Full text data of STAMBP
STAMBP
(AMSH)
[Confidence: low (only semi-automatic identification from reviews)]
STAM-binding protein; 3.4.19.- (Associated molecule with the SH3 domain of STAM; Endosome-associated ubiquitin isopeptidase)
STAM-binding protein; 3.4.19.- (Associated molecule with the SH3 domain of STAM; Endosome-associated ubiquitin isopeptidase)
UniProt
O95630
ID STABP_HUMAN Reviewed; 424 AA.
AC O95630; D6W5H7; Q3MJE7;
DT 19-JUL-2005, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-MAY-1999, sequence version 1.
DT 22-JAN-2014, entry version 113.
DE RecName: Full=STAM-binding protein;
DE EC=3.4.19.-;
DE AltName: Full=Associated molecule with the SH3 domain of STAM;
DE AltName: Full=Endosome-associated ubiquitin isopeptidase;
GN Name=STAMBP; Synonyms=AMSH;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND INTERACTION WITH STAM1.
RC TISSUE=Peripheral blood lymphocyte;
RX PubMed=10383417; DOI=10.1074/jbc.274.27.19129;
RA Tanaka N., Kaneko K., Asao H., Kasai H., Endo Y., Fujita T.,
RA Takeshita T., Sugamura K.;
RT "Possible involvement of a novel STAM-associated molecule 'AMSH' in
RT intracellular signal transduction mediated by cytokines.";
RL J. Biol. Chem. 274:19129-19135(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain, Eye, and Lymph;
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 FUNCTION, INTERACTION WITH SMAD6 AND SMAD7, SUBCELLULAR LOCATION, AND
RP PHOSPHORYLATION AT SER-2; SER-48; SER-243; SER-245 AND SER-247.
RX PubMed=11483516; DOI=10.1093/emboj/20.15.4132;
RA Itoh F., Asao H., Sugamura K., Heldin C.-H., ten Dijke P., Itoh S.;
RT "Promoting bone morphogenetic protein signaling through negative
RT regulation of inhibitory Smads.";
RL EMBO J. 20:4132-4142(2001).
RN [6]
RP INVOLVEMENT OF GLU-280; HIS-335 AND HIS-337 IN ZINC-BINDING.
RX PubMed=12370088;
RA Maytal-Kivity V., Reis N., Hofmann K., Glickman M.H.;
RT "MPN+, a putative catalytic motif found in a subset of MPN domain
RT proteins from eukaryotes and prokaryotes, is critical for Rpn11
RT function.";
RL BMC Biochem. 3:28-28(2002).
RN [7]
RP MUTAGENESIS OF ASP-348, FUNCTION, SUBCELLULAR LOCATION, AND
RP INTERACTION WITH STAM1.
RX PubMed=15314065; DOI=10.1083/jcb.200401141;
RA McCullough J., Clague M.J., Urbe S.;
RT "AMSH is an endosome-associated ubiquitin isopeptidase.";
RL J. Cell Biol. 166:487-492(2004).
RN [8]
RP INTERACTION WITH SMURF2 AND RNF11, AND UBIQUITINATION.
RX PubMed=14755250; DOI=10.1038/sj.onc.1207319;
RA Li H., Seth A.K.;
RT "An RNF11: Smurf2 complex mediates ubiquitination of the AMSH
RT protein.";
RL Oncogene 23:1801-1808(2004).
RN [9]
RP INTERACTION WITH CHMP3.
RX PubMed=17146056; DOI=10.1073/pnas.0603788103;
RA Zamborlini A., Usami Y., Radoshitzky S.R., Popova E., Palu G.,
RA Goettlinger H.;
RT "Release of autoinhibition converts ESCRT-III components into potent
RT inhibitors of HIV-1 budding.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:19140-19145(2006).
RN [10]
RP FUNCTION, INTERACTION WITH CHMP3, AND SUBCELLULAR LOCATION.
RX PubMed=17261583; DOI=10.1074/jbc.M611635200;
RA Ma Y.M., Boucrot E., Villen J., Affar el B., Gygi S.P.,
RA Goettlinger H.G., Kirchhausen T.;
RT "Targeting of AMSH to endosomes is required for epidermal growth
RT factor receptor degradation.";
RL J. Biol. Chem. 282:9805-9812(2007).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [12]
RP FUNCTION, AND VARIANTS MICCAP PRO-14; CYS-38; GLY-42; CYS-63; TYR-100
RP AND ILE-313.
RX PubMed=23542699; DOI=10.1038/ng.2602;
RG FORGE Canada Consortium;
RA McDonell L.M., Mirzaa G.M., Alcantara D., Schwartzentruber J.,
RA Carter M.T., Lee L.J., Clericuzio C.L., Graham J.M. Jr.,
RA Morris-Rosendahl D.J., Polster T., Acsadi G., Townshend S.,
RA Williams S., Halbert A., Isidor B., David A., Smyser C.D.,
RA Paciorkowski A.R., Willing M., Woulfe J., Das S., Beaulieu C.L.,
RA Marcadier J., Geraghty M.T., Frey B.J., Majewski J., Bulman D.E.,
RA Dobyns W.B., O'Driscoll M., Boycott K.M.;
RT "Mutations in STAMBP, encoding a deubiquitinating enzyme, cause
RT microcephaly-capillary malformation syndrome.";
RL Nat. Genet. 45:556-562(2013).
CC -!- FUNCTION: Zinc metalloprotease that specifically cleaves 'Lys-63'-
CC linked polyubiquitin chains. Does not cleave 'Lys-48'-linked
CC polyubiquitin chains (By similarity). Plays a role in signal
CC transduction for cell growth and MYC induction mediated by IL-2
CC and GM-CSF. Potentiates BMP (bone morphogenetic protein) signaling
CC by antagonizing the inhibitory action of SMAD6 and SMAD7. Has a
CC key role in regulation of cell surface receptor-mediated
CC endocytosis and ubiquitin-dependent sorting of receptors to
CC lysosomes. Endosomal localization of STAMBP is required for
CC efficient EGFR degradation but not for its internalization (By
CC similarity). Involved in the negative regulation of PI3K-AKT-mTOR
CC and RAS-MAP signaling pathways.
CC -!- COFACTOR: Binds 2 zinc ions per subunit (By similarity).
CC -!- ENZYME REGULATION: Inhibited by N-ethylmaleimide.
CC -!- SUBUNIT: Interacts with STAM1. Interacts with SMAD6 and SMAD7.
CC Interacts with CHMP3; the interaction appears to relieve the
CC autoinhibition of CHMP3. Interacts with SMURF2 and RNF11; this
CC interaction promotes ubiquitination.
CC -!- INTERACTION:
CC Q9HD42:CHMP1A; NbExp=3; IntAct=EBI-396676, EBI-1057156;
CC Q7LBR1:CHMP1B; NbExp=5; IntAct=EBI-396676, EBI-2118090;
CC Q9Y3E7:CHMP3; NbExp=5; IntAct=EBI-396676, EBI-2118119;
CC Q9NZZ3:CHMP5; NbExp=2; IntAct=EBI-396676, EBI-751303;
CC P62993:GRB2; NbExp=3; IntAct=EBI-396676, EBI-401755;
CC Q9Y3C5:RNF11; NbExp=2; IntAct=EBI-396676, EBI-396669;
CC O43541-2:SMAD6; NbExp=2; IntAct=EBI-396676, EBI-4324970;
CC Q92783:STAM; NbExp=6; IntAct=EBI-396676, EBI-752333;
CC O75886:STAM2; NbExp=3; IntAct=EBI-396676, EBI-373258;
CC -!- SUBCELLULAR LOCATION: Nucleus. Membrane; Peripheral membrane
CC protein. Cytoplasm. Early endosome.
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed.
CC -!- DOMAIN: The JAMM motif is essential for the protease activity (By
CC similarity).
CC -!- PTM: Phosphorylated after BMP type I receptor activation.
CC -!- PTM: Ubiquitinated by SMURF2 in the presence of RNF11.
CC -!- DISEASE: Microcephaly-capillary malformation syndrome (MICCAP)
CC [MIM:614261]: A congenital disorder characterized by severe
CC progressive microcephaly, early-onset refractory epilepsy,
CC profound developmental delay, and multiple small capillary
CC malformations spread diffusely on the body. Additional more
CC variable features include dysmorphic facial features, distal limb
CC abnormalities, and mild heart defects. Note=The disease is caused
CC by mutations affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: X-ray crystallography studies of STAMBPL1, another
CC member of the peptidase M67C family, has shown that Glu-280 binds
CC zinc indirectly via a water molecule. Nevertheless, this residue
CC is essential for catalytic activity.
CC -!- SIMILARITY: Belongs to the peptidase M67C family.
CC -!- SIMILARITY: Contains 1 MPN (JAB/Mov34) domain.
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DR EMBL; U73522; AAD05037.1; -; mRNA.
DR EMBL; AC073046; AAX88908.1; -; Genomic_DNA.
DR EMBL; CH471053; EAW99715.1; -; Genomic_DNA.
DR EMBL; CH471053; EAW99716.1; -; Genomic_DNA.
DR EMBL; BC007682; AAH07682.1; -; mRNA.
DR EMBL; BC065574; AAH65574.1; -; mRNA.
DR EMBL; BC101467; AAI01468.1; -; mRNA.
DR EMBL; BC101469; AAI01470.1; -; mRNA.
DR RefSeq; NP_006454.1; NM_006463.4.
DR RefSeq; NP_964010.1; NM_201647.2.
DR RefSeq; NP_998787.1; NM_213622.2.
DR RefSeq; XP_005264145.1; XM_005264088.1.
DR RefSeq; XP_005264146.1; XM_005264089.1.
DR UniGene; Hs.469018; -.
DR PDB; 2XZE; X-ray; 1.75 A; A/B=1-146.
DR PDB; 3RZU; X-ray; 2.50 A; A/B/C/D/E/F/G=243-424.
DR PDB; 3RZV; X-ray; 1.67 A; A=219-424.
DR PDBsum; 2XZE; -.
DR PDBsum; 3RZU; -.
DR PDBsum; 3RZV; -.
DR ProteinModelPortal; O95630; -.
DR SMR; O95630; 2-142, 248-424.
DR DIP; DIP-33062N; -.
DR IntAct; O95630; 29.
DR MINT; MINT-96921; -.
DR STRING; 9606.ENSP00000344742; -.
DR MEROPS; M67.006; -.
DR PhosphoSite; O95630; -.
DR REPRODUCTION-2DPAGE; IPI00007943; -.
DR PaxDb; O95630; -.
DR PeptideAtlas; O95630; -.
DR PRIDE; O95630; -.
DR DNASU; 10617; -.
DR Ensembl; ENST00000339566; ENSP00000344742; ENSG00000124356.
DR Ensembl; ENST00000394070; ENSP00000377633; ENSG00000124356.
DR Ensembl; ENST00000394073; ENSP00000377636; ENSG00000124356.
DR Ensembl; ENST00000409707; ENSP00000386548; ENSG00000124356.
DR GeneID; 10617; -.
DR KEGG; hsa:10617; -.
DR UCSC; uc002sjs.3; human.
DR CTD; 10617; -.
DR GeneCards; GC02P074056; -.
DR HGNC; HGNC:16950; STAMBP.
DR HPA; HPA035800; -.
DR MIM; 606247; gene.
DR MIM; 614261; phenotype.
DR neXtProt; NX_O95630; -.
DR Orphanet; 294016; Microcephaly-capillary malformation syndrome.
DR PharmGKB; PA134955569; -.
DR eggNOG; COG1310; -.
DR HOGENOM; HOG000195792; -.
DR HOVERGEN; HBG058519; -.
DR InParanoid; O95630; -.
DR KO; K11866; -.
DR OMA; PSDCHTT; -.
DR OrthoDB; EOG7NW698; -.
DR PhylomeDB; O95630; -.
DR SignaLink; O95630; -.
DR GeneWiki; STAMBP; -.
DR GenomeRNAi; 10617; -.
DR NextBio; 40340; -.
DR PRO; PR:O95630; -.
DR ArrayExpress; O95630; -.
DR Bgee; O95630; -.
DR CleanEx; HS_STAMBP; -.
DR Genevestigator; O95630; -.
DR GO; GO:0032154; C:cleavage furrow; IDA:MGI.
DR GO; GO:0005737; C:cytoplasm; IDA:HPA.
DR GO; GO:0005769; C:early endosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IDA:HPA.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0004843; F:deubiquitinase activity; IDA:MGI.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0008237; F:metallopeptidase activity; IEA:UniProtKB-KW.
DR GO; GO:0007259; P:JAK-STAT cascade; TAS:ProtInc.
DR GO; GO:0000281; P:mitotic cytokinesis; IMP:MGI.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IEA:Ensembl.
DR GO; GO:0014067; P:negative regulation of phosphatidylinositol 3-kinase cascade; IMP:UniProtKB.
DR GO; GO:0046580; P:negative regulation of Ras protein signal transduction; IMP:UniProtKB.
DR GO; GO:0008284; P:positive regulation of cell proliferation; TAS:ProtInc.
DR GO; GO:0016579; P:protein deubiquitination; IMP:MGI.
DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR InterPro; IPR000555; JAB_MPN_dom.
DR InterPro; IPR015063; USP8_dimer.
DR Pfam; PF01398; JAB; 1.
DR Pfam; PF08969; USP8_dimer; 1.
DR SMART; SM00232; JAB_MPN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Complete proteome; Cytoplasm; Disease mutation;
KW Endosome; Hydrolase; Membrane; Metal-binding; Metalloprotease;
KW Nucleus; Phosphoprotein; Protease; Reference proteome;
KW Ubl conjugation; Ubl conjugation pathway; Zinc.
FT CHAIN 1 424 STAM-binding protein.
FT /FTId=PRO_0000194869.
FT DOMAIN 252 361 MPN.
FT REGION 1 127 Interaction with CHMP3.
FT REGION 227 231 Interaction with STAM1.
FT MOTIF 335 348 JAMM motif.
FT COMPBIAS 104 177 Glu-rich.
FT METAL 335 335 Zinc 1; catalytic (By similarity).
FT METAL 337 337 Zinc 1; catalytic (By similarity).
FT METAL 348 348 Zinc 1; catalytic (By similarity).
FT METAL 350 350 Zinc 2 (By similarity).
FT METAL 390 390 Zinc 2 (By similarity).
FT METAL 396 396 Zinc 2 (By similarity).
FT METAL 398 398 Zinc 2 (By similarity).
FT SITE 280 280 Indirect zinc-binding (By similarity).
FT MOD_RES 2 2 Phosphoserine.
FT MOD_RES 48 48 Phosphoserine.
FT MOD_RES 243 243 Phosphoserine.
FT MOD_RES 245 245 Phosphoserine.
FT MOD_RES 247 247 Phosphoserine.
FT VARIANT 14 14 R -> P (in MICCAP).
FT /FTId=VAR_069806.
FT VARIANT 38 38 R -> C (in MICCAP).
FT /FTId=VAR_069807.
FT VARIANT 42 42 E -> G (in MICCAP).
FT /FTId=VAR_069808.
FT VARIANT 63 63 Y -> C (in MICCAP).
FT /FTId=VAR_069809.
FT VARIANT 100 100 F -> Y (in MICCAP).
FT /FTId=VAR_069810.
FT VARIANT 313 313 T -> I (in MICCAP).
FT /FTId=VAR_069811.
FT MUTAGEN 348 348 D->A: Promotes accumulation of ubiquitin
FT on endosomes, ablates enzymatic activity
FT toward polyubiquitin substrate and allows
FT ubiquitinated STAM stabilization.
FT HELIX 11 22
FT HELIX 33 53
FT HELIX 56 71
FT HELIX 74 76
FT TURN 78 82
FT HELIX 88 97
FT HELIX 99 137
FT STRAND 257 260
FT HELIX 263 276
FT STRAND 282 290
FT STRAND 293 301
FT STRAND 304 306
FT STRAND 311 313
FT HELIX 316 326
FT STRAND 329 336
FT STRAND 338 340
FT HELIX 346 358
FT STRAND 363 368
FT TURN 369 372
FT STRAND 373 379
FT HELIX 381 389
FT STRAND 404 407
FT STRAND 409 414
FT STRAND 419 422
SQ SEQUENCE 424 AA; 48077 MW; 7B6E08A245BD9D43 CRC64;
MSDHGDVSLP PEDRVRALSQ LGSAVEVNED IPPRRYFRSG VEIIRMASIY SEEGNIEHAF
ILYNKYITLF IEKLPKHRDY KSAVIPEKKD TVKKLKEIAF PKAEELKAEL LKRYTKEYTE
YNEEKKKEAE ELARNMAIQQ ELEKEKQRVA QQKQQQLEQE QFHAFEEMIR NQELEKERLK
IVQEFGKVDP GLGGPLVPDL EKPSLDVFPT LTVSSIQPSD CHTTVRPAKP PVVDRSLKPG
ALSNSESIPT IDGLRHVVVP GRLCPQFLQL ASANTARGVE TCGILCGKLM RNEFTITHVL
IPKQSAGSDY CNTENEEELF LIQDQQGLIT LGWIHTHPTQ TAFLSSVDLH THCSYQMMLP
ESVAIVCSPK FQETGFFKLT DHGLEEISSC RQKGFHPHSK DPPLFCSCSH VTVVDRAVTI
TDLR
//
ID STABP_HUMAN Reviewed; 424 AA.
AC O95630; D6W5H7; Q3MJE7;
DT 19-JUL-2005, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-MAY-1999, sequence version 1.
DT 22-JAN-2014, entry version 113.
DE RecName: Full=STAM-binding protein;
DE EC=3.4.19.-;
DE AltName: Full=Associated molecule with the SH3 domain of STAM;
DE AltName: Full=Endosome-associated ubiquitin isopeptidase;
GN Name=STAMBP; Synonyms=AMSH;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND INTERACTION WITH STAM1.
RC TISSUE=Peripheral blood lymphocyte;
RX PubMed=10383417; DOI=10.1074/jbc.274.27.19129;
RA Tanaka N., Kaneko K., Asao H., Kasai H., Endo Y., Fujita T.,
RA Takeshita T., Sugamura K.;
RT "Possible involvement of a novel STAM-associated molecule 'AMSH' in
RT intracellular signal transduction mediated by cytokines.";
RL J. Biol. Chem. 274:19129-19135(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain, Eye, and Lymph;
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 FUNCTION, INTERACTION WITH SMAD6 AND SMAD7, SUBCELLULAR LOCATION, AND
RP PHOSPHORYLATION AT SER-2; SER-48; SER-243; SER-245 AND SER-247.
RX PubMed=11483516; DOI=10.1093/emboj/20.15.4132;
RA Itoh F., Asao H., Sugamura K., Heldin C.-H., ten Dijke P., Itoh S.;
RT "Promoting bone morphogenetic protein signaling through negative
RT regulation of inhibitory Smads.";
RL EMBO J. 20:4132-4142(2001).
RN [6]
RP INVOLVEMENT OF GLU-280; HIS-335 AND HIS-337 IN ZINC-BINDING.
RX PubMed=12370088;
RA Maytal-Kivity V., Reis N., Hofmann K., Glickman M.H.;
RT "MPN+, a putative catalytic motif found in a subset of MPN domain
RT proteins from eukaryotes and prokaryotes, is critical for Rpn11
RT function.";
RL BMC Biochem. 3:28-28(2002).
RN [7]
RP MUTAGENESIS OF ASP-348, FUNCTION, SUBCELLULAR LOCATION, AND
RP INTERACTION WITH STAM1.
RX PubMed=15314065; DOI=10.1083/jcb.200401141;
RA McCullough J., Clague M.J., Urbe S.;
RT "AMSH is an endosome-associated ubiquitin isopeptidase.";
RL J. Cell Biol. 166:487-492(2004).
RN [8]
RP INTERACTION WITH SMURF2 AND RNF11, AND UBIQUITINATION.
RX PubMed=14755250; DOI=10.1038/sj.onc.1207319;
RA Li H., Seth A.K.;
RT "An RNF11: Smurf2 complex mediates ubiquitination of the AMSH
RT protein.";
RL Oncogene 23:1801-1808(2004).
RN [9]
RP INTERACTION WITH CHMP3.
RX PubMed=17146056; DOI=10.1073/pnas.0603788103;
RA Zamborlini A., Usami Y., Radoshitzky S.R., Popova E., Palu G.,
RA Goettlinger H.;
RT "Release of autoinhibition converts ESCRT-III components into potent
RT inhibitors of HIV-1 budding.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:19140-19145(2006).
RN [10]
RP FUNCTION, INTERACTION WITH CHMP3, AND SUBCELLULAR LOCATION.
RX PubMed=17261583; DOI=10.1074/jbc.M611635200;
RA Ma Y.M., Boucrot E., Villen J., Affar el B., Gygi S.P.,
RA Goettlinger H.G., Kirchhausen T.;
RT "Targeting of AMSH to endosomes is required for epidermal growth
RT factor receptor degradation.";
RL J. Biol. Chem. 282:9805-9812(2007).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [12]
RP FUNCTION, AND VARIANTS MICCAP PRO-14; CYS-38; GLY-42; CYS-63; TYR-100
RP AND ILE-313.
RX PubMed=23542699; DOI=10.1038/ng.2602;
RG FORGE Canada Consortium;
RA McDonell L.M., Mirzaa G.M., Alcantara D., Schwartzentruber J.,
RA Carter M.T., Lee L.J., Clericuzio C.L., Graham J.M. Jr.,
RA Morris-Rosendahl D.J., Polster T., Acsadi G., Townshend S.,
RA Williams S., Halbert A., Isidor B., David A., Smyser C.D.,
RA Paciorkowski A.R., Willing M., Woulfe J., Das S., Beaulieu C.L.,
RA Marcadier J., Geraghty M.T., Frey B.J., Majewski J., Bulman D.E.,
RA Dobyns W.B., O'Driscoll M., Boycott K.M.;
RT "Mutations in STAMBP, encoding a deubiquitinating enzyme, cause
RT microcephaly-capillary malformation syndrome.";
RL Nat. Genet. 45:556-562(2013).
CC -!- FUNCTION: Zinc metalloprotease that specifically cleaves 'Lys-63'-
CC linked polyubiquitin chains. Does not cleave 'Lys-48'-linked
CC polyubiquitin chains (By similarity). Plays a role in signal
CC transduction for cell growth and MYC induction mediated by IL-2
CC and GM-CSF. Potentiates BMP (bone morphogenetic protein) signaling
CC by antagonizing the inhibitory action of SMAD6 and SMAD7. Has a
CC key role in regulation of cell surface receptor-mediated
CC endocytosis and ubiquitin-dependent sorting of receptors to
CC lysosomes. Endosomal localization of STAMBP is required for
CC efficient EGFR degradation but not for its internalization (By
CC similarity). Involved in the negative regulation of PI3K-AKT-mTOR
CC and RAS-MAP signaling pathways.
CC -!- COFACTOR: Binds 2 zinc ions per subunit (By similarity).
CC -!- ENZYME REGULATION: Inhibited by N-ethylmaleimide.
CC -!- SUBUNIT: Interacts with STAM1. Interacts with SMAD6 and SMAD7.
CC Interacts with CHMP3; the interaction appears to relieve the
CC autoinhibition of CHMP3. Interacts with SMURF2 and RNF11; this
CC interaction promotes ubiquitination.
CC -!- INTERACTION:
CC Q9HD42:CHMP1A; NbExp=3; IntAct=EBI-396676, EBI-1057156;
CC Q7LBR1:CHMP1B; NbExp=5; IntAct=EBI-396676, EBI-2118090;
CC Q9Y3E7:CHMP3; NbExp=5; IntAct=EBI-396676, EBI-2118119;
CC Q9NZZ3:CHMP5; NbExp=2; IntAct=EBI-396676, EBI-751303;
CC P62993:GRB2; NbExp=3; IntAct=EBI-396676, EBI-401755;
CC Q9Y3C5:RNF11; NbExp=2; IntAct=EBI-396676, EBI-396669;
CC O43541-2:SMAD6; NbExp=2; IntAct=EBI-396676, EBI-4324970;
CC Q92783:STAM; NbExp=6; IntAct=EBI-396676, EBI-752333;
CC O75886:STAM2; NbExp=3; IntAct=EBI-396676, EBI-373258;
CC -!- SUBCELLULAR LOCATION: Nucleus. Membrane; Peripheral membrane
CC protein. Cytoplasm. Early endosome.
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed.
CC -!- DOMAIN: The JAMM motif is essential for the protease activity (By
CC similarity).
CC -!- PTM: Phosphorylated after BMP type I receptor activation.
CC -!- PTM: Ubiquitinated by SMURF2 in the presence of RNF11.
CC -!- DISEASE: Microcephaly-capillary malformation syndrome (MICCAP)
CC [MIM:614261]: A congenital disorder characterized by severe
CC progressive microcephaly, early-onset refractory epilepsy,
CC profound developmental delay, and multiple small capillary
CC malformations spread diffusely on the body. Additional more
CC variable features include dysmorphic facial features, distal limb
CC abnormalities, and mild heart defects. Note=The disease is caused
CC by mutations affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: X-ray crystallography studies of STAMBPL1, another
CC member of the peptidase M67C family, has shown that Glu-280 binds
CC zinc indirectly via a water molecule. Nevertheless, this residue
CC is essential for catalytic activity.
CC -!- SIMILARITY: Belongs to the peptidase M67C family.
CC -!- SIMILARITY: Contains 1 MPN (JAB/Mov34) domain.
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DR EMBL; U73522; AAD05037.1; -; mRNA.
DR EMBL; AC073046; AAX88908.1; -; Genomic_DNA.
DR EMBL; CH471053; EAW99715.1; -; Genomic_DNA.
DR EMBL; CH471053; EAW99716.1; -; Genomic_DNA.
DR EMBL; BC007682; AAH07682.1; -; mRNA.
DR EMBL; BC065574; AAH65574.1; -; mRNA.
DR EMBL; BC101467; AAI01468.1; -; mRNA.
DR EMBL; BC101469; AAI01470.1; -; mRNA.
DR RefSeq; NP_006454.1; NM_006463.4.
DR RefSeq; NP_964010.1; NM_201647.2.
DR RefSeq; NP_998787.1; NM_213622.2.
DR RefSeq; XP_005264145.1; XM_005264088.1.
DR RefSeq; XP_005264146.1; XM_005264089.1.
DR UniGene; Hs.469018; -.
DR PDB; 2XZE; X-ray; 1.75 A; A/B=1-146.
DR PDB; 3RZU; X-ray; 2.50 A; A/B/C/D/E/F/G=243-424.
DR PDB; 3RZV; X-ray; 1.67 A; A=219-424.
DR PDBsum; 2XZE; -.
DR PDBsum; 3RZU; -.
DR PDBsum; 3RZV; -.
DR ProteinModelPortal; O95630; -.
DR SMR; O95630; 2-142, 248-424.
DR DIP; DIP-33062N; -.
DR IntAct; O95630; 29.
DR MINT; MINT-96921; -.
DR STRING; 9606.ENSP00000344742; -.
DR MEROPS; M67.006; -.
DR PhosphoSite; O95630; -.
DR REPRODUCTION-2DPAGE; IPI00007943; -.
DR PaxDb; O95630; -.
DR PeptideAtlas; O95630; -.
DR PRIDE; O95630; -.
DR DNASU; 10617; -.
DR Ensembl; ENST00000339566; ENSP00000344742; ENSG00000124356.
DR Ensembl; ENST00000394070; ENSP00000377633; ENSG00000124356.
DR Ensembl; ENST00000394073; ENSP00000377636; ENSG00000124356.
DR Ensembl; ENST00000409707; ENSP00000386548; ENSG00000124356.
DR GeneID; 10617; -.
DR KEGG; hsa:10617; -.
DR UCSC; uc002sjs.3; human.
DR CTD; 10617; -.
DR GeneCards; GC02P074056; -.
DR HGNC; HGNC:16950; STAMBP.
DR HPA; HPA035800; -.
DR MIM; 606247; gene.
DR MIM; 614261; phenotype.
DR neXtProt; NX_O95630; -.
DR Orphanet; 294016; Microcephaly-capillary malformation syndrome.
DR PharmGKB; PA134955569; -.
DR eggNOG; COG1310; -.
DR HOGENOM; HOG000195792; -.
DR HOVERGEN; HBG058519; -.
DR InParanoid; O95630; -.
DR KO; K11866; -.
DR OMA; PSDCHTT; -.
DR OrthoDB; EOG7NW698; -.
DR PhylomeDB; O95630; -.
DR SignaLink; O95630; -.
DR GeneWiki; STAMBP; -.
DR GenomeRNAi; 10617; -.
DR NextBio; 40340; -.
DR PRO; PR:O95630; -.
DR ArrayExpress; O95630; -.
DR Bgee; O95630; -.
DR CleanEx; HS_STAMBP; -.
DR Genevestigator; O95630; -.
DR GO; GO:0032154; C:cleavage furrow; IDA:MGI.
DR GO; GO:0005737; C:cytoplasm; IDA:HPA.
DR GO; GO:0005769; C:early endosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IDA:HPA.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0004843; F:deubiquitinase activity; IDA:MGI.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0008237; F:metallopeptidase activity; IEA:UniProtKB-KW.
DR GO; GO:0007259; P:JAK-STAT cascade; TAS:ProtInc.
DR GO; GO:0000281; P:mitotic cytokinesis; IMP:MGI.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IEA:Ensembl.
DR GO; GO:0014067; P:negative regulation of phosphatidylinositol 3-kinase cascade; IMP:UniProtKB.
DR GO; GO:0046580; P:negative regulation of Ras protein signal transduction; IMP:UniProtKB.
DR GO; GO:0008284; P:positive regulation of cell proliferation; TAS:ProtInc.
DR GO; GO:0016579; P:protein deubiquitination; IMP:MGI.
DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR InterPro; IPR000555; JAB_MPN_dom.
DR InterPro; IPR015063; USP8_dimer.
DR Pfam; PF01398; JAB; 1.
DR Pfam; PF08969; USP8_dimer; 1.
DR SMART; SM00232; JAB_MPN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Complete proteome; Cytoplasm; Disease mutation;
KW Endosome; Hydrolase; Membrane; Metal-binding; Metalloprotease;
KW Nucleus; Phosphoprotein; Protease; Reference proteome;
KW Ubl conjugation; Ubl conjugation pathway; Zinc.
FT CHAIN 1 424 STAM-binding protein.
FT /FTId=PRO_0000194869.
FT DOMAIN 252 361 MPN.
FT REGION 1 127 Interaction with CHMP3.
FT REGION 227 231 Interaction with STAM1.
FT MOTIF 335 348 JAMM motif.
FT COMPBIAS 104 177 Glu-rich.
FT METAL 335 335 Zinc 1; catalytic (By similarity).
FT METAL 337 337 Zinc 1; catalytic (By similarity).
FT METAL 348 348 Zinc 1; catalytic (By similarity).
FT METAL 350 350 Zinc 2 (By similarity).
FT METAL 390 390 Zinc 2 (By similarity).
FT METAL 396 396 Zinc 2 (By similarity).
FT METAL 398 398 Zinc 2 (By similarity).
FT SITE 280 280 Indirect zinc-binding (By similarity).
FT MOD_RES 2 2 Phosphoserine.
FT MOD_RES 48 48 Phosphoserine.
FT MOD_RES 243 243 Phosphoserine.
FT MOD_RES 245 245 Phosphoserine.
FT MOD_RES 247 247 Phosphoserine.
FT VARIANT 14 14 R -> P (in MICCAP).
FT /FTId=VAR_069806.
FT VARIANT 38 38 R -> C (in MICCAP).
FT /FTId=VAR_069807.
FT VARIANT 42 42 E -> G (in MICCAP).
FT /FTId=VAR_069808.
FT VARIANT 63 63 Y -> C (in MICCAP).
FT /FTId=VAR_069809.
FT VARIANT 100 100 F -> Y (in MICCAP).
FT /FTId=VAR_069810.
FT VARIANT 313 313 T -> I (in MICCAP).
FT /FTId=VAR_069811.
FT MUTAGEN 348 348 D->A: Promotes accumulation of ubiquitin
FT on endosomes, ablates enzymatic activity
FT toward polyubiquitin substrate and allows
FT ubiquitinated STAM stabilization.
FT HELIX 11 22
FT HELIX 33 53
FT HELIX 56 71
FT HELIX 74 76
FT TURN 78 82
FT HELIX 88 97
FT HELIX 99 137
FT STRAND 257 260
FT HELIX 263 276
FT STRAND 282 290
FT STRAND 293 301
FT STRAND 304 306
FT STRAND 311 313
FT HELIX 316 326
FT STRAND 329 336
FT STRAND 338 340
FT HELIX 346 358
FT STRAND 363 368
FT TURN 369 372
FT STRAND 373 379
FT HELIX 381 389
FT STRAND 404 407
FT STRAND 409 414
FT STRAND 419 422
SQ SEQUENCE 424 AA; 48077 MW; 7B6E08A245BD9D43 CRC64;
MSDHGDVSLP PEDRVRALSQ LGSAVEVNED IPPRRYFRSG VEIIRMASIY SEEGNIEHAF
ILYNKYITLF IEKLPKHRDY KSAVIPEKKD TVKKLKEIAF PKAEELKAEL LKRYTKEYTE
YNEEKKKEAE ELARNMAIQQ ELEKEKQRVA QQKQQQLEQE QFHAFEEMIR NQELEKERLK
IVQEFGKVDP GLGGPLVPDL EKPSLDVFPT LTVSSIQPSD CHTTVRPAKP PVVDRSLKPG
ALSNSESIPT IDGLRHVVVP GRLCPQFLQL ASANTARGVE TCGILCGKLM RNEFTITHVL
IPKQSAGSDY CNTENEEELF LIQDQQGLIT LGWIHTHPTQ TAFLSSVDLH THCSYQMMLP
ESVAIVCSPK FQETGFFKLT DHGLEEISSC RQKGFHPHSK DPPLFCSCSH VTVVDRAVTI
TDLR
//
MIM
606247
*RECORD*
*FIELD* NO
606247
*FIELD* TI
*606247 STAM-BINDING PROTEIN; STAMBP
;;ASSOCIATED MOLECULE WITH THE SH3 DOMAIN OF STAM; AMSH
read more*FIELD* TX
DESCRIPTION
The STAMBP gene encodes a deubiquitinating (DUB) isopeptidase that has a
key role in cell surface receptor-mediated endocytosis and sorting
(summary by McDonell et al., 2013).
CLONING
Signal-transducing adaptor molecule (STAM; 601899) acts downstream of
interleukin-2 (IL2; 147680)-induced signaling through JAK3 (600173). It
also interacts with JAK2 (147796) after granulocyte-macrophage
colony-stimulating factor (GMCSF; 138960) stimulation. STAM contains an
SH3 domain that is required for induction of MYC (190080) and cell
growth. By Far Western screening of an activated peripheral blood
leukocyte cDNA library to identify cDNAs binding to the SH3 domain of
STAM, Tanaka et al. (1999) obtained a cDNA encoding AMSH. The deduced
424-amino acid protein contains 2 potential SH3-binding domains (PxxP
motifs), a JAB1 (604850) subdomain homologous (JSH) region, and a
putative bipartite nuclear localization signal. Northern blot analysis
revealed ubiquitous expression of a 2.1-kb AMSH transcript.
Using in situ hybridization and Northern blot analysis, Ishii et al.
(2001) observed that Amsh was expressed diffusely in both mantle and
ventricular layers throughout the mouse brain at embryonic day 14. By
postnatal day 10, Amsh expression was localized to the olfactory bulb,
cerebral cortex, hippocampus, and cerebellum.
In transfected COS-7 cells, Kikuchi et al. (2003) found that
fluorescence-tagged AMSH was expressed diffusely in the cytoplasm and in
a punctate pattern surrounding the nuclear membrane.
GENE FUNCTION
By immunoprecipitation and immunoblot analysis, Tanaka et al. (1999)
showed that the SH3 domain of STAM was required for AMSH binding at the
PxxP motif at pro227 to pro231. Mutation analysis indicated that MYC
induction and cell growth were eliminated in the presence of exogenous
AMSH lacking the 190 C-terminal residues. Tanaka et al. (1999) concluded
that the STAM-AMSH complex plays a critical role in signaling for MYC
induction and cell cycle progression downstream of JAK3 and JAK2 after
IL2 or GMCSF stimulation.
Using RNF11 (612598) as bait in a yeast 2-hybrid screen of a human ovary
cDNA library, Li and Seth (2004) showed that human RNF11 interacted with
several proteins, including AMSH. The interaction of RNF11 with AMSH was
independent of the RNF11 RING finger domain and PY motif. AMSH was
ubiquitinated by the E3 ubiquitin ligase SMURF2 (605532) in the presence
of RNF11, and reduction in the steady-state level of AMSH required both
RNF11 and SMURF2. Li and Seth (2004) concluded that RNF11 recruits AMSH
to SMURF2 for ubiquitination, leading to its degradation by the 26S
proteasome.
Using several protein interaction assays, Tsang et al. (2006) showed
that AMSH interacted directly with the ESCRT-III components CHMP1B
(606486) and CHMP3 (VPS24; 610052). The 3 proteins partially colocalized
with M6PR (154540) on late endosomal membranes.
Kikuchi et al. (2003) found that both the nuclear localization signal
and the MPN domain of AMSH are required for its nuclear localization.
Coimmunoprecipitation analysis of transfected 293T cells showed that
epitope-tagged AMSH bound STAM, STAM2 (606244), and GRB2 (108355).
MAPPING
Using FISH, Tanaka et al. (1999) mapped the STAMBP gene to 2p13-p12.
MOLECULAR GENETICS
In 10 patients from 9 families with microcephaly-capillary malformation
syndrome (MICCAP; 614261), McDonell et al. (2013) identified biallelic
mutations in the STAMBP gene (see, e.g., 600247.0001-600247.0007). The
mutation types included 6 missense variants, 2 nonsense mutations, 2
frameshift mutations, and 3 intronic mutations. The first mutations were
identified by exome sequencing. Some of the patients had previously been
reported by Carter et al. (2011), Isidor et al. (2011), and Mirzaa et
al. (2011). The phenotype was characterized by severe progressive
microcephaly, early-onset refractory epilepsy, profound developmental
delay, and multiple small capillary malformations spread diffusely on
the body. Additional features, such as dysmorphic facial features and
distal limb abnormalities, were also present. Protein studies showed
decreased or absent STAMBP protein in mutant cells. Cellular studies by
McDonell et al. (2013) showed that siRNA-mediated silencing of STAMBP in
human medulloblastoma cells caused increased amounts of
conjugated-ubiquitin aggregates; patient lymphocytes showed a similar
aggregation that could be rescued by transfection with wildtype STAMBP.
The abnormal cellular phenotype was associated with induction of
apoptosis and increased autophagic flux. Patient cells also showed
increases in the downstream RAS signaling pathway and increased
phosphorylation of downstream proteins compared to controls, indicating
persistent activation and insensitive active signal transduction, even
under starvation conditions. McDonell et al. (2013) hypothesized that
the induction of apoptosis may be responsible for microcephaly, whereas
overactivation of the RAS pathway may be responsible for the capillary
malformations.
ANIMAL MODEL
Using gene targeting, Ishii et al. (2001) generated Amsh-deficient mice.
These mice were indistinguishable from their littermates at birth but
exhibited postnatal growth retardation and died between postnatal day 19
(P19) and P23. Histopathologic analysis of brain sections detected a
significant loss of neurons and apoptotic cells in the CA1 subfield of
the Amsh-deficient hippocampus. Brain atrophy developed by P16 and was
accompanied by complete loss of the CA1 neurons in the hippocampus and
marked atrophy of the cerebral cortex. Using in vitro primary cultures,
Ishii et al. (2001) observed that Amsh-deficient hippocampal neuronal
cells were unable to survive in vitro, while Amsh-deficient cerebellar
neurons, thymocytes, and embryonic fibroblasts survived normally. They
concluded that Amsh is an essential molecule for the survival of
neuronal cells in early postnatal mice.
*FIELD* AV
.0001
MICROCEPHALY-CAPILLARY MALFORMATION SYNDROME
STAMBP, GLU42GLY
In 2 African American sibs with microcephaly-capillary malformation
syndrome (MICCAP; 614261) reported by Mirzaa et al. (2011), McDonell et
al. (2013) identified compound heterozygous mutations in the STAMBP
gene: a c.125A-G transition, resulting in a glu42-to-gly (E42G)
substitution, and a c.532C-T transition, resulting in an arg178-to-ter
(R178X; 606247.0002) substitution. The mutations, which were identified
by exome sequencing and were not found in several large control exome
databases, segregated with the disorder.
.0002
MICROCEPHALY-CAPILLARY MALFORMATION SYNDROME
STAMBP, ARG178TER
See 606247.0001 and McDonell et al. (2013).
.0003
MICROCEPHALY-CAPILLARY MALFORMATION SYNDROME
STAMBP, ARG38CYS
In a boy of European descent with MICCAP (614261) reported by Mirzaa et
al. (2011), McDonell et al. (2013) identified compound heterozygous
mutations in the STAMBP gene: a c.112C-T transition, resulting in an
arg38-to-cys (R38C) substitution, and a c.279+5G-T splice site mutation
(606247.0004), predicted to include an extra codon in exon 4, supporting
a pathogenic effect. The mutations, which were identified by exome
sequencing and were not found in several large control exome databases,
segregated with the disorder. Another patient of Polynesian descent was
compound heterozygous for R38C and a 1-bp deletion (c.411delC;
606247.0007), predicted to result in a frameshift and premature
termination (Ile138SerfsTer12).
.0004
MICROCEPHALY-CAPILLARY MALFORMATION SYNDROME
STAMBP, IVS4DS, G-T, +5
See 606247.0004 and McDonell et al. (2013).
.0005
MICROCEPHALY-CAPILLARY MALFORMATION SYNDROME
STAMBP, ARG424TER
In a boy of European descent with MICCAP (614261), McDonell et al.
(2013) identified a homozygous c.1270C-T transition in the STAMBP gene,
resulting in an arg424-to-ter (R424X) substitution. Analysis of parental
DNA showed that the homozygosity was due to maternal isodisomy of
chromosome 2. An unrelated patient was compound heterozygous for the
R424X mutation and a c.299T-A transversion, resulting in a phe100-to-tyr
(F100Y; 606247.0006) substitution. Both patients had previously been
reported by Carter et al. (2011).
.0006
MICROCEPHALY-CAPILLARY MALFORMATION SYNDROME
STAMBP, PHE100TYR
See 606247.0005 and McDonell et al. (2013).
.0007
MICROCEPHALY-CAPILLARY MALFORMATION SYNDROME
STAMBP, 1-BP DEL, 411C
See 606247.0003 and McDonell et al. (2013).
*FIELD* RF
1. Carter, M. T.; Geraghty, M. T.; De La Cruz, L.; Reichard, R. R.;
Boccuto, L.; Schwartz, C. E.; Clericuzio, C. L.: A new syndrome with
multiple capillary malformations, intractable seizures, and brain
and limb anomalies. Am. J. Med. Genet. 155A: 301-306, 2011.
2. Ishii, N.; Owada, Y.; Yamada, M.; Miura, S.; Murata, K.; Asao,
H.; Kondo, H.; Sugamura, K.: Loss of neurons in the hippocampus and
cerebral cortex of AMSH-deficient mice. Molec. Cell. Biol. 21: 8626-8637,
2001.
3. Isidor, B.; Barbarot, S.; Beneteau, C.; Le Caignec, C.; David,
A.: Multiple capillary skin malformations, epilepsy, microcephaly,
mental retardation, hypoplasia of the distal phalanges: report of
a new case and further delineation of a new syndrome. (Letter) Am.
J. Med. Genet. 155A: 1458-1460, 2011.
4. Kikuchi, K.; Ishii, N.; Asao, H.; Sugamura, K.: Identification
of AMSH-LP containing a Jab1/MPN domain metalloenzyme motif. Biochem.
Biophys. Res. Commun. 306: 637-643, 2003.
5. Li, H.; Seth, A.: An RNF11: Smurf2 complex mediates ubiquitination
of the AMSH protein. Oncogene 23: 1801-1808, 2004.
6. McDonell, L. M.; Mirzaa, G. M.; Alcantara, D.; Schwartzentruber,
J.; Carter, M. T.; Lee, L. J.; Clericuzio, C. L.; Graham, J. M., Jr.;
Morris-Rosendahl, D. J.; Polster, T.; Acsadi, G.; Townshend, S.;
and 19 others: Mutations in STAMBP, encoding a deubiquitinating
enzyme, cause microcephaly-capillary malformation syndrome. Nature
Genet. 45: 556-562, 2013.
7. Mirzaa, G. M.; Paciorkowski, A. R.; Smyser, C. D.; Willing, M.
C.; Lind, A. C.; Dobyns, W. B.: The microcephaly-capillary malformation
syndrome. Am. J. Med. Genet. 155A: 2080-2087, 2011.
8. Tanaka, N.; Kaneko, K.; Asao, H.; Kasai, H.; Endo, Y.; Fujita,
T.; Takeshita, T.; Sugamura, K.: Possible involvement of a novel
STAM-associated molecule 'AMSH' in intracellular signal transduction
mediated by cytokines. J. Biol. Chem. 274: 19129-19135, 1999.
9. Tsang, H. T. H.; Connell, J. W.; Brown, S. E.; Thompson, A.; Reid,
E.; Sanderson, C. M.: A systematic analysis of human CHMP protein
interactions: additional MIT domain-containing proteins bind to multiple
components of the human ESCRT III complex. Genomics 88: 333-346,
2006.
*FIELD* CN
Cassandra L. Kniffin - updated: 5/31/2013
Patricia A. Hartz - updated: 2/10/2009
Patricia A. Hartz - updated: 10/24/2008
Patricia A. Hartz - updated: 3/27/2007
Dawn Watkins-Chow - updated: 4/17/2002
*FIELD* CD
Paul J. Converse: 8/31/2001
*FIELD* ED
carol: 09/10/2013
carol: 6/10/2013
carol: 6/3/2013
ckniffin: 5/31/2013
carol: 4/22/2009
mgross: 2/10/2009
alopez: 10/24/2008
alopez: 10/3/2008
terry: 10/2/2008
carol: 5/19/2008
mgross: 3/27/2007
mgross: 4/17/2002
mgross: 8/31/2001
*RECORD*
*FIELD* NO
606247
*FIELD* TI
*606247 STAM-BINDING PROTEIN; STAMBP
;;ASSOCIATED MOLECULE WITH THE SH3 DOMAIN OF STAM; AMSH
read more*FIELD* TX
DESCRIPTION
The STAMBP gene encodes a deubiquitinating (DUB) isopeptidase that has a
key role in cell surface receptor-mediated endocytosis and sorting
(summary by McDonell et al., 2013).
CLONING
Signal-transducing adaptor molecule (STAM; 601899) acts downstream of
interleukin-2 (IL2; 147680)-induced signaling through JAK3 (600173). It
also interacts with JAK2 (147796) after granulocyte-macrophage
colony-stimulating factor (GMCSF; 138960) stimulation. STAM contains an
SH3 domain that is required for induction of MYC (190080) and cell
growth. By Far Western screening of an activated peripheral blood
leukocyte cDNA library to identify cDNAs binding to the SH3 domain of
STAM, Tanaka et al. (1999) obtained a cDNA encoding AMSH. The deduced
424-amino acid protein contains 2 potential SH3-binding domains (PxxP
motifs), a JAB1 (604850) subdomain homologous (JSH) region, and a
putative bipartite nuclear localization signal. Northern blot analysis
revealed ubiquitous expression of a 2.1-kb AMSH transcript.
Using in situ hybridization and Northern blot analysis, Ishii et al.
(2001) observed that Amsh was expressed diffusely in both mantle and
ventricular layers throughout the mouse brain at embryonic day 14. By
postnatal day 10, Amsh expression was localized to the olfactory bulb,
cerebral cortex, hippocampus, and cerebellum.
In transfected COS-7 cells, Kikuchi et al. (2003) found that
fluorescence-tagged AMSH was expressed diffusely in the cytoplasm and in
a punctate pattern surrounding the nuclear membrane.
GENE FUNCTION
By immunoprecipitation and immunoblot analysis, Tanaka et al. (1999)
showed that the SH3 domain of STAM was required for AMSH binding at the
PxxP motif at pro227 to pro231. Mutation analysis indicated that MYC
induction and cell growth were eliminated in the presence of exogenous
AMSH lacking the 190 C-terminal residues. Tanaka et al. (1999) concluded
that the STAM-AMSH complex plays a critical role in signaling for MYC
induction and cell cycle progression downstream of JAK3 and JAK2 after
IL2 or GMCSF stimulation.
Using RNF11 (612598) as bait in a yeast 2-hybrid screen of a human ovary
cDNA library, Li and Seth (2004) showed that human RNF11 interacted with
several proteins, including AMSH. The interaction of RNF11 with AMSH was
independent of the RNF11 RING finger domain and PY motif. AMSH was
ubiquitinated by the E3 ubiquitin ligase SMURF2 (605532) in the presence
of RNF11, and reduction in the steady-state level of AMSH required both
RNF11 and SMURF2. Li and Seth (2004) concluded that RNF11 recruits AMSH
to SMURF2 for ubiquitination, leading to its degradation by the 26S
proteasome.
Using several protein interaction assays, Tsang et al. (2006) showed
that AMSH interacted directly with the ESCRT-III components CHMP1B
(606486) and CHMP3 (VPS24; 610052). The 3 proteins partially colocalized
with M6PR (154540) on late endosomal membranes.
Kikuchi et al. (2003) found that both the nuclear localization signal
and the MPN domain of AMSH are required for its nuclear localization.
Coimmunoprecipitation analysis of transfected 293T cells showed that
epitope-tagged AMSH bound STAM, STAM2 (606244), and GRB2 (108355).
MAPPING
Using FISH, Tanaka et al. (1999) mapped the STAMBP gene to 2p13-p12.
MOLECULAR GENETICS
In 10 patients from 9 families with microcephaly-capillary malformation
syndrome (MICCAP; 614261), McDonell et al. (2013) identified biallelic
mutations in the STAMBP gene (see, e.g., 600247.0001-600247.0007). The
mutation types included 6 missense variants, 2 nonsense mutations, 2
frameshift mutations, and 3 intronic mutations. The first mutations were
identified by exome sequencing. Some of the patients had previously been
reported by Carter et al. (2011), Isidor et al. (2011), and Mirzaa et
al. (2011). The phenotype was characterized by severe progressive
microcephaly, early-onset refractory epilepsy, profound developmental
delay, and multiple small capillary malformations spread diffusely on
the body. Additional features, such as dysmorphic facial features and
distal limb abnormalities, were also present. Protein studies showed
decreased or absent STAMBP protein in mutant cells. Cellular studies by
McDonell et al. (2013) showed that siRNA-mediated silencing of STAMBP in
human medulloblastoma cells caused increased amounts of
conjugated-ubiquitin aggregates; patient lymphocytes showed a similar
aggregation that could be rescued by transfection with wildtype STAMBP.
The abnormal cellular phenotype was associated with induction of
apoptosis and increased autophagic flux. Patient cells also showed
increases in the downstream RAS signaling pathway and increased
phosphorylation of downstream proteins compared to controls, indicating
persistent activation and insensitive active signal transduction, even
under starvation conditions. McDonell et al. (2013) hypothesized that
the induction of apoptosis may be responsible for microcephaly, whereas
overactivation of the RAS pathway may be responsible for the capillary
malformations.
ANIMAL MODEL
Using gene targeting, Ishii et al. (2001) generated Amsh-deficient mice.
These mice were indistinguishable from their littermates at birth but
exhibited postnatal growth retardation and died between postnatal day 19
(P19) and P23. Histopathologic analysis of brain sections detected a
significant loss of neurons and apoptotic cells in the CA1 subfield of
the Amsh-deficient hippocampus. Brain atrophy developed by P16 and was
accompanied by complete loss of the CA1 neurons in the hippocampus and
marked atrophy of the cerebral cortex. Using in vitro primary cultures,
Ishii et al. (2001) observed that Amsh-deficient hippocampal neuronal
cells were unable to survive in vitro, while Amsh-deficient cerebellar
neurons, thymocytes, and embryonic fibroblasts survived normally. They
concluded that Amsh is an essential molecule for the survival of
neuronal cells in early postnatal mice.
*FIELD* AV
.0001
MICROCEPHALY-CAPILLARY MALFORMATION SYNDROME
STAMBP, GLU42GLY
In 2 African American sibs with microcephaly-capillary malformation
syndrome (MICCAP; 614261) reported by Mirzaa et al. (2011), McDonell et
al. (2013) identified compound heterozygous mutations in the STAMBP
gene: a c.125A-G transition, resulting in a glu42-to-gly (E42G)
substitution, and a c.532C-T transition, resulting in an arg178-to-ter
(R178X; 606247.0002) substitution. The mutations, which were identified
by exome sequencing and were not found in several large control exome
databases, segregated with the disorder.
.0002
MICROCEPHALY-CAPILLARY MALFORMATION SYNDROME
STAMBP, ARG178TER
See 606247.0001 and McDonell et al. (2013).
.0003
MICROCEPHALY-CAPILLARY MALFORMATION SYNDROME
STAMBP, ARG38CYS
In a boy of European descent with MICCAP (614261) reported by Mirzaa et
al. (2011), McDonell et al. (2013) identified compound heterozygous
mutations in the STAMBP gene: a c.112C-T transition, resulting in an
arg38-to-cys (R38C) substitution, and a c.279+5G-T splice site mutation
(606247.0004), predicted to include an extra codon in exon 4, supporting
a pathogenic effect. The mutations, which were identified by exome
sequencing and were not found in several large control exome databases,
segregated with the disorder. Another patient of Polynesian descent was
compound heterozygous for R38C and a 1-bp deletion (c.411delC;
606247.0007), predicted to result in a frameshift and premature
termination (Ile138SerfsTer12).
.0004
MICROCEPHALY-CAPILLARY MALFORMATION SYNDROME
STAMBP, IVS4DS, G-T, +5
See 606247.0004 and McDonell et al. (2013).
.0005
MICROCEPHALY-CAPILLARY MALFORMATION SYNDROME
STAMBP, ARG424TER
In a boy of European descent with MICCAP (614261), McDonell et al.
(2013) identified a homozygous c.1270C-T transition in the STAMBP gene,
resulting in an arg424-to-ter (R424X) substitution. Analysis of parental
DNA showed that the homozygosity was due to maternal isodisomy of
chromosome 2. An unrelated patient was compound heterozygous for the
R424X mutation and a c.299T-A transversion, resulting in a phe100-to-tyr
(F100Y; 606247.0006) substitution. Both patients had previously been
reported by Carter et al. (2011).
.0006
MICROCEPHALY-CAPILLARY MALFORMATION SYNDROME
STAMBP, PHE100TYR
See 606247.0005 and McDonell et al. (2013).
.0007
MICROCEPHALY-CAPILLARY MALFORMATION SYNDROME
STAMBP, 1-BP DEL, 411C
See 606247.0003 and McDonell et al. (2013).
*FIELD* RF
1. Carter, M. T.; Geraghty, M. T.; De La Cruz, L.; Reichard, R. R.;
Boccuto, L.; Schwartz, C. E.; Clericuzio, C. L.: A new syndrome with
multiple capillary malformations, intractable seizures, and brain
and limb anomalies. Am. J. Med. Genet. 155A: 301-306, 2011.
2. Ishii, N.; Owada, Y.; Yamada, M.; Miura, S.; Murata, K.; Asao,
H.; Kondo, H.; Sugamura, K.: Loss of neurons in the hippocampus and
cerebral cortex of AMSH-deficient mice. Molec. Cell. Biol. 21: 8626-8637,
2001.
3. Isidor, B.; Barbarot, S.; Beneteau, C.; Le Caignec, C.; David,
A.: Multiple capillary skin malformations, epilepsy, microcephaly,
mental retardation, hypoplasia of the distal phalanges: report of
a new case and further delineation of a new syndrome. (Letter) Am.
J. Med. Genet. 155A: 1458-1460, 2011.
4. Kikuchi, K.; Ishii, N.; Asao, H.; Sugamura, K.: Identification
of AMSH-LP containing a Jab1/MPN domain metalloenzyme motif. Biochem.
Biophys. Res. Commun. 306: 637-643, 2003.
5. Li, H.; Seth, A.: An RNF11: Smurf2 complex mediates ubiquitination
of the AMSH protein. Oncogene 23: 1801-1808, 2004.
6. McDonell, L. M.; Mirzaa, G. M.; Alcantara, D.; Schwartzentruber,
J.; Carter, M. T.; Lee, L. J.; Clericuzio, C. L.; Graham, J. M., Jr.;
Morris-Rosendahl, D. J.; Polster, T.; Acsadi, G.; Townshend, S.;
and 19 others: Mutations in STAMBP, encoding a deubiquitinating
enzyme, cause microcephaly-capillary malformation syndrome. Nature
Genet. 45: 556-562, 2013.
7. Mirzaa, G. M.; Paciorkowski, A. R.; Smyser, C. D.; Willing, M.
C.; Lind, A. C.; Dobyns, W. B.: The microcephaly-capillary malformation
syndrome. Am. J. Med. Genet. 155A: 2080-2087, 2011.
8. Tanaka, N.; Kaneko, K.; Asao, H.; Kasai, H.; Endo, Y.; Fujita,
T.; Takeshita, T.; Sugamura, K.: Possible involvement of a novel
STAM-associated molecule 'AMSH' in intracellular signal transduction
mediated by cytokines. J. Biol. Chem. 274: 19129-19135, 1999.
9. Tsang, H. T. H.; Connell, J. W.; Brown, S. E.; Thompson, A.; Reid,
E.; Sanderson, C. M.: A systematic analysis of human CHMP protein
interactions: additional MIT domain-containing proteins bind to multiple
components of the human ESCRT III complex. Genomics 88: 333-346,
2006.
*FIELD* CN
Cassandra L. Kniffin - updated: 5/31/2013
Patricia A. Hartz - updated: 2/10/2009
Patricia A. Hartz - updated: 10/24/2008
Patricia A. Hartz - updated: 3/27/2007
Dawn Watkins-Chow - updated: 4/17/2002
*FIELD* CD
Paul J. Converse: 8/31/2001
*FIELD* ED
carol: 09/10/2013
carol: 6/10/2013
carol: 6/3/2013
ckniffin: 5/31/2013
carol: 4/22/2009
mgross: 2/10/2009
alopez: 10/24/2008
alopez: 10/3/2008
terry: 10/2/2008
carol: 5/19/2008
mgross: 3/27/2007
mgross: 4/17/2002
mgross: 8/31/2001
MIM
614261
*RECORD*
*FIELD* NO
614261
*FIELD* TI
#614261 MICROCEPHALY-CAPILLARY MALFORMATION SYNDROME; MICCAP
*FIELD* TX
A number sign (#) is used with this entry because microcephaly-capillary
read moremalformation syndrome (MICCAP) is caused by homozygous or compound
heterozygous mutation in the STAMBP gene (606247) on chromosome 2p13.
DESCRIPTION
The microcephaly-capillary malformation syndrome is a congenital
disorder characterized by severe progressive microcephaly, early-onset
refractory epilepsy, profound developmental delay, and multiple small
capillary malformations spread diffusely on the body. Additional more
variable features include dysmorphic facial features, distal limb
abnormalities, and mild heart defects (summary by Carter et al., 2011
and Mirzaa et al., 2011).
CLINICAL FEATURES
Carter et al. (2011) reported 2 unrelated male infants with a similar
congenital neurologic disorder. At birth, both were small for
gestational age and were noted to have microcephaly and multiple
capillary malformations of the skin affecting all areas of the body and
ranging in size from 2 to 25 mm in 1 boy and 2 to 5 mm in the other.
Dysmorphic facial features included whorled hair pattern, hypertelorism,
ptosis, and downturned mouth. One had epicanthal folds, long palpebral
fissures, and low-set ears, whereas the other had a short nose,
asymmetric maxillary hypoplasia, and narrow cleft palate. Both had
abnormalities of the distal limbs, including hypoplastic distal
phalanges, brachydactyly of the hands and feet, hypoplastic nails, and
displaced toes. Both developed intractable seizures in the first months
of life and showed profound developmental delay. One patient had
myoclonus; both had central hypotonia. Variable features included atrial
or ventricular septal defect, hearing loss, and vesicoureteral reflux.
Serial brain MRI of 1 child showed progressive cerebral atrophy, delayed
myelination, and thin corpus callosum. The second child, who died at age
17 months, had cerebral atrophy with white matter loss, thin corpus
callosum, and hippocampal atrophy.
Mirzaa et al. (2011) reported 3 children from 2 unrelated families with
what they termed microcephaly-capillary (MIC-CAP) malformation syndrome.
Two sibs, born of African American parents, had severe microcephaly (6
to 8 SD below the mean), dysmorphic facial features, and multiple
capillary malformations. Both had failure to thrive with feeding
difficulties, early-onset intractable seizures, severe developmental
delay, and spasticity. Multiple capillary malformations ranged in size
from 2 to 10 mm. Other features included optic nerve atrophy, sloping
forehead, wide nasal bridge, hypertelorism, and distal limb anomalies,
such as brachydactyly and nail hypoplasia. The boy had patent foramen
ovale, mild concentric right ventricular hypertrophy, and dilated median
pulmonary artery. The third child was born prematurely (36 weeks and 5
days' gestation) of a pregnancy complicated by oligohydramnios,
intrauterine growth restriction, and chorioamnionitis. He developed
refractory seizures and myoclonus soon after birth. He had microcephaly,
multiple capillary malformations ranging in size from 1 to 15 mm, and
mild micrognathia. He had essentially no development and spastic
quadriparesis. Brain imaging of all 3 infants showed a simplified gyral
pattern and enlarged extraaxial space. Mirzaa et al. (2011) concluded
that this constellation of findings represents a novel autosomal
recessive syndrome characterized by severe microcephaly, capillary
malformations, and developmental handicap.
Isidor et al. (2011) reported a girl, born to unrelated parents, with a
phenotype similar to, but less severe than, that described by Carter et
al. (2011). She was born at term after an uneventful pregnancy, and
showed neonatal feeding difficulties. Physical examination showed large
anterior fontanel, anteverted nares, thin upper lip, short fifth fingers
with hypoplastic nails on the second and fifth fingers, short toes, and
axial hypotonia. She also had multiple small capillary malformations
over the trunk, abdomen, and limbs. Around age 12 months, she developed
severe refractory hemiclonic seizures with secondary generalization.
Later in childhood, she showed delayed psychomotor development, poor
speech development, aggressive behavior, and progressive microcephaly.
The capillary malformations appeared to grow with body size. She had
moderate mental retardation; brain MRI was normal.
INHERITANCE
The family reported by Mirzaa et al. (2011) with MICCAP included an
affected brother and sister, suggesting autosomal recessive inheritance.
MOLECULAR GENETICS
In 10 patients from 9 families with MICCAP, McDonell et al. (2013)
identified biallelic mutations in the STAMBP gene (see, e.g.,
600247.0001-600247.0007). The mutation types included 6 missense
variants, 2 nonsense mutations, 2 frameshift mutations, and 3 intronic
mutations. The first mutations were identified by exome sequencing. Some
of the patients had previously been reported by Carter et al. (2011),
Isidor et al. (2011), and Mirzaa et al. (2011). Protein studies showed
decreased or absent STAMBP protein in mutant cells. Cellular studies by
McDonell et al. (2013) showed that siRNA-mediated silencing of STAMBP in
human medulloblastoma cells caused increased amounts of
conjugated-ubiquitin aggregates; patient lymphocytes showed a similar
aggregation pattern that could be rescued by transfection with wildtype
STAMBP. The abnormal cellular phenotype was associated with induction of
apoptosis and increased autophagic flux. Patient cells also showed
increases in the downstream RAS signaling pathway and increased
phosphorylation of downstream proteins compared to controls, indicating
persistent activation and insensitive active signal transduction, even
under starvation conditions. McDonell et al. (2013) hypothesized that
the induction of apoptosis may be responsible for microcephaly, whereas
overactivation of the RAS pathway may be responsible for the capillary
malformations.
*FIELD* RF
1. Carter, M. T.; Geraghty, M. T.; De La Cruz, L.; Reichard, R. R.;
Boccuto, L.; Schwartz, C. E.; Clericuzio, C. L.: A new syndrome with
multiple capillary malformations, intractable seizures, and brain
and limb anomalies. Am. J. Med. Genet. 155A: 301-306, 2011.
2. Isidor, B.; Barbarot, S.; Beneteau, C.; Le Caignec, C.; David,
A.: Multiple capillary skin malformations, epilepsy, microcephaly,
mental retardation, hypoplasia of the distal phalanges: report of
a new case and further delineation of a new syndrome. (Letter) Am.
J. Med. Genet. 155A: 1458-1460, 2011.
3. McDonell, L. M.; Mirzaa, G. M.; Alcantara, D.; Schwartzentruber,
J.; Carter, M. T.; Lee, L. J.; Clericuzio, C. L.; Graham, J. M., Jr.;
Morris-Rosendahl, D. J.; Polster, T.; Acsadi, G.; Townshend, S.;
and 19 others: Mutations in STAMBP, encoding a deubiquitinating
enzyme, cause microcephaly-capillary malformation syndrome. Nature
Genet. 45: 556-562, 2013.
4. Mirzaa, G. M.; Paciorkowski, A. R.; Smyser, C. D.; Willing, M.
C.; Lind, A. C.; Dobyns, W. B.: The microcephaly-capillary malformation
syndrome. Am. J. Med. Genet. 155A: 2080-2087, 2011.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature;
[Other];
Small for gestational age;
Failure to thrive
HEAD AND NECK:
[Head];
Microcephaly, progressive (3 to 8 SD below the mean);
[Face];
Sloping forehead;
Hypoplastic maxilla;
[Ears];
Low-set ears;
Hearing loss;
[Eyes];
Hypertelorism;
Ptosis;
Optic atrophy;
[Nose];
Short nose;
Broad nose;
[Mouth];
Cleft palate
CARDIOVASCULAR:
[Heart];
Atrial septal defect;
Ventricular septal defect;
Patent foramen ovale;
Right ventricular hypertrophy;
[Vascular];
Capillary malformations, small, multiple, diffuse
GENITOURINARY:
[Bladder];
Vesicoureteral reflux (1 patient)
SKELETAL:
[Hands];
Hypoplastic distal phalanges;
Brachydactyly;
Clinodactyly;
[Feet];
Hypoplastic distal phalanges;
Brachydactyly;
Abnormal toe positioning
SKIN, NAILS, HAIR:
[Skin];
Capillary malformations, small, multiple, diffuse;
[Nails];
Hypoplastic nails;
[Hair];
Abnormal hair whorls
MUSCLE, SOFT TISSUE:
Hypotonia
NEUROLOGIC:
[Central nervous system];
Delayed psychomotor development, profound;
Refractory seizures;
Myoclonus;
Spastic quadriparesis;
Delayed myelination;
Cerebral atrophy;
Thin corpus callosum;
Hippocampal hypoplasia;
Simplified cortical gyral pattern;
Enlarged extraaxial space on brain imaging
MISCELLANEOUS:
Onset at birth;
Capillary malformation are apparent at birth;
Seizures usually occur in the first months of life;
One patient was less severely affected;
Variable facial dysmorphic features;
Variable cardiac defects
MOLECULAR BASIS:
Caused by mutation in the STAM-binding protein gene (STAMBP, 606247.0001)
*FIELD* CN
Cassandra L. Kniffin - updated: 5/31/2013
*FIELD* CD
Cassandra L. Kniffin: 10/3/2011
*FIELD* ED
joanna: 09/30/2013
ckniffin: 5/31/2013
joanna: 10/5/2011
ckniffin: 10/3/2011
*FIELD* CN
Cassandra L. Kniffin - updated: 5/31/2013
Cassandra L. Kniffin - updated: 10/24/2011
*FIELD* CD
Cassandra L. Kniffin: 10/3/2011
*FIELD* ED
carol: 06/03/2013
ckniffin: 5/31/2013
carol: 10/25/2011
terry: 10/24/2011
ckniffin: 10/24/2011
carol: 10/5/2011
carol: 10/4/2011
ckniffin: 10/3/2011
*RECORD*
*FIELD* NO
614261
*FIELD* TI
#614261 MICROCEPHALY-CAPILLARY MALFORMATION SYNDROME; MICCAP
*FIELD* TX
A number sign (#) is used with this entry because microcephaly-capillary
read moremalformation syndrome (MICCAP) is caused by homozygous or compound
heterozygous mutation in the STAMBP gene (606247) on chromosome 2p13.
DESCRIPTION
The microcephaly-capillary malformation syndrome is a congenital
disorder characterized by severe progressive microcephaly, early-onset
refractory epilepsy, profound developmental delay, and multiple small
capillary malformations spread diffusely on the body. Additional more
variable features include dysmorphic facial features, distal limb
abnormalities, and mild heart defects (summary by Carter et al., 2011
and Mirzaa et al., 2011).
CLINICAL FEATURES
Carter et al. (2011) reported 2 unrelated male infants with a similar
congenital neurologic disorder. At birth, both were small for
gestational age and were noted to have microcephaly and multiple
capillary malformations of the skin affecting all areas of the body and
ranging in size from 2 to 25 mm in 1 boy and 2 to 5 mm in the other.
Dysmorphic facial features included whorled hair pattern, hypertelorism,
ptosis, and downturned mouth. One had epicanthal folds, long palpebral
fissures, and low-set ears, whereas the other had a short nose,
asymmetric maxillary hypoplasia, and narrow cleft palate. Both had
abnormalities of the distal limbs, including hypoplastic distal
phalanges, brachydactyly of the hands and feet, hypoplastic nails, and
displaced toes. Both developed intractable seizures in the first months
of life and showed profound developmental delay. One patient had
myoclonus; both had central hypotonia. Variable features included atrial
or ventricular septal defect, hearing loss, and vesicoureteral reflux.
Serial brain MRI of 1 child showed progressive cerebral atrophy, delayed
myelination, and thin corpus callosum. The second child, who died at age
17 months, had cerebral atrophy with white matter loss, thin corpus
callosum, and hippocampal atrophy.
Mirzaa et al. (2011) reported 3 children from 2 unrelated families with
what they termed microcephaly-capillary (MIC-CAP) malformation syndrome.
Two sibs, born of African American parents, had severe microcephaly (6
to 8 SD below the mean), dysmorphic facial features, and multiple
capillary malformations. Both had failure to thrive with feeding
difficulties, early-onset intractable seizures, severe developmental
delay, and spasticity. Multiple capillary malformations ranged in size
from 2 to 10 mm. Other features included optic nerve atrophy, sloping
forehead, wide nasal bridge, hypertelorism, and distal limb anomalies,
such as brachydactyly and nail hypoplasia. The boy had patent foramen
ovale, mild concentric right ventricular hypertrophy, and dilated median
pulmonary artery. The third child was born prematurely (36 weeks and 5
days' gestation) of a pregnancy complicated by oligohydramnios,
intrauterine growth restriction, and chorioamnionitis. He developed
refractory seizures and myoclonus soon after birth. He had microcephaly,
multiple capillary malformations ranging in size from 1 to 15 mm, and
mild micrognathia. He had essentially no development and spastic
quadriparesis. Brain imaging of all 3 infants showed a simplified gyral
pattern and enlarged extraaxial space. Mirzaa et al. (2011) concluded
that this constellation of findings represents a novel autosomal
recessive syndrome characterized by severe microcephaly, capillary
malformations, and developmental handicap.
Isidor et al. (2011) reported a girl, born to unrelated parents, with a
phenotype similar to, but less severe than, that described by Carter et
al. (2011). She was born at term after an uneventful pregnancy, and
showed neonatal feeding difficulties. Physical examination showed large
anterior fontanel, anteverted nares, thin upper lip, short fifth fingers
with hypoplastic nails on the second and fifth fingers, short toes, and
axial hypotonia. She also had multiple small capillary malformations
over the trunk, abdomen, and limbs. Around age 12 months, she developed
severe refractory hemiclonic seizures with secondary generalization.
Later in childhood, she showed delayed psychomotor development, poor
speech development, aggressive behavior, and progressive microcephaly.
The capillary malformations appeared to grow with body size. She had
moderate mental retardation; brain MRI was normal.
INHERITANCE
The family reported by Mirzaa et al. (2011) with MICCAP included an
affected brother and sister, suggesting autosomal recessive inheritance.
MOLECULAR GENETICS
In 10 patients from 9 families with MICCAP, McDonell et al. (2013)
identified biallelic mutations in the STAMBP gene (see, e.g.,
600247.0001-600247.0007). The mutation types included 6 missense
variants, 2 nonsense mutations, 2 frameshift mutations, and 3 intronic
mutations. The first mutations were identified by exome sequencing. Some
of the patients had previously been reported by Carter et al. (2011),
Isidor et al. (2011), and Mirzaa et al. (2011). Protein studies showed
decreased or absent STAMBP protein in mutant cells. Cellular studies by
McDonell et al. (2013) showed that siRNA-mediated silencing of STAMBP in
human medulloblastoma cells caused increased amounts of
conjugated-ubiquitin aggregates; patient lymphocytes showed a similar
aggregation pattern that could be rescued by transfection with wildtype
STAMBP. The abnormal cellular phenotype was associated with induction of
apoptosis and increased autophagic flux. Patient cells also showed
increases in the downstream RAS signaling pathway and increased
phosphorylation of downstream proteins compared to controls, indicating
persistent activation and insensitive active signal transduction, even
under starvation conditions. McDonell et al. (2013) hypothesized that
the induction of apoptosis may be responsible for microcephaly, whereas
overactivation of the RAS pathway may be responsible for the capillary
malformations.
*FIELD* RF
1. Carter, M. T.; Geraghty, M. T.; De La Cruz, L.; Reichard, R. R.;
Boccuto, L.; Schwartz, C. E.; Clericuzio, C. L.: A new syndrome with
multiple capillary malformations, intractable seizures, and brain
and limb anomalies. Am. J. Med. Genet. 155A: 301-306, 2011.
2. Isidor, B.; Barbarot, S.; Beneteau, C.; Le Caignec, C.; David,
A.: Multiple capillary skin malformations, epilepsy, microcephaly,
mental retardation, hypoplasia of the distal phalanges: report of
a new case and further delineation of a new syndrome. (Letter) Am.
J. Med. Genet. 155A: 1458-1460, 2011.
3. McDonell, L. M.; Mirzaa, G. M.; Alcantara, D.; Schwartzentruber,
J.; Carter, M. T.; Lee, L. J.; Clericuzio, C. L.; Graham, J. M., Jr.;
Morris-Rosendahl, D. J.; Polster, T.; Acsadi, G.; Townshend, S.;
and 19 others: Mutations in STAMBP, encoding a deubiquitinating
enzyme, cause microcephaly-capillary malformation syndrome. Nature
Genet. 45: 556-562, 2013.
4. Mirzaa, G. M.; Paciorkowski, A. R.; Smyser, C. D.; Willing, M.
C.; Lind, A. C.; Dobyns, W. B.: The microcephaly-capillary malformation
syndrome. Am. J. Med. Genet. 155A: 2080-2087, 2011.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature;
[Other];
Small for gestational age;
Failure to thrive
HEAD AND NECK:
[Head];
Microcephaly, progressive (3 to 8 SD below the mean);
[Face];
Sloping forehead;
Hypoplastic maxilla;
[Ears];
Low-set ears;
Hearing loss;
[Eyes];
Hypertelorism;
Ptosis;
Optic atrophy;
[Nose];
Short nose;
Broad nose;
[Mouth];
Cleft palate
CARDIOVASCULAR:
[Heart];
Atrial septal defect;
Ventricular septal defect;
Patent foramen ovale;
Right ventricular hypertrophy;
[Vascular];
Capillary malformations, small, multiple, diffuse
GENITOURINARY:
[Bladder];
Vesicoureteral reflux (1 patient)
SKELETAL:
[Hands];
Hypoplastic distal phalanges;
Brachydactyly;
Clinodactyly;
[Feet];
Hypoplastic distal phalanges;
Brachydactyly;
Abnormal toe positioning
SKIN, NAILS, HAIR:
[Skin];
Capillary malformations, small, multiple, diffuse;
[Nails];
Hypoplastic nails;
[Hair];
Abnormal hair whorls
MUSCLE, SOFT TISSUE:
Hypotonia
NEUROLOGIC:
[Central nervous system];
Delayed psychomotor development, profound;
Refractory seizures;
Myoclonus;
Spastic quadriparesis;
Delayed myelination;
Cerebral atrophy;
Thin corpus callosum;
Hippocampal hypoplasia;
Simplified cortical gyral pattern;
Enlarged extraaxial space on brain imaging
MISCELLANEOUS:
Onset at birth;
Capillary malformation are apparent at birth;
Seizures usually occur in the first months of life;
One patient was less severely affected;
Variable facial dysmorphic features;
Variable cardiac defects
MOLECULAR BASIS:
Caused by mutation in the STAM-binding protein gene (STAMBP, 606247.0001)
*FIELD* CN
Cassandra L. Kniffin - updated: 5/31/2013
*FIELD* CD
Cassandra L. Kniffin: 10/3/2011
*FIELD* ED
joanna: 09/30/2013
ckniffin: 5/31/2013
joanna: 10/5/2011
ckniffin: 10/3/2011
*FIELD* CN
Cassandra L. Kniffin - updated: 5/31/2013
Cassandra L. Kniffin - updated: 10/24/2011
*FIELD* CD
Cassandra L. Kniffin: 10/3/2011
*FIELD* ED
carol: 06/03/2013
ckniffin: 5/31/2013
carol: 10/25/2011
terry: 10/24/2011
ckniffin: 10/24/2011
carol: 10/5/2011
carol: 10/4/2011
ckniffin: 10/3/2011