Full text data of PDCD10
PDCD10
(CCM3, TFAR15)
[Confidence: low (only semi-automatic identification from reviews)]
Programmed cell death protein 10 (Cerebral cavernous malformations 3 protein; TF-1 cell apoptosis-related protein 15)
Programmed cell death protein 10 (Cerebral cavernous malformations 3 protein; TF-1 cell apoptosis-related protein 15)
UniProt
Q9BUL8
ID PDC10_HUMAN Reviewed; 212 AA.
AC Q9BUL8; A8K515; D3DNN5; O14811;
DT 11-OCT-2005, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-JUN-2001, sequence version 1.
DT 22-JAN-2014, entry version 102.
DE RecName: Full=Programmed cell death protein 10;
DE AltName: Full=Cerebral cavernous malformations 3 protein;
DE AltName: Full=TF-1 cell apoptosis-related protein 15;
GN Name=PDCD10; Synonyms=CCM3, TFAR15;
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], AND VARIANT ALA-102.
RA Wang Y.G., Liu H.T., Ma D.L., Zhang Y.M.;
RT "cDNA cloning and expression of an apoptosis-related gene, human TFAR-
RT 15 gene.";
RL Sci. China, Ser. C, Life Sci. 42:323-329(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16641997; DOI=10.1038/nature04728;
RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R.,
RA Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R.,
RA Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V.,
RA Hume J., Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R.,
RA Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Wei S.,
RA Wheeler D.A., Wright M.W., Worley K.C., Yuan Y., Zhang Z., Adams C.Q.,
RA Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clendenning J., Clerc-Blankenburg K.P., Chen R., Chen Z., Davis C.,
RA Delgado O., Dinh H.H., Dong W., Draper H., Ernst S., Fu G.,
RA Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., Hao B.,
RA Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., Jackson L.R.,
RA Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., Liu J.,
RA Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Palmeiri A.,
RA Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J.,
RA Zhang X., Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H.,
RA Reinhardt R., Naylor S.L., Yang H., Olson M., Weinstock G.,
RA Gibbs R.A.;
RT "The DNA sequence, annotation and analysis of human chromosome 3.";
RL Nature 440:1194-1198(2006).
RN [5]
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Skin, and Urinary bladder;
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 [7]
RP PROTEIN SEQUENCE OF 36-45 AND 117-124, AND MASS SPECTROMETRY.
RC TISSUE=Platelet;
RA Bienvenut W.V., Claeys D.;
RL Submitted (NOV-2005) to UniProtKB.
RN [8]
RP FUNCTION, TISSUE SPECIFICITY, AND INVOLVEMENT IN CCM3.
RX PubMed=15543491; DOI=10.1086/426952;
RA Bergametti F., Denier C., Labauge P., Arnoult M., Boetto S.,
RA Clanet M., Coubes P., Echenne B., Ibrahim R., Irthum B., Jacquet G.,
RA Lonjon M., Moreau J.J., Neau J.P., Parker F., Tremoulet M.,
RA Tournier-Lasserve E.;
RT "Mutations within the programmed cell death 10 gene cause cerebral
RT cavernous malformations.";
RL Am. J. Hum. Genet. 76:42-51(2005).
RN [9]
RP INTERACTION WITH MST4, FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=17360971; DOI=10.1091/mbc.E06-07-0608;
RA Ma X., Zhao H., Shan J., Long F., Chen Y., Chen Y., Zhang Y., Han X.,
RA Ma D.;
RT "PDCD10 interacts with Ste20-related kinase MST4 to promote cell
RT growth and transformation via modulation of the ERK pathway.";
RL Mol. Biol. Cell 18:1965-1978(2007).
RN [10]
RP INTERACTION WITH STK25; CCM2 AND MST4, AND IDENTIFICATION IN A COMPLEX
RP WITH CCM1 AND CCM2.
RX PubMed=19370760; DOI=10.1002/humu.20996;
RA Voss K., Stahl S., Hogan B.M., Reinders J., Schleider E.,
RA Schulte-Merker S., Felbor U.;
RT "Functional analyses of human and zebrafish 18-amino acid in-frame
RT deletion pave the way for domain mapping of the cerebral cavernous
RT malformation 3 protein.";
RL Hum. Mutat. 30:1003-1011(2009).
RN [11]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-179, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [12]
RP FUNCTION, INTERACTION WITH GOLGA2; MST4; STK24 AND STK25, AND
RP SUBCELLULAR LOCATION.
RX PubMed=20332113; DOI=10.1242/jcs.061341;
RA Fidalgo M., Fraile M., Pires A., Force T., Pombo C., Zalvide J.;
RT "CCM3/PDCD10 stabilizes GCKIII proteins to promote Golgi assembly and
RT cell orientation.";
RL J. Cell Sci. 123:1274-1284(2010).
RN [13]
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 [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [15]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS), SUBUNIT, INTERACTION WITH CCM2
RP AND PXN, SUBCELLULAR LOCATION, AND MUTAGENESIS OF LYS-132; ALA-135;
RP LYS-139; LYS-172; SER-175 AND LYS-179.
RX PubMed=20489202; DOI=10.1074/jbc.M110.128470;
RA Li X., Zhang R., Zhang H., He Y., Ji W., Min W., Boggon T.J.;
RT "Crystal structure of CCM3, a cerebral cavernous malformation protein
RT critical for vascular integrity.";
RL J. Biol. Chem. 285:24099-24107(2010).
CC -!- FUNCTION: Promotes cell proliferation. Modulates apoptotic
CC pathways. Increases mitogen-activated protein kinase activity and
CC MST4 activity. Important for cell migration, and for normal
CC structure and assembly of the Golgi complex. Important for
CC KDR/VEGFR2 signaling. Increases the stability of KDR/VEGFR2 and
CC prevents its breakdown. Required for normal cardiovascular
CC development. Required for normal angiogenesis, vasculogenesis and
CC hematopoiesis during embryonic development (By similarity).
CC -!- SUBUNIT: Homodimer. Interacts (via C-terminus) with CCM2 and PXN.
CC Interacts (via N-terminus) with MST4, STK24 and STK25. Interacts
CC with GOLGA2. Identified in a complex with CCM1 and CCM2. Interacts
CC with KDR/VEGFR2. Interaction with KDR/VEGFR2 is enhanced by
CC stimulation with VEGFA (By similarity).
CC -!- INTERACTION:
CC Q9BSQ5:CCM2; NbExp=5; IntAct=EBI-740195, EBI-1573056;
CC Q12923:PTPN13; NbExp=3; IntAct=EBI-740195, EBI-355227;
CC Q9Y6E0:STK24; NbExp=7; IntAct=EBI-740195, EBI-740175;
CC O00506:STK25; NbExp=9; IntAct=EBI-740195, EBI-618295;
CC O43815:STRN; NbExp=2; IntAct=EBI-740195, EBI-1046642;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Golgi apparatus membrane;
CC Peripheral membrane protein; Cytoplasmic side. Cell membrane;
CC Peripheral membrane protein; Cytoplasmic side. Note=Partially co-
CC localizes with endogenous PXN at the leading edges of migrating
CC cells.
CC -!- TISSUE SPECIFICITY: Ubiquitous.
CC -!- DISEASE: Cerebral cavernous malformations 3 (CCM3) [MIM:603285]: A
CC congenital vascular anomaly of the central nervous system that can
CC result in hemorrhagic stroke, seizures, recurrent headaches, and
CC focal neurologic deficits. The lesions are characterized by
CC grossly enlarged blood vessels consisting of a single layer of
CC endothelium and without any intervening neural tissue, ranging in
CC diameter from a few millimeters to several centimeters. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the PDCD10 family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/PDCD10";
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DR EMBL; AF022385; AAB72225.1; -; mRNA.
DR EMBL; CR457107; CAG33388.1; -; mRNA.
DR EMBL; AK291130; BAF83819.1; -; mRNA.
DR EMBL; AC079822; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471052; EAW78574.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW78575.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW78576.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW78577.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW78578.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW78580.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW78581.1; -; Genomic_DNA.
DR EMBL; BC002506; AAH02506.1; -; mRNA.
DR EMBL; BC016353; AAH16353.1; -; mRNA.
DR RefSeq; NP_009148.2; NM_007217.3.
DR RefSeq; NP_665858.1; NM_145859.1.
DR RefSeq; NP_665859.1; NM_145860.1.
DR RefSeq; XP_005247143.1; XM_005247086.1.
DR RefSeq; XP_005247144.1; XM_005247087.1.
DR RefSeq; XP_005247145.1; XM_005247088.1.
DR UniGene; Hs.478150; -.
DR PDB; 3AJM; X-ray; 2.30 A; A/B=8-212.
DR PDB; 3L8I; X-ray; 2.50 A; A/B/C/D=1-212.
DR PDB; 3L8J; X-ray; 3.05 A; A=14-212.
DR PDB; 3RQE; X-ray; 2.80 A; A/B/C/D=1-212.
DR PDB; 3RQF; X-ray; 2.70 A; A/B/C/D=1-212.
DR PDB; 3RQG; X-ray; 2.50 A; A/B/C/D=1-212.
DR PDB; 3W8H; X-ray; 2.43 A; A=8-212.
DR PDB; 3W8I; X-ray; 2.40 A; A=8-212.
DR PDB; 4GEH; X-ray; 1.95 A; A/C=9-212.
DR PDBsum; 3AJM; -.
DR PDBsum; 3L8I; -.
DR PDBsum; 3L8J; -.
DR PDBsum; 3RQE; -.
DR PDBsum; 3RQF; -.
DR PDBsum; 3RQG; -.
DR PDBsum; 3W8H; -.
DR PDBsum; 3W8I; -.
DR PDBsum; 4GEH; -.
DR ProteinModelPortal; Q9BUL8; -.
DR SMR; Q9BUL8; 11-211.
DR DIP; DIP-40607N; -.
DR IntAct; Q9BUL8; 25.
DR MINT; MINT-5003501; -.
DR STRING; 9606.ENSP00000338141; -.
DR PhosphoSite; Q9BUL8; -.
DR DMDM; 74733232; -.
DR OGP; Q9BUL8; -.
DR PaxDb; Q9BUL8; -.
DR PRIDE; Q9BUL8; -.
DR DNASU; 11235; -.
DR Ensembl; ENST00000392750; ENSP00000376506; ENSG00000114209.
DR Ensembl; ENST00000461494; ENSP00000420021; ENSG00000114209.
DR Ensembl; ENST00000470131; ENSP00000417202; ENSG00000114209.
DR Ensembl; ENST00000473645; ENSP00000418317; ENSG00000114209.
DR Ensembl; ENST00000497056; ENSP00000420553; ENSG00000114209.
DR GeneID; 11235; -.
DR KEGG; hsa:11235; -.
DR UCSC; uc003fex.3; human.
DR CTD; 11235; -.
DR GeneCards; GC03M167381; -.
DR HGNC; HGNC:8761; PDCD10.
DR HPA; HPA027095; -.
DR MIM; 603285; phenotype.
DR MIM; 609118; gene.
DR neXtProt; NX_Q9BUL8; -.
DR Orphanet; 221061; Hereditary cerebral cavernous malformation.
DR PharmGKB; PA33111; -.
DR eggNOG; NOG275788; -.
DR HOGENOM; HOG000007888; -.
DR HOVERGEN; HBG052811; -.
DR InParanoid; Q9BUL8; -.
DR OMA; KREFVKY; -.
DR OrthoDB; EOG7ZPNM3; -.
DR PhylomeDB; Q9BUL8; -.
DR ChiTaRS; PDCD10; human.
DR EvolutionaryTrace; Q9BUL8; -.
DR GeneWiki; PDCD10; -.
DR GenomeRNAi; 11235; -.
DR NextBio; 42758; -.
DR PRO; PR:Q9BUL8; -.
DR ArrayExpress; Q9BUL8; -.
DR Bgee; Q9BUL8; -.
DR CleanEx; HS_PDCD10; -.
DR Genevestigator; Q9BUL8; -.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0001525; P:angiogenesis; IEA:UniProtKB-KW.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IDA:UniProtKB.
DR GO; GO:0008284; P:positive regulation of cell proliferation; IDA:UniProtKB.
DR GO; GO:0043406; P:positive regulation of MAP kinase activity; IDA:UniProtKB.
DR InterPro; IPR009652; DUF1241.
DR PANTHER; PTHR13250; PTHR13250; 1.
DR Pfam; PF06840; DUF1241; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Angiogenesis; Apoptosis; Cell membrane;
KW Complete proteome; Cytoplasm; Direct protein sequencing;
KW Golgi apparatus; Membrane; Polymorphism; Reference proteome.
FT CHAIN 1 212 Programmed cell death protein 10.
FT /FTId=PRO_0000187562.
FT MOD_RES 179 179 N6-acetyllysine.
FT VARIANT 102 102 D -> A (in dbSNP:rs1129087).
FT /FTId=VAR_023578.
FT MUTAGEN 132 132 K->D: Loss of interaction with CCM2 and
FT PXN; when associated with D-139; D-172
FT and D-179.
FT MUTAGEN 135 135 A->D: Loss of interaction with CCM2.
FT MUTAGEN 139 139 K->D: Loss of interaction with CCM2 and
FT PXN; when associated with D-132; D-172
FT and D-179.
FT MUTAGEN 172 172 K->D: Loss of interaction with CCM2 and
FT PXN; when associated with D-132; D-139
FT and D-179.
FT MUTAGEN 175 175 S->D: Loss of interaction with CCM2.
FT MUTAGEN 179 179 K->D: Loss of interaction with CCM2 and
FT PXN; when associated with D-132; D-139
FT and D-172.
FT HELIX 17 19
FT HELIX 20 24
FT HELIX 26 34
FT HELIX 38 54
FT HELIX 58 69
FT HELIX 76 82
FT TURN 83 85
FT HELIX 88 91
FT HELIX 98 115
FT HELIX 117 120
FT STRAND 121 123
FT HELIX 124 151
FT TURN 152 156
FT HELIX 157 184
FT HELIX 187 208
SQ SEQUENCE 212 AA; 24702 MW; 5AA613F71FAAEF56 CRC64;
MRMTMEEMKN EAETTSMVSM PLYAVMYPVF NELERVNLSA AQTLRAAFIK AEKENPGLTQ
DIIMKILEKK SVEVNFTESL LRMAADDVEE YMIERPEPEF QDLNEKARAL KQILSKIPDE
INDRVRFLQT IKDIASAIKE LLDTVNNVFK KYQYQNRRAL EHQKKEFVKY SKSFSDTLKT
YFKDGKAINV FVSANRLIHQ TNLILQTFKT VA
//
ID PDC10_HUMAN Reviewed; 212 AA.
AC Q9BUL8; A8K515; D3DNN5; O14811;
DT 11-OCT-2005, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-JUN-2001, sequence version 1.
DT 22-JAN-2014, entry version 102.
DE RecName: Full=Programmed cell death protein 10;
DE AltName: Full=Cerebral cavernous malformations 3 protein;
DE AltName: Full=TF-1 cell apoptosis-related protein 15;
GN Name=PDCD10; Synonyms=CCM3, TFAR15;
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], AND VARIANT ALA-102.
RA Wang Y.G., Liu H.T., Ma D.L., Zhang Y.M.;
RT "cDNA cloning and expression of an apoptosis-related gene, human TFAR-
RT 15 gene.";
RL Sci. China, Ser. C, Life Sci. 42:323-329(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16641997; DOI=10.1038/nature04728;
RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R.,
RA Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R.,
RA Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V.,
RA Hume J., Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R.,
RA Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Wei S.,
RA Wheeler D.A., Wright M.W., Worley K.C., Yuan Y., Zhang Z., Adams C.Q.,
RA Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clendenning J., Clerc-Blankenburg K.P., Chen R., Chen Z., Davis C.,
RA Delgado O., Dinh H.H., Dong W., Draper H., Ernst S., Fu G.,
RA Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., Hao B.,
RA Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., Jackson L.R.,
RA Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., Liu J.,
RA Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Palmeiri A.,
RA Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J.,
RA Zhang X., Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H.,
RA Reinhardt R., Naylor S.L., Yang H., Olson M., Weinstock G.,
RA Gibbs R.A.;
RT "The DNA sequence, annotation and analysis of human chromosome 3.";
RL Nature 440:1194-1198(2006).
RN [5]
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Skin, and Urinary bladder;
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 [7]
RP PROTEIN SEQUENCE OF 36-45 AND 117-124, AND MASS SPECTROMETRY.
RC TISSUE=Platelet;
RA Bienvenut W.V., Claeys D.;
RL Submitted (NOV-2005) to UniProtKB.
RN [8]
RP FUNCTION, TISSUE SPECIFICITY, AND INVOLVEMENT IN CCM3.
RX PubMed=15543491; DOI=10.1086/426952;
RA Bergametti F., Denier C., Labauge P., Arnoult M., Boetto S.,
RA Clanet M., Coubes P., Echenne B., Ibrahim R., Irthum B., Jacquet G.,
RA Lonjon M., Moreau J.J., Neau J.P., Parker F., Tremoulet M.,
RA Tournier-Lasserve E.;
RT "Mutations within the programmed cell death 10 gene cause cerebral
RT cavernous malformations.";
RL Am. J. Hum. Genet. 76:42-51(2005).
RN [9]
RP INTERACTION WITH MST4, FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=17360971; DOI=10.1091/mbc.E06-07-0608;
RA Ma X., Zhao H., Shan J., Long F., Chen Y., Chen Y., Zhang Y., Han X.,
RA Ma D.;
RT "PDCD10 interacts with Ste20-related kinase MST4 to promote cell
RT growth and transformation via modulation of the ERK pathway.";
RL Mol. Biol. Cell 18:1965-1978(2007).
RN [10]
RP INTERACTION WITH STK25; CCM2 AND MST4, AND IDENTIFICATION IN A COMPLEX
RP WITH CCM1 AND CCM2.
RX PubMed=19370760; DOI=10.1002/humu.20996;
RA Voss K., Stahl S., Hogan B.M., Reinders J., Schleider E.,
RA Schulte-Merker S., Felbor U.;
RT "Functional analyses of human and zebrafish 18-amino acid in-frame
RT deletion pave the way for domain mapping of the cerebral cavernous
RT malformation 3 protein.";
RL Hum. Mutat. 30:1003-1011(2009).
RN [11]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-179, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [12]
RP FUNCTION, INTERACTION WITH GOLGA2; MST4; STK24 AND STK25, AND
RP SUBCELLULAR LOCATION.
RX PubMed=20332113; DOI=10.1242/jcs.061341;
RA Fidalgo M., Fraile M., Pires A., Force T., Pombo C., Zalvide J.;
RT "CCM3/PDCD10 stabilizes GCKIII proteins to promote Golgi assembly and
RT cell orientation.";
RL J. Cell Sci. 123:1274-1284(2010).
RN [13]
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 [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [15]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS), SUBUNIT, INTERACTION WITH CCM2
RP AND PXN, SUBCELLULAR LOCATION, AND MUTAGENESIS OF LYS-132; ALA-135;
RP LYS-139; LYS-172; SER-175 AND LYS-179.
RX PubMed=20489202; DOI=10.1074/jbc.M110.128470;
RA Li X., Zhang R., Zhang H., He Y., Ji W., Min W., Boggon T.J.;
RT "Crystal structure of CCM3, a cerebral cavernous malformation protein
RT critical for vascular integrity.";
RL J. Biol. Chem. 285:24099-24107(2010).
CC -!- FUNCTION: Promotes cell proliferation. Modulates apoptotic
CC pathways. Increases mitogen-activated protein kinase activity and
CC MST4 activity. Important for cell migration, and for normal
CC structure and assembly of the Golgi complex. Important for
CC KDR/VEGFR2 signaling. Increases the stability of KDR/VEGFR2 and
CC prevents its breakdown. Required for normal cardiovascular
CC development. Required for normal angiogenesis, vasculogenesis and
CC hematopoiesis during embryonic development (By similarity).
CC -!- SUBUNIT: Homodimer. Interacts (via C-terminus) with CCM2 and PXN.
CC Interacts (via N-terminus) with MST4, STK24 and STK25. Interacts
CC with GOLGA2. Identified in a complex with CCM1 and CCM2. Interacts
CC with KDR/VEGFR2. Interaction with KDR/VEGFR2 is enhanced by
CC stimulation with VEGFA (By similarity).
CC -!- INTERACTION:
CC Q9BSQ5:CCM2; NbExp=5; IntAct=EBI-740195, EBI-1573056;
CC Q12923:PTPN13; NbExp=3; IntAct=EBI-740195, EBI-355227;
CC Q9Y6E0:STK24; NbExp=7; IntAct=EBI-740195, EBI-740175;
CC O00506:STK25; NbExp=9; IntAct=EBI-740195, EBI-618295;
CC O43815:STRN; NbExp=2; IntAct=EBI-740195, EBI-1046642;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Golgi apparatus membrane;
CC Peripheral membrane protein; Cytoplasmic side. Cell membrane;
CC Peripheral membrane protein; Cytoplasmic side. Note=Partially co-
CC localizes with endogenous PXN at the leading edges of migrating
CC cells.
CC -!- TISSUE SPECIFICITY: Ubiquitous.
CC -!- DISEASE: Cerebral cavernous malformations 3 (CCM3) [MIM:603285]: A
CC congenital vascular anomaly of the central nervous system that can
CC result in hemorrhagic stroke, seizures, recurrent headaches, and
CC focal neurologic deficits. The lesions are characterized by
CC grossly enlarged blood vessels consisting of a single layer of
CC endothelium and without any intervening neural tissue, ranging in
CC diameter from a few millimeters to several centimeters. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the PDCD10 family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/PDCD10";
CC -----------------------------------------------------------------------
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DR EMBL; AF022385; AAB72225.1; -; mRNA.
DR EMBL; CR457107; CAG33388.1; -; mRNA.
DR EMBL; AK291130; BAF83819.1; -; mRNA.
DR EMBL; AC079822; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471052; EAW78574.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW78575.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW78576.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW78577.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW78578.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW78580.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW78581.1; -; Genomic_DNA.
DR EMBL; BC002506; AAH02506.1; -; mRNA.
DR EMBL; BC016353; AAH16353.1; -; mRNA.
DR RefSeq; NP_009148.2; NM_007217.3.
DR RefSeq; NP_665858.1; NM_145859.1.
DR RefSeq; NP_665859.1; NM_145860.1.
DR RefSeq; XP_005247143.1; XM_005247086.1.
DR RefSeq; XP_005247144.1; XM_005247087.1.
DR RefSeq; XP_005247145.1; XM_005247088.1.
DR UniGene; Hs.478150; -.
DR PDB; 3AJM; X-ray; 2.30 A; A/B=8-212.
DR PDB; 3L8I; X-ray; 2.50 A; A/B/C/D=1-212.
DR PDB; 3L8J; X-ray; 3.05 A; A=14-212.
DR PDB; 3RQE; X-ray; 2.80 A; A/B/C/D=1-212.
DR PDB; 3RQF; X-ray; 2.70 A; A/B/C/D=1-212.
DR PDB; 3RQG; X-ray; 2.50 A; A/B/C/D=1-212.
DR PDB; 3W8H; X-ray; 2.43 A; A=8-212.
DR PDB; 3W8I; X-ray; 2.40 A; A=8-212.
DR PDB; 4GEH; X-ray; 1.95 A; A/C=9-212.
DR PDBsum; 3AJM; -.
DR PDBsum; 3L8I; -.
DR PDBsum; 3L8J; -.
DR PDBsum; 3RQE; -.
DR PDBsum; 3RQF; -.
DR PDBsum; 3RQG; -.
DR PDBsum; 3W8H; -.
DR PDBsum; 3W8I; -.
DR PDBsum; 4GEH; -.
DR ProteinModelPortal; Q9BUL8; -.
DR SMR; Q9BUL8; 11-211.
DR DIP; DIP-40607N; -.
DR IntAct; Q9BUL8; 25.
DR MINT; MINT-5003501; -.
DR STRING; 9606.ENSP00000338141; -.
DR PhosphoSite; Q9BUL8; -.
DR DMDM; 74733232; -.
DR OGP; Q9BUL8; -.
DR PaxDb; Q9BUL8; -.
DR PRIDE; Q9BUL8; -.
DR DNASU; 11235; -.
DR Ensembl; ENST00000392750; ENSP00000376506; ENSG00000114209.
DR Ensembl; ENST00000461494; ENSP00000420021; ENSG00000114209.
DR Ensembl; ENST00000470131; ENSP00000417202; ENSG00000114209.
DR Ensembl; ENST00000473645; ENSP00000418317; ENSG00000114209.
DR Ensembl; ENST00000497056; ENSP00000420553; ENSG00000114209.
DR GeneID; 11235; -.
DR KEGG; hsa:11235; -.
DR UCSC; uc003fex.3; human.
DR CTD; 11235; -.
DR GeneCards; GC03M167381; -.
DR HGNC; HGNC:8761; PDCD10.
DR HPA; HPA027095; -.
DR MIM; 603285; phenotype.
DR MIM; 609118; gene.
DR neXtProt; NX_Q9BUL8; -.
DR Orphanet; 221061; Hereditary cerebral cavernous malformation.
DR PharmGKB; PA33111; -.
DR eggNOG; NOG275788; -.
DR HOGENOM; HOG000007888; -.
DR HOVERGEN; HBG052811; -.
DR InParanoid; Q9BUL8; -.
DR OMA; KREFVKY; -.
DR OrthoDB; EOG7ZPNM3; -.
DR PhylomeDB; Q9BUL8; -.
DR ChiTaRS; PDCD10; human.
DR EvolutionaryTrace; Q9BUL8; -.
DR GeneWiki; PDCD10; -.
DR GenomeRNAi; 11235; -.
DR NextBio; 42758; -.
DR PRO; PR:Q9BUL8; -.
DR ArrayExpress; Q9BUL8; -.
DR Bgee; Q9BUL8; -.
DR CleanEx; HS_PDCD10; -.
DR Genevestigator; Q9BUL8; -.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0001525; P:angiogenesis; IEA:UniProtKB-KW.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IDA:UniProtKB.
DR GO; GO:0008284; P:positive regulation of cell proliferation; IDA:UniProtKB.
DR GO; GO:0043406; P:positive regulation of MAP kinase activity; IDA:UniProtKB.
DR InterPro; IPR009652; DUF1241.
DR PANTHER; PTHR13250; PTHR13250; 1.
DR Pfam; PF06840; DUF1241; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Angiogenesis; Apoptosis; Cell membrane;
KW Complete proteome; Cytoplasm; Direct protein sequencing;
KW Golgi apparatus; Membrane; Polymorphism; Reference proteome.
FT CHAIN 1 212 Programmed cell death protein 10.
FT /FTId=PRO_0000187562.
FT MOD_RES 179 179 N6-acetyllysine.
FT VARIANT 102 102 D -> A (in dbSNP:rs1129087).
FT /FTId=VAR_023578.
FT MUTAGEN 132 132 K->D: Loss of interaction with CCM2 and
FT PXN; when associated with D-139; D-172
FT and D-179.
FT MUTAGEN 135 135 A->D: Loss of interaction with CCM2.
FT MUTAGEN 139 139 K->D: Loss of interaction with CCM2 and
FT PXN; when associated with D-132; D-172
FT and D-179.
FT MUTAGEN 172 172 K->D: Loss of interaction with CCM2 and
FT PXN; when associated with D-132; D-139
FT and D-179.
FT MUTAGEN 175 175 S->D: Loss of interaction with CCM2.
FT MUTAGEN 179 179 K->D: Loss of interaction with CCM2 and
FT PXN; when associated with D-132; D-139
FT and D-172.
FT HELIX 17 19
FT HELIX 20 24
FT HELIX 26 34
FT HELIX 38 54
FT HELIX 58 69
FT HELIX 76 82
FT TURN 83 85
FT HELIX 88 91
FT HELIX 98 115
FT HELIX 117 120
FT STRAND 121 123
FT HELIX 124 151
FT TURN 152 156
FT HELIX 157 184
FT HELIX 187 208
SQ SEQUENCE 212 AA; 24702 MW; 5AA613F71FAAEF56 CRC64;
MRMTMEEMKN EAETTSMVSM PLYAVMYPVF NELERVNLSA AQTLRAAFIK AEKENPGLTQ
DIIMKILEKK SVEVNFTESL LRMAADDVEE YMIERPEPEF QDLNEKARAL KQILSKIPDE
INDRVRFLQT IKDIASAIKE LLDTVNNVFK KYQYQNRRAL EHQKKEFVKY SKSFSDTLKT
YFKDGKAINV FVSANRLIHQ TNLILQTFKT VA
//
MIM
603285
*RECORD*
*FIELD* NO
603285
*FIELD* TI
#603285 CEREBRAL CAVERNOUS MALFORMATIONS 3; CCM3
*FIELD* TX
A number sign (#) is used with this entry because of evidence that this
read moreform of cerebral cavernous malformations (CCM3) can be caused by
mutation in the PDCD10 gene (609118).
Evidence suggests that a 2-hit mechanism involving biallelic germline
and somatic mutations is responsible for CCM3 pathogenesis, see
PATHOGENESIS and MOLECULAR GENETICS sections.
For a phenotypic description and discussion of genetic heterogeneity of
cerebral cavernous malformations, see CCM1 (116860).
CLINICAL FEATURES
Denier et al. (2006) compared the clinical features of mutation carriers
from 86 families with CCM1, 25 families with CCM2 (603284), and 17
families with CCM3, ascertained from academic medical centers in France.
Of the 3 groups, CCM3 families had the lowest number of affected
individuals per family, and the highest proportion of patients with
onset of symptoms before age 15 years. Cerebral hemorrhage was the most
common initial presentation in patients with CCM3.
PATHOGENESIS
For each of the 3 CCM genes, Pagenstecher et al. (2009) showed complete
localized loss of either KRIT1 (604214), CCM2/malcavernin (607929), or
PDCD10 protein expression depending on the respective inherited
mutation. Cavernous but not adjacent normal or reactive endothelial
cells of known germline mutation carriers displayed immunohistochemical
negativity only for the corresponding CCM protein, but stained
positively for the 2 other proteins. Immunohistochemical studies
demonstrated endothelial cell mosaicism as neoangiogenic vessels within
caverns from a CCM1 patient, normal brain endothelium from a CCM2
patient, and capillary endothelial cells of vessels in a revascularized
thrombosed cavern from a CCM3 patient stained positively for KRIT1,
CCM2/malcavernin, and PDCD10 respectively. Pagenstecher et al. (2009)
suggested that complete lack of CCM protein in affected endothelial
cells from CCM germline mutation carriers supports a 2-hit mechanism for
CCM formation.
MAPPING
Among Hispanic Americans, virtually all cerebral cavernous malformation
(CCM) is attributable to a founder mutation localized to 7q (CCM1;
116860). Craig et al. (1998) reported analysis of linkage in 20
non-Hispanic Caucasian kindreds with familial CCM. Linkage to new loci,
CCM2 at 7p15-p13 and CCM3 at 3q25.2-q27, was demonstrated. Multilocus
analysis yielded a maximum lod score of 14.11, with 14% of kindreds
linked to CCM1, 20% linked to CCM2, and 40% linked to CCM3, with highly
significant evidence for linkage to 3 loci; linkage to 3 loci was
supported with an odds ratio of 2.6 x 10(5):1 over linkage to 2 loci,
and 1.6 x 10(9):1 over linkage to 1 locus. Multipoint analysis among
families with high posterior probabilities of linkage to each of the 3
loci refined the locations of CCM2 and CCM3 to approximately 22 cM
intervals. Linkage to these 3 loci can account for inheritance of CCM in
all kindreds studied. Significant locus-specific differences in
penetrance were identified.
MOLECULAR GENETICS
Bergametti et al. (2005) reported the identification of the PDCD10 gene
(609118) as the CCM3 gene. The CCM3 locus had been mapped to 3q26-q27
within a 22-cM interval bracketed by D3S1763 and D3S1262. They
hypothesized that genomic deletions might occur at the CCM3 locus as had
been reported at the CCM2 locus. Therefore, through high-density
microsatellite genotyping of 20 families, they identified, in 1 family,
null alleles that resulted from a deletion within a 4-Mb interval
flanked by markers D3S3668 and D3S1614. This de novo deletion
encompassed D3S1763, which strongly suggested that the CCM3 gene lay
within a 970-kb region bracketed by D3S1763 and D3S1614. Six additional
distinct deleterious mutations within PDCD10, 1 of the 5 known genes
mapped within this interval, were identified in 7 families. Three of
these mutations were nonsense mutations, and 2 led to an aberrant
splicing of exon 9, with a frameshift and a longer open reading frame
within exon 10. The last of the 6 mutations led to an aberrant splicing
of exon 5, without frameshift. Three of these mutations occurred de
novo. All of them cosegregated with the disease in the families and were
not observed in 200 control chromosomes.
By screening 8 exons of the PDCD10 gene, Verlaan et al. (2005)
identified 2 different heterozygous mutations in 2 of 15 unrelated
families with CCM that did not have mutations in the KRIT1 (604214) or
CCM2 (607929) genes. The findings suggested that mutations in the PDCD10
gene account for only a small percentage of CCM families and that there
is likely another causative gene.
In an Italian patient with CCM, Liquori et al. (2008) identified
heterozygosity for complete deletion of the CCM3 gene (609118.0007).
Through repeated cycles of amplification, subcloning, and sequencing of
multiple clones per amplicon, Akers et al. (2009) identified somatic
mutations that were otherwise invisible by direct sequencing of the bulk
amplicon. Biallelic germline and somatic mutations were identified in
CCM lesions from all 3 forms of inherited CCMs. The somatic mutations
were found only in a subset of the endothelial cells lining the
cavernous vessels and not in interstitial lesion cells. Although widely
expressed in the different cell types of the brain, the authors also
suggested a unique role for the CCM proteins in endothelial cell
biology. Akers et al. (2009) suggested that CCM lesion genesis may
require complete loss of function for 1 of the CCM genes.
*FIELD* RF
1. Akers, A. L.; Johnson, E.; Steinberg, G. K.; Zabramski, J. M.;
Marchuk, D. A.: Biallelic somatic and germline mutations in cerebral
cavernous malformations (CCMs): evidence for a two-hit mechanism of
CCM pathogenesis. Hum. Molec. Genet. 18: 919-930, 2009.
2. Bergametti, F.; Denier, C.; Labauge, P.; Arnoult, M.; Boetto, S.;
Clanet, M.; Coubes, P.; Echenne, B.; Ibrahim, R.; Irthum, B.; Jacquet,
G.; Lonjon, M.; Moreau, J. J.; Neau, J. P.; Parker, F.; Tremoulet,
M.; Tournier-Lasserve, E.; Societe Francaise de Neurochirurgie:
Mutations within the programmed cell death 10 gene cause cerebral
cavernous malformations. Am. J. Hum. Genet. 76: 42-51, 2005.
3. Craig, H. D.; Gunel, M.; Cepeda, O.; Johnson, E. W.; Ptacek, L.;
Steinberg, G. K.; Ogilvy, C. S.; Berg, M. J.; Crawford, S. C.; Scott,
R. M.; Steichen-Gersdorf, E.; Sabroe, R.; Kennedy, C. T. C.; Mettler,
G.; Beis, M. J.; Fryer, A.; Awad, I. A.; Lifton, R. P.: Multilocus
linkage identifies two new loci for a mendelian form of stroke, cerebral
cavernous malformation, at 7p15-13 and 3q25.2-27. Hum. Molec. Genet. 7:
1851-1858, 1998.
4. Denier, C.; Labauge, P.; Bergametti, F.; Marchelli, F.; Riant,
F.; Arnoult, M.; Maciazek, J.; Vicaut, E.; Brunereau, L.; Tournier-Lasserve,
E.; Societe Francaise de Neurochirurgie: Genotype-phenotype correlations
in cerebral cavernous malformations patients. Ann. Neurol. 60: 550-556,
2006.
5. Liquori, C. L.; Penco, S.; Gault, J.; Leedom, T. P.; Tassi, L.;
Esposito, T.; Awad, I. A.; Frati, L.; Johnson, E. W.; Squitieri, F.;
Marchuk, D. A.; Gianfrancesco, F.: Different spectra of genomic deletions
within the CCM genes between Italian and American CCM patient cohorts. Neurogenetics 9:
25-31, 2008.
6. Pagenstecher, A.; Stahl, S.; Sure, U.; Felbor, U.: A two-hit mechanism
causes cerebral cavernous malformations: complete inactivation of
CCM1, CCM2 or CCM3 in affected endothelial cells. Hum. Molec. Genet. 18:
911-918, 2009.
7. Verlaan, D. J.; Roussel, J.; Laurent, S. B.; Elger, C. E.; Siegel,
A. M.; Rouleau, G. A.: CCM3 mutations are uncommon in cerebral cavernous
malformations. Neurology 65: 1982-1983, 2005.
*FIELD* CN
George E. Tiller - updated: 8/26/2009
Cassandra L. Kniffin - updated: 11/6/2007
Cassandra L. Kniffin - updated: 4/6/2006
Victor A. McKusick - updated: 12/15/2004
*FIELD* CD
Victor A. McKusick: 11/13/1998
*FIELD* ED
wwang: 09/21/2010
wwang: 8/26/2009
wwang: 4/15/2008
ckniffin: 3/18/2008
wwang: 11/19/2007
ckniffin: 11/6/2007
wwang: 4/12/2006
ckniffin: 4/6/2006
alopez: 12/17/2004
terry: 12/15/2004
mgross: 3/18/2004
alopez: 10/1/1999
carol: 1/13/1999
carol: 11/13/1998
*RECORD*
*FIELD* NO
603285
*FIELD* TI
#603285 CEREBRAL CAVERNOUS MALFORMATIONS 3; CCM3
*FIELD* TX
A number sign (#) is used with this entry because of evidence that this
read moreform of cerebral cavernous malformations (CCM3) can be caused by
mutation in the PDCD10 gene (609118).
Evidence suggests that a 2-hit mechanism involving biallelic germline
and somatic mutations is responsible for CCM3 pathogenesis, see
PATHOGENESIS and MOLECULAR GENETICS sections.
For a phenotypic description and discussion of genetic heterogeneity of
cerebral cavernous malformations, see CCM1 (116860).
CLINICAL FEATURES
Denier et al. (2006) compared the clinical features of mutation carriers
from 86 families with CCM1, 25 families with CCM2 (603284), and 17
families with CCM3, ascertained from academic medical centers in France.
Of the 3 groups, CCM3 families had the lowest number of affected
individuals per family, and the highest proportion of patients with
onset of symptoms before age 15 years. Cerebral hemorrhage was the most
common initial presentation in patients with CCM3.
PATHOGENESIS
For each of the 3 CCM genes, Pagenstecher et al. (2009) showed complete
localized loss of either KRIT1 (604214), CCM2/malcavernin (607929), or
PDCD10 protein expression depending on the respective inherited
mutation. Cavernous but not adjacent normal or reactive endothelial
cells of known germline mutation carriers displayed immunohistochemical
negativity only for the corresponding CCM protein, but stained
positively for the 2 other proteins. Immunohistochemical studies
demonstrated endothelial cell mosaicism as neoangiogenic vessels within
caverns from a CCM1 patient, normal brain endothelium from a CCM2
patient, and capillary endothelial cells of vessels in a revascularized
thrombosed cavern from a CCM3 patient stained positively for KRIT1,
CCM2/malcavernin, and PDCD10 respectively. Pagenstecher et al. (2009)
suggested that complete lack of CCM protein in affected endothelial
cells from CCM germline mutation carriers supports a 2-hit mechanism for
CCM formation.
MAPPING
Among Hispanic Americans, virtually all cerebral cavernous malformation
(CCM) is attributable to a founder mutation localized to 7q (CCM1;
116860). Craig et al. (1998) reported analysis of linkage in 20
non-Hispanic Caucasian kindreds with familial CCM. Linkage to new loci,
CCM2 at 7p15-p13 and CCM3 at 3q25.2-q27, was demonstrated. Multilocus
analysis yielded a maximum lod score of 14.11, with 14% of kindreds
linked to CCM1, 20% linked to CCM2, and 40% linked to CCM3, with highly
significant evidence for linkage to 3 loci; linkage to 3 loci was
supported with an odds ratio of 2.6 x 10(5):1 over linkage to 2 loci,
and 1.6 x 10(9):1 over linkage to 1 locus. Multipoint analysis among
families with high posterior probabilities of linkage to each of the 3
loci refined the locations of CCM2 and CCM3 to approximately 22 cM
intervals. Linkage to these 3 loci can account for inheritance of CCM in
all kindreds studied. Significant locus-specific differences in
penetrance were identified.
MOLECULAR GENETICS
Bergametti et al. (2005) reported the identification of the PDCD10 gene
(609118) as the CCM3 gene. The CCM3 locus had been mapped to 3q26-q27
within a 22-cM interval bracketed by D3S1763 and D3S1262. They
hypothesized that genomic deletions might occur at the CCM3 locus as had
been reported at the CCM2 locus. Therefore, through high-density
microsatellite genotyping of 20 families, they identified, in 1 family,
null alleles that resulted from a deletion within a 4-Mb interval
flanked by markers D3S3668 and D3S1614. This de novo deletion
encompassed D3S1763, which strongly suggested that the CCM3 gene lay
within a 970-kb region bracketed by D3S1763 and D3S1614. Six additional
distinct deleterious mutations within PDCD10, 1 of the 5 known genes
mapped within this interval, were identified in 7 families. Three of
these mutations were nonsense mutations, and 2 led to an aberrant
splicing of exon 9, with a frameshift and a longer open reading frame
within exon 10. The last of the 6 mutations led to an aberrant splicing
of exon 5, without frameshift. Three of these mutations occurred de
novo. All of them cosegregated with the disease in the families and were
not observed in 200 control chromosomes.
By screening 8 exons of the PDCD10 gene, Verlaan et al. (2005)
identified 2 different heterozygous mutations in 2 of 15 unrelated
families with CCM that did not have mutations in the KRIT1 (604214) or
CCM2 (607929) genes. The findings suggested that mutations in the PDCD10
gene account for only a small percentage of CCM families and that there
is likely another causative gene.
In an Italian patient with CCM, Liquori et al. (2008) identified
heterozygosity for complete deletion of the CCM3 gene (609118.0007).
Through repeated cycles of amplification, subcloning, and sequencing of
multiple clones per amplicon, Akers et al. (2009) identified somatic
mutations that were otherwise invisible by direct sequencing of the bulk
amplicon. Biallelic germline and somatic mutations were identified in
CCM lesions from all 3 forms of inherited CCMs. The somatic mutations
were found only in a subset of the endothelial cells lining the
cavernous vessels and not in interstitial lesion cells. Although widely
expressed in the different cell types of the brain, the authors also
suggested a unique role for the CCM proteins in endothelial cell
biology. Akers et al. (2009) suggested that CCM lesion genesis may
require complete loss of function for 1 of the CCM genes.
*FIELD* RF
1. Akers, A. L.; Johnson, E.; Steinberg, G. K.; Zabramski, J. M.;
Marchuk, D. A.: Biallelic somatic and germline mutations in cerebral
cavernous malformations (CCMs): evidence for a two-hit mechanism of
CCM pathogenesis. Hum. Molec. Genet. 18: 919-930, 2009.
2. Bergametti, F.; Denier, C.; Labauge, P.; Arnoult, M.; Boetto, S.;
Clanet, M.; Coubes, P.; Echenne, B.; Ibrahim, R.; Irthum, B.; Jacquet,
G.; Lonjon, M.; Moreau, J. J.; Neau, J. P.; Parker, F.; Tremoulet,
M.; Tournier-Lasserve, E.; Societe Francaise de Neurochirurgie:
Mutations within the programmed cell death 10 gene cause cerebral
cavernous malformations. Am. J. Hum. Genet. 76: 42-51, 2005.
3. Craig, H. D.; Gunel, M.; Cepeda, O.; Johnson, E. W.; Ptacek, L.;
Steinberg, G. K.; Ogilvy, C. S.; Berg, M. J.; Crawford, S. C.; Scott,
R. M.; Steichen-Gersdorf, E.; Sabroe, R.; Kennedy, C. T. C.; Mettler,
G.; Beis, M. J.; Fryer, A.; Awad, I. A.; Lifton, R. P.: Multilocus
linkage identifies two new loci for a mendelian form of stroke, cerebral
cavernous malformation, at 7p15-13 and 3q25.2-27. Hum. Molec. Genet. 7:
1851-1858, 1998.
4. Denier, C.; Labauge, P.; Bergametti, F.; Marchelli, F.; Riant,
F.; Arnoult, M.; Maciazek, J.; Vicaut, E.; Brunereau, L.; Tournier-Lasserve,
E.; Societe Francaise de Neurochirurgie: Genotype-phenotype correlations
in cerebral cavernous malformations patients. Ann. Neurol. 60: 550-556,
2006.
5. Liquori, C. L.; Penco, S.; Gault, J.; Leedom, T. P.; Tassi, L.;
Esposito, T.; Awad, I. A.; Frati, L.; Johnson, E. W.; Squitieri, F.;
Marchuk, D. A.; Gianfrancesco, F.: Different spectra of genomic deletions
within the CCM genes between Italian and American CCM patient cohorts. Neurogenetics 9:
25-31, 2008.
6. Pagenstecher, A.; Stahl, S.; Sure, U.; Felbor, U.: A two-hit mechanism
causes cerebral cavernous malformations: complete inactivation of
CCM1, CCM2 or CCM3 in affected endothelial cells. Hum. Molec. Genet. 18:
911-918, 2009.
7. Verlaan, D. J.; Roussel, J.; Laurent, S. B.; Elger, C. E.; Siegel,
A. M.; Rouleau, G. A.: CCM3 mutations are uncommon in cerebral cavernous
malformations. Neurology 65: 1982-1983, 2005.
*FIELD* CN
George E. Tiller - updated: 8/26/2009
Cassandra L. Kniffin - updated: 11/6/2007
Cassandra L. Kniffin - updated: 4/6/2006
Victor A. McKusick - updated: 12/15/2004
*FIELD* CD
Victor A. McKusick: 11/13/1998
*FIELD* ED
wwang: 09/21/2010
wwang: 8/26/2009
wwang: 4/15/2008
ckniffin: 3/18/2008
wwang: 11/19/2007
ckniffin: 11/6/2007
wwang: 4/12/2006
ckniffin: 4/6/2006
alopez: 12/17/2004
terry: 12/15/2004
mgross: 3/18/2004
alopez: 10/1/1999
carol: 1/13/1999
carol: 11/13/1998
MIM
609118
*RECORD*
*FIELD* NO
609118
*FIELD* TI
*609118 PROGRAMMED CELL DEATH 10; PDCD10
;;CCM3 GENE;;
TFAR15
*FIELD* TX
CLONING
read moreBergametti et al. (2005) noted that PDCD10 cDNA was originally cloned on
the basis of its upregulated expression in the human myeloid cell line
TF-1, in which apoptosis was induced by deprivation of granulocyte
macrophage colony-stimulating factor (CSF2; 138960), and that PDCD10
cDNA and genomic structures were reported in several genome databases
with more than 150 reported ESTs. The coding portion of the cDNA is 636
bp long and encodes a 212-amino acid predicted protein. Three
alternative transcripts that differed only in their 5-prime untranslated
regions had been identified. Database searches by Bergametti et al.
(2005) did not identify any paralog but identified several strongly
conserved orthologs both in vertebrate and invertebrate species.
Searches of protein databases with the coding sequence of human PDCD10
did not reveal a signal peptide, transmembrane domain, or any known
functional domain. Northern blot analysis showed varying levels of a
1.35-kb transcript in all tissues tested, with highest expression in
heart, skeletal muscle, and placenta.
GENE STRUCTURE
The PDCD10 gene extends more than 50 kb and includes 7 coding exons and
three 5-prime noncoding exons (Bergametti et al., 2005). The ATG
initiator codon is located in the fourth exon.
GENE FUNCTION
The implication of the PDCD10 gene in cerebral cavernous malformations
strongly suggested that it is a new player in vascular morphogenesis
and/or remodeling (Bergametti et al., 2005).
By GST pull-down and coimmunoprecipitation analysis, Voss et al. (2007)
demonstrated that CCM2/malcavernin (607929) coprecipitated and
colocalized with PDCD10. Yeast 2-hybrid analysis showed that PDCD10
directly bound to STK25 (602255) and the phosphatase domain of FAP1
(600267). PDCD10 was phosphorylated by STK25, whereas the C-terminal
domain of FAP1 dephosphorylated PDCD10. Further experiments showed that
STK25 and CCM2 formed a protein complex. The findings linked PDCD10 and
STK25 with CCM2, which is part of signaling pathways that are essential
for vascular development. Voss et al. (2007) hypothesized that PDCD10 is
part of the KRIT1 (604214)/CCM2 protein complex through its interaction
with CCM2, and therefore may participate in CCM1-dependent modulation of
beta-1 integrin (ITGB1; 135630) signaling.
Borikova et al. (2010) showed that knockdown of Ccm1, Ccm2, or Ccm3 in
mouse embryonic endothelial cells induced RhoA (165390) overexpression
and persistent RhoA activity at the cell edge, as well as in the
cytoplasm and nucleus. RhoA activation was especially pronounced
following Ccm1 knockdown. Knockdown of Ccm1, Ccm2, or Ccm3 inhibited
formation of vessel-like tubes and invasion of extracellular matrix.
Knockdown or inhibition of Rock2 (604002) countered these effects and
was associated with inhibition of RhoA-stimulated phosphorylation of
myosin light chain-2 (MLC2; see 160781). Borikova et al. (2010)
concluded that the CCM protein complex regulates RhoA activation and
cytoskeletal dynamics.
MOLECULAR GENETICS
Cerebral cavernous malformations (CCMs) are hamartomatous vascular
malformations characterized by abnormally enlarged capillary cavities
without intervening brain parenchyma. They cause seizures and cerebral
hemorrhages, which can result in focal neurologic deficits. Several
genetic forms have been identified: 1 form, CCM1 (116860) which maps to
7q, is caused by loss-of-function mutations in the KRIT1 gene. A second
form, CCM2 (603284), which maps to 7p, is due to loss-of-function
mutations in the CCM2 gene. Bergametti et al. (2005) reported the
identification of PDCD10 as the gene mutant in the CCM3 locus, which had
been mapped to 3q26-q27. Bergametti et al. (2005) hypothesized that
genomic deletions might occur at the CCM3 locus, as reported previously
to occur at the CCM2 locus. Using high-density microsatellite genotyping
of 20 families, they identified, in 1 of these, null alleles that
resulted from deletion within an interval overlapping the previously
identified linkage mapping interval. They found that PDCD10, which was 1
of 5 known genes mapping within this interval, contained 6 distinct
deleterious mutations in 7 families. Three of these mutations were
nonsense mutations, and 2 led to an aberrant splicing of exon 9, with a
frameshift and a longer open reading frame within exon 10. The last of
the 6 mutations led to an aberrant splicing of exon 5, without
frameshift. Three of these mutations occurred de novo. All of them
cosegregated with the disease in the families and were not observed in
200 control chromosomes.
By screening 8 exons of the PDCD10 gene, Verlaan et al. (2005)
identified 2 different heterozygous mutations in 2 of 15 unrelated
families with CCM that did not have mutations in the KRIT1 or CCM2
genes. The findings suggested that mutations in the PDCD10 gene account
for only a small percentage of CCM families and that there is likely
another causative gene.
In an Italian patient with CCM3, Liquori et al. (2008) identified a
heterozygous deletion of the entire gene (609118.0007).
For each of the 3 CCM genes, Pagenstecher et al. (2009) showed complete
localized loss of either KRIT1, CCM2/malcavernin, or PDCD10 protein
expression depending on the respective inherited mutation. Cavernous but
not adjacent normal or reactive endothelial cells of known germline
mutation carriers displayed immunohistochemical negativity only for the
corresponding CCM protein, but stained positively for the 2 other
proteins. Immunohistochemical studies demonstrated endothelial cell
mosaicism as neoangiogenic vessels within caverns from a CCM1 patient,
normal brain endothelium from a CCM2 patient, and capillary endothelial
cells of vessels in a revascularized thrombosed cavern from a CCM3
patient stained positively for KRIT1, CCM2/malcavernin, and PDCD10
respectively. Pagenstecher et al. (2009) suggested that complete lack of
CCM protein in affected endothelial cells from CCM germline mutation
carriers supports a 2-hit mechanism for CCM formation.
Through repeated cycles of amplification, subcloning, and sequencing of
multiple clones per amplicon, Akers et al. (2009) identified somatic
mutations that were otherwise invisible by direct sequencing of the bulk
amplicon. Biallelic germline and somatic mutations were identified in
CCM lesions from all 3 forms of inherited CCMs. The somatic mutations
were found only in a subset of the endothelial cells lining the
cavernous vessels and not in interstitial lesion cells. Although widely
expressed in the different cell types of the brain, the authors also
suggested a unique role for the CCM proteins in endothelial cell
biology. Akers et al. (2009) suggested that CCM lesion genesis may
require complete loss of function for 1 of the CCM genes.
ANIMAL MODEL
Boulday et al. (2011) noted that deletion of Ccm1, Ccm2, or Ccm3 in mice
is embryonic lethal. They generated mice with an endothelial-specific
Ccm2 deletion at postnatal day 1, which resulted in vascular lesions
mimicking human CCM lesions. Deletion of Ccm1 or Ccm3 at postnatal day 1
resulted in similar cerebellar and retinal lesions. Ccm2 lesion
development was restricted to the venous bed. Boulday et al. (2011)
concluded that the consequences of Ccm2 deletion depend on the
developmental timing of the ablation and are associated with a
developmental stage with intense angiogenesis.
*FIELD* AV
.0001
CEREBRAL CAVERNOUS MALFORMATIONS 3
PDCD10, 586C-T
In 2 families, Bergametti et al. (2005) found that individuals with
cerebral cavernous malformations (603285) had a C-to-T transition at
nucleotide 586 in exon 10 of the PDCD10 gene, resulting in a stop codon
at codon 196. In 1 family the affected individuals were 2 sisters; in
the second family mother and daughter were affected.
.0002
CEREBRAL CAVERNOUS MALFORMATIONS 3
PDCD10, 385C-T
In a family in which mother and daughter had cerebral cavernous
malformations (603285), Bergametti et al. (2005) found that the affected
individuals carried a C-to-T transition of nucleotide 385 in exon 7 of
the PDCD10 gene, resulting in a stop codon at codon 129.
.0003
CEREBRAL CAVERNOUS MALFORMATIONS 3
PDCD10, 103C-T
Bergametti et al. (2005) found that a single individual with cerebral
cavernous malformations (603285) had a de novo mutation in exon 5 of the
PDCD10 gene: 103C-T, resulting in a stop codon at codon 35.
.0004
CEREBRAL CAVERNOUS MALFORMATIONS 3
PDCD10, 54-BP DEL
In a family in which a father and 2 sons had cerebral cavernous
malformations (603285), Bergametti et al. (2005) found a 54-bp deletion
in the PDCD10 cDNA that removed nucleotides 97 to 150 (97_150del54). The
effect of the mutation was deletion of exon 5.
.0005
CEREBRAL CAVERNOUS MALFORMATIONS 3
PDCD10, 4-BP DEL
In a family in which the father and a son had cerebral cavernous
malformations (603285), Bergametti et al. (2005) found that affected
individuals had a 4-bp deletion involving 1 of the 2 AAGT short repeats
located between exon 9 and intron 9 of the PDCD10 gene (556_557+2del4)
resulting in abnormal splicing of exon 9, leading to a frameshift and a
change in the position of the stop codon (TGA, nt637-639/TGA,
nt681-683).
.0006
CEREBRAL CAVERNOUS MALFORMATIONS 3
PDCD10, IVS8AS, G-A, -1
In a family with a single case of cerebral cavernous malformations
(603285), Bergametti et al. (2005) found that the proband had a de novo
splice site mutation in intron 8 of the PDCD10 gene (475-1G-A).
.0007
CEREBRAL CAVERNOUS MALFORMATIONS 3
PDCD10, DEL
In an Italian patient with CCM3 (603285), Liquori et al. (2008)
identified a heterozygous deletion of the entire gene.
*FIELD* RF
1. Akers, A. L.; Johnson, E.; Steinberg, G. K.; Zabramski, J. M.;
Marchuk, D. A.: Biallelic somatic and germline mutations in cerebral
cavernous malformations (CCMs): evidence for a two-hit mechanism of
CCM pathogenesis. Hum. Molec. Genet. 18: 919-930, 2009.
2. Bergametti, F.; Denier, C.; Labauge, P.; Arnoult, M.; Boetto, S.;
Clanet, M.; Coubes, P.; Echenne, B.; Ibrahim, R.; Irthum, B.; Jacquet,
G.; Lonjon, M.; Moreau, J. J.; Neau, J. P.; Parker, F.; Tremoulet,
M.; Tournier-Lasserve, E.; Societe Francaise de Neurochirurgie:
Mutations within the programmed cell death 10 gene cause cerebral
cavernous malformations. Am. J. Hum. Genet. 76: 42-51, 2005.
3. Borikova, A. L.; Dibble, C. F.; Sciaky, N.; Welch, C. M.; Abell,
A. N.; Bencharit, S.; Johnson, G. L.: Rho kinase inhibition rescues
the endothelial cell cerebral cavernous malformation phenotype. J.
Biol. Chem. 285: 11760-11764, 2010.
4. Boulday, G.; Rudini, N.; Maddaluno, L.; Blecon, A.; Arnould, M.;
Gaudric, A.; Chapon, F.; Adams, R. H.; Dejana, E.; Tournier-Lasserve,
E.: Developmental timing of CCM2 loss influences cerebral cavernous
malformations in mice. J. Exp. Med. 208: 1835-1847, 2011.
5. Liquori, C. L.; Penco, S.; Gault, J.; Leedom, T. P.; Tassi, L.;
Esposito, T.; Awad, I. A.; Frati, L.; Johnson, E. W.; Squitieri, F.;
Marchuk, D. A.; Gianfrancesco, F.: Different spectra of genomic deletions
within the CCM genes between Italian and American CCM patient cohorts. Neurogenetics 9:
25-31, 2008.
6. Pagenstecher, A.; Stahl, S.; Sure, U.; Felbor, U.: A two-hit mechanism
causes cerebral cavernous malformations: complete inactivation of
CCM1, CCM2 or CCM3 in affected endothelial cells. Hum. Molec. Genet. 18:
911-918, 2009.
7. Verlaan, D. J.; Roussel, J.; Laurent, S. B.; Elger, C. E.; Siegel,
A. M.; Rouleau, G. A.: CCM3 mutations are uncommon in cerebral cavernous
malformations. Neurology 65: 1982-1983, 2005.
8. Voss, K.; Stahl, S.; Schleider, E.; Ullrich, S.; Nickel, J.; Mueller,
T. D.; Felbor, U.: CCM3 interacts with CCM2 indicating common pathogenesis
for cerebral cavernous malformations. Neurogenetics 8: 249-256,
2007.
*FIELD* CN
Paul J. Converse - updated: 1/11/2012
Patricia A. Hartz - updated: 1/5/2011
George E. Tiller - updated: 8/12/2009
Cassandra L. Kniffin - updated: 3/18/2008
Cassandra L. Kniffin - updated: 11/27/2007
Cassandra L. Kniffin - updated: 4/6/2006
*FIELD* CD
Victor A. McKusick: 12/17/2004
*FIELD* ED
mgross: 01/20/2012
terry: 1/11/2012
mgross: 1/5/2011
wwang: 8/26/2009
terry: 8/12/2009
wwang: 4/15/2008
ckniffin: 3/18/2008
wwang: 12/3/2007
ckniffin: 11/27/2007
wwang: 4/12/2006
ckniffin: 4/6/2006
alopez: 12/17/2004
*RECORD*
*FIELD* NO
609118
*FIELD* TI
*609118 PROGRAMMED CELL DEATH 10; PDCD10
;;CCM3 GENE;;
TFAR15
*FIELD* TX
CLONING
read moreBergametti et al. (2005) noted that PDCD10 cDNA was originally cloned on
the basis of its upregulated expression in the human myeloid cell line
TF-1, in which apoptosis was induced by deprivation of granulocyte
macrophage colony-stimulating factor (CSF2; 138960), and that PDCD10
cDNA and genomic structures were reported in several genome databases
with more than 150 reported ESTs. The coding portion of the cDNA is 636
bp long and encodes a 212-amino acid predicted protein. Three
alternative transcripts that differed only in their 5-prime untranslated
regions had been identified. Database searches by Bergametti et al.
(2005) did not identify any paralog but identified several strongly
conserved orthologs both in vertebrate and invertebrate species.
Searches of protein databases with the coding sequence of human PDCD10
did not reveal a signal peptide, transmembrane domain, or any known
functional domain. Northern blot analysis showed varying levels of a
1.35-kb transcript in all tissues tested, with highest expression in
heart, skeletal muscle, and placenta.
GENE STRUCTURE
The PDCD10 gene extends more than 50 kb and includes 7 coding exons and
three 5-prime noncoding exons (Bergametti et al., 2005). The ATG
initiator codon is located in the fourth exon.
GENE FUNCTION
The implication of the PDCD10 gene in cerebral cavernous malformations
strongly suggested that it is a new player in vascular morphogenesis
and/or remodeling (Bergametti et al., 2005).
By GST pull-down and coimmunoprecipitation analysis, Voss et al. (2007)
demonstrated that CCM2/malcavernin (607929) coprecipitated and
colocalized with PDCD10. Yeast 2-hybrid analysis showed that PDCD10
directly bound to STK25 (602255) and the phosphatase domain of FAP1
(600267). PDCD10 was phosphorylated by STK25, whereas the C-terminal
domain of FAP1 dephosphorylated PDCD10. Further experiments showed that
STK25 and CCM2 formed a protein complex. The findings linked PDCD10 and
STK25 with CCM2, which is part of signaling pathways that are essential
for vascular development. Voss et al. (2007) hypothesized that PDCD10 is
part of the KRIT1 (604214)/CCM2 protein complex through its interaction
with CCM2, and therefore may participate in CCM1-dependent modulation of
beta-1 integrin (ITGB1; 135630) signaling.
Borikova et al. (2010) showed that knockdown of Ccm1, Ccm2, or Ccm3 in
mouse embryonic endothelial cells induced RhoA (165390) overexpression
and persistent RhoA activity at the cell edge, as well as in the
cytoplasm and nucleus. RhoA activation was especially pronounced
following Ccm1 knockdown. Knockdown of Ccm1, Ccm2, or Ccm3 inhibited
formation of vessel-like tubes and invasion of extracellular matrix.
Knockdown or inhibition of Rock2 (604002) countered these effects and
was associated with inhibition of RhoA-stimulated phosphorylation of
myosin light chain-2 (MLC2; see 160781). Borikova et al. (2010)
concluded that the CCM protein complex regulates RhoA activation and
cytoskeletal dynamics.
MOLECULAR GENETICS
Cerebral cavernous malformations (CCMs) are hamartomatous vascular
malformations characterized by abnormally enlarged capillary cavities
without intervening brain parenchyma. They cause seizures and cerebral
hemorrhages, which can result in focal neurologic deficits. Several
genetic forms have been identified: 1 form, CCM1 (116860) which maps to
7q, is caused by loss-of-function mutations in the KRIT1 gene. A second
form, CCM2 (603284), which maps to 7p, is due to loss-of-function
mutations in the CCM2 gene. Bergametti et al. (2005) reported the
identification of PDCD10 as the gene mutant in the CCM3 locus, which had
been mapped to 3q26-q27. Bergametti et al. (2005) hypothesized that
genomic deletions might occur at the CCM3 locus, as reported previously
to occur at the CCM2 locus. Using high-density microsatellite genotyping
of 20 families, they identified, in 1 of these, null alleles that
resulted from deletion within an interval overlapping the previously
identified linkage mapping interval. They found that PDCD10, which was 1
of 5 known genes mapping within this interval, contained 6 distinct
deleterious mutations in 7 families. Three of these mutations were
nonsense mutations, and 2 led to an aberrant splicing of exon 9, with a
frameshift and a longer open reading frame within exon 10. The last of
the 6 mutations led to an aberrant splicing of exon 5, without
frameshift. Three of these mutations occurred de novo. All of them
cosegregated with the disease in the families and were not observed in
200 control chromosomes.
By screening 8 exons of the PDCD10 gene, Verlaan et al. (2005)
identified 2 different heterozygous mutations in 2 of 15 unrelated
families with CCM that did not have mutations in the KRIT1 or CCM2
genes. The findings suggested that mutations in the PDCD10 gene account
for only a small percentage of CCM families and that there is likely
another causative gene.
In an Italian patient with CCM3, Liquori et al. (2008) identified a
heterozygous deletion of the entire gene (609118.0007).
For each of the 3 CCM genes, Pagenstecher et al. (2009) showed complete
localized loss of either KRIT1, CCM2/malcavernin, or PDCD10 protein
expression depending on the respective inherited mutation. Cavernous but
not adjacent normal or reactive endothelial cells of known germline
mutation carriers displayed immunohistochemical negativity only for the
corresponding CCM protein, but stained positively for the 2 other
proteins. Immunohistochemical studies demonstrated endothelial cell
mosaicism as neoangiogenic vessels within caverns from a CCM1 patient,
normal brain endothelium from a CCM2 patient, and capillary endothelial
cells of vessels in a revascularized thrombosed cavern from a CCM3
patient stained positively for KRIT1, CCM2/malcavernin, and PDCD10
respectively. Pagenstecher et al. (2009) suggested that complete lack of
CCM protein in affected endothelial cells from CCM germline mutation
carriers supports a 2-hit mechanism for CCM formation.
Through repeated cycles of amplification, subcloning, and sequencing of
multiple clones per amplicon, Akers et al. (2009) identified somatic
mutations that were otherwise invisible by direct sequencing of the bulk
amplicon. Biallelic germline and somatic mutations were identified in
CCM lesions from all 3 forms of inherited CCMs. The somatic mutations
were found only in a subset of the endothelial cells lining the
cavernous vessels and not in interstitial lesion cells. Although widely
expressed in the different cell types of the brain, the authors also
suggested a unique role for the CCM proteins in endothelial cell
biology. Akers et al. (2009) suggested that CCM lesion genesis may
require complete loss of function for 1 of the CCM genes.
ANIMAL MODEL
Boulday et al. (2011) noted that deletion of Ccm1, Ccm2, or Ccm3 in mice
is embryonic lethal. They generated mice with an endothelial-specific
Ccm2 deletion at postnatal day 1, which resulted in vascular lesions
mimicking human CCM lesions. Deletion of Ccm1 or Ccm3 at postnatal day 1
resulted in similar cerebellar and retinal lesions. Ccm2 lesion
development was restricted to the venous bed. Boulday et al. (2011)
concluded that the consequences of Ccm2 deletion depend on the
developmental timing of the ablation and are associated with a
developmental stage with intense angiogenesis.
*FIELD* AV
.0001
CEREBRAL CAVERNOUS MALFORMATIONS 3
PDCD10, 586C-T
In 2 families, Bergametti et al. (2005) found that individuals with
cerebral cavernous malformations (603285) had a C-to-T transition at
nucleotide 586 in exon 10 of the PDCD10 gene, resulting in a stop codon
at codon 196. In 1 family the affected individuals were 2 sisters; in
the second family mother and daughter were affected.
.0002
CEREBRAL CAVERNOUS MALFORMATIONS 3
PDCD10, 385C-T
In a family in which mother and daughter had cerebral cavernous
malformations (603285), Bergametti et al. (2005) found that the affected
individuals carried a C-to-T transition of nucleotide 385 in exon 7 of
the PDCD10 gene, resulting in a stop codon at codon 129.
.0003
CEREBRAL CAVERNOUS MALFORMATIONS 3
PDCD10, 103C-T
Bergametti et al. (2005) found that a single individual with cerebral
cavernous malformations (603285) had a de novo mutation in exon 5 of the
PDCD10 gene: 103C-T, resulting in a stop codon at codon 35.
.0004
CEREBRAL CAVERNOUS MALFORMATIONS 3
PDCD10, 54-BP DEL
In a family in which a father and 2 sons had cerebral cavernous
malformations (603285), Bergametti et al. (2005) found a 54-bp deletion
in the PDCD10 cDNA that removed nucleotides 97 to 150 (97_150del54). The
effect of the mutation was deletion of exon 5.
.0005
CEREBRAL CAVERNOUS MALFORMATIONS 3
PDCD10, 4-BP DEL
In a family in which the father and a son had cerebral cavernous
malformations (603285), Bergametti et al. (2005) found that affected
individuals had a 4-bp deletion involving 1 of the 2 AAGT short repeats
located between exon 9 and intron 9 of the PDCD10 gene (556_557+2del4)
resulting in abnormal splicing of exon 9, leading to a frameshift and a
change in the position of the stop codon (TGA, nt637-639/TGA,
nt681-683).
.0006
CEREBRAL CAVERNOUS MALFORMATIONS 3
PDCD10, IVS8AS, G-A, -1
In a family with a single case of cerebral cavernous malformations
(603285), Bergametti et al. (2005) found that the proband had a de novo
splice site mutation in intron 8 of the PDCD10 gene (475-1G-A).
.0007
CEREBRAL CAVERNOUS MALFORMATIONS 3
PDCD10, DEL
In an Italian patient with CCM3 (603285), Liquori et al. (2008)
identified a heterozygous deletion of the entire gene.
*FIELD* RF
1. Akers, A. L.; Johnson, E.; Steinberg, G. K.; Zabramski, J. M.;
Marchuk, D. A.: Biallelic somatic and germline mutations in cerebral
cavernous malformations (CCMs): evidence for a two-hit mechanism of
CCM pathogenesis. Hum. Molec. Genet. 18: 919-930, 2009.
2. Bergametti, F.; Denier, C.; Labauge, P.; Arnoult, M.; Boetto, S.;
Clanet, M.; Coubes, P.; Echenne, B.; Ibrahim, R.; Irthum, B.; Jacquet,
G.; Lonjon, M.; Moreau, J. J.; Neau, J. P.; Parker, F.; Tremoulet,
M.; Tournier-Lasserve, E.; Societe Francaise de Neurochirurgie:
Mutations within the programmed cell death 10 gene cause cerebral
cavernous malformations. Am. J. Hum. Genet. 76: 42-51, 2005.
3. Borikova, A. L.; Dibble, C. F.; Sciaky, N.; Welch, C. M.; Abell,
A. N.; Bencharit, S.; Johnson, G. L.: Rho kinase inhibition rescues
the endothelial cell cerebral cavernous malformation phenotype. J.
Biol. Chem. 285: 11760-11764, 2010.
4. Boulday, G.; Rudini, N.; Maddaluno, L.; Blecon, A.; Arnould, M.;
Gaudric, A.; Chapon, F.; Adams, R. H.; Dejana, E.; Tournier-Lasserve,
E.: Developmental timing of CCM2 loss influences cerebral cavernous
malformations in mice. J. Exp. Med. 208: 1835-1847, 2011.
5. Liquori, C. L.; Penco, S.; Gault, J.; Leedom, T. P.; Tassi, L.;
Esposito, T.; Awad, I. A.; Frati, L.; Johnson, E. W.; Squitieri, F.;
Marchuk, D. A.; Gianfrancesco, F.: Different spectra of genomic deletions
within the CCM genes between Italian and American CCM patient cohorts. Neurogenetics 9:
25-31, 2008.
6. Pagenstecher, A.; Stahl, S.; Sure, U.; Felbor, U.: A two-hit mechanism
causes cerebral cavernous malformations: complete inactivation of
CCM1, CCM2 or CCM3 in affected endothelial cells. Hum. Molec. Genet. 18:
911-918, 2009.
7. Verlaan, D. J.; Roussel, J.; Laurent, S. B.; Elger, C. E.; Siegel,
A. M.; Rouleau, G. A.: CCM3 mutations are uncommon in cerebral cavernous
malformations. Neurology 65: 1982-1983, 2005.
8. Voss, K.; Stahl, S.; Schleider, E.; Ullrich, S.; Nickel, J.; Mueller,
T. D.; Felbor, U.: CCM3 interacts with CCM2 indicating common pathogenesis
for cerebral cavernous malformations. Neurogenetics 8: 249-256,
2007.
*FIELD* CN
Paul J. Converse - updated: 1/11/2012
Patricia A. Hartz - updated: 1/5/2011
George E. Tiller - updated: 8/12/2009
Cassandra L. Kniffin - updated: 3/18/2008
Cassandra L. Kniffin - updated: 11/27/2007
Cassandra L. Kniffin - updated: 4/6/2006
*FIELD* CD
Victor A. McKusick: 12/17/2004
*FIELD* ED
mgross: 01/20/2012
terry: 1/11/2012
mgross: 1/5/2011
wwang: 8/26/2009
terry: 8/12/2009
wwang: 4/15/2008
ckniffin: 3/18/2008
wwang: 12/3/2007
ckniffin: 11/27/2007
wwang: 4/12/2006
ckniffin: 4/6/2006
alopez: 12/17/2004