243800), Al-Dosari et al. (2008) identified
a homozygous G-to-A transition in intron 12 of the UBR1 gene, predicted
to result in the skipping of exon 13, a frameshift, and premature
termination. The mutation was not found in 130 control chromosomes. At
birth, the patient had low birth weight, dysmorphic features with
aplastic alae nasi and unusual hair pattern, imperforate anus, hearing
loss, and hypothyroidism. He also developed severe liver involvement
with cholestasis and fibrosis causing liver failure. He did not have
evidence of pancreatic insufficiency.
*FIELD* RF
1. Al-Dosari, M. S.; Al-Muhsen, S.; Al-Jazaeri, A.; Mayerle, J.; Zenker,
M.; Alkuraya, F. S.: Johanson-Blizzard syndrome: report of a novel
mutation and severe liver involvement. Am. J. Med. Genet. 146A:
1875-1879, 2008.
2. Elting, M.; Kariminejad, A.; de Sonnaville, M.-L.; Ottenkamp, J.;
Bauhuber, S.; Bozorgmehr, B.; Zenker, M.; Cobben, J. M.: Johanson-Blizzard
syndrome caused by identical UBR1 mutations in two unrelated girls,
one with a cardiomyopathy. Am. J. Med. Genet. 146A: 3058-3061, 2008.
3. Kwon, Y. T.; Reiss, Y.; Fried, V. A.; Hershko, A.; Yoon, J. K.;
Gonda, D. K.; Sangan, P.; Copeland, N. G.; Jenkins, N. A.; Varshavsky,
A.: The mouse and human genes encoding the recognition component
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*FIELD* CN
Cassandra L. Kniffin - updated: 6/18/2012
Cassandra L. Kniffin - updated: 12/29/2008
Victor A. McKusick - updated: 12/1/2005
*FIELD* CD
Victor A. McKusick: 5/30/2001
*FIELD* ED
carol: 09/10/2013
carol: 6/19/2012
ckniffin: 6/18/2012
terry: 2/29/2012
terry: 1/27/2012
wwang: 1/6/2009
ckniffin: 12/29/2008
wwang: 6/25/2007
terry: 6/21/2007
alopez: 2/3/2006
alopez: 1/18/2006
alopez: 12/6/2005
terry: 12/1/2005
carol: 11/14/2003
joanna: 1/28/2002
mgross: 5/30/2001