Full text data of ARHGDIA
ARHGDIA
(GDIA1)
[Confidence: low (only semi-automatic identification from reviews)]
Rho GDP-dissociation inhibitor 1; Rho GDI 1 (Rho-GDI alpha)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Rho GDP-dissociation inhibitor 1; Rho GDI 1 (Rho-GDI alpha)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P52565
ID GDIR1_HUMAN Reviewed; 204 AA.
AC P52565; A8MXW0; B2R5X1; B4DDD3; B4DUV9; Q6IBM5;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 3.
DT 22-JAN-2014, entry version 139.
DE RecName: Full=Rho GDP-dissociation inhibitor 1;
DE Short=Rho GDI 1;
DE AltName: Full=Rho-GDI alpha;
GN Name=ARHGDIA; Synonyms=GDIA1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=8262133; DOI=10.1006/excr.1993.1298;
RA Leffers H., Nielsen M.S., Andersen A.H., Honore B., Madsen P.,
RA Vandekerckhove J., Celis J.E.;
RT "Identification of two human Rho GDP dissociation inhibitor proteins
RT whose overexpression leads to disruption of the actin cytoskeleton.";
RL Exp. Cell Res. 209:165-174(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Maeda A., Kaibuchi K., Takai Y.;
RT "Molecular cloning of human rho GDI.";
RL Submitted (APR-1993) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Chuang T.H., Bokoch G.M.;
RT "cDNA sequence of human rho GDP dissociation inhibitor.";
RL Submitted (JUL-1992) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1).
RA Mulheron J.G., Schwinn D.A., Caron M.G., Liggett S.B.;
RT "Genomic sequence of a human rho GDP dissociation inhibitor (GDI).";
RL Submitted (MAR-1992) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Brain cortex, and Neuroblastoma;
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RA Puhl H.L. III, Ikeda S.R., Aronstam R.S.;
RT "cDNA clones of human proteins involved in signal transduction
RT sequenced by the Guthrie cDNA resource center (www.cdna.org).";
RL Submitted (APR-2002) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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 [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16625196; DOI=10.1038/nature04689;
RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R.,
RA Gnerre S., Goldstein S., Grafham D.V., Grocock R., Hafez N.,
RA Hagopian D.S., Hart E., Norman C.H., Humphray S., Jaffe D.B.,
RA Jones M., Kamal M., Khodiyar V.K., LaButti K., Laird G., Lehoczky J.,
RA Liu X., Lokyitsang T., Loveland J., Lui A., Macdonald P., Major J.E.,
RA Matthews L., Mauceli E., McCarroll S.A., Mihalev A.H., Mudge J.,
RA Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., Schwartz D.C.,
RA Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT "DNA sequence of human chromosome 17 and analysis of rearrangement in
RT the human lineage.";
RL Nature 440:1045-1049(2006).
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Colon, Lung, Muscle, Skin, Tonsil, and Uterus;
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 [12]
RP PROTEIN SEQUENCE OF 2-42, CLEAVAGE OF INITIATOR METHIONINE,
RP ACETYLATION AT ALA-2, AND MASS SPECTROMETRY.
RC TISSUE=T-cell;
RA Bienvenut W.V., Kanor S., Tissot J.-D., Quadroni M.;
RL Submitted (MAY-2006) to UniProtKB.
RN [13]
RP PROTEIN SEQUENCE OF 34-50; 139-167 AND 181-199, AND MASS SPECTROMETRY.
RC TISSUE=Brain, Cajal-Retzius cell, and Fetal brain cortex;
RA Lubec G., Vishwanath V., Chen W.-Q., Sun Y.;
RL Submitted (DEC-2008) to UniProtKB.
RN [14]
RP PROTEIN SEQUENCE OF 34-37; 136-142 AND 181-199.
RC TISSUE=Neutrophil;
RX PubMed=8504089; DOI=10.1021/bi00072a029;
RA Kwong C.H., Malech H.L., Rotrosen D., Leto T.L.;
RT "Regulation of the human neutrophil NADPH oxidase by rho-related G-
RT proteins.";
RL Biochemistry 32:5711-5717(1993).
RN [15]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-141, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=16916647; DOI=10.1016/j.molcel.2006.06.026;
RA Kim S.C., Sprung R., Chen Y., Xu Y., Ball H., Pei J., Cheng T.,
RA Kho Y., Xiao H., Xiao L., Grishin N.V., White M., Yang X.-J., Zhao Y.;
RT "Substrate and functional diversity of lysine acetylation revealed by
RT a proteomics survey.";
RL Mol. Cell 23:607-618(2006).
RN [16]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [17]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-105; LYS-127; LYS-141 AND
RP LYS-178, 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 [18]
RP INTERACTION WITH FER.
RX PubMed=21122136; DOI=10.1186/1471-2091-11-48;
RA Fei F., Kweon S.M., Haataja L., De Sepulveda P., Groffen J.,
RA Heisterkamp N.;
RT "The Fer tyrosine kinase regulates interactions of Rho GDP-
RT Dissociation Inhibitor alpha with the small GTPase Rac.";
RL BMC Biochem. 11:48-48(2010).
RN [19]
RP INTERACTION WITH PSMD10 AND RHOA.
RX PubMed=20628200; DOI=10.1172/JCI42542;
RA Man J.H., Liang B., Gu Y.X., Zhou T., Li A.L., Li T., Jin B.F.,
RA Bai B., Zhang H.Y., Zhang W.N., Li W.H., Gong W.L., Li H.Y.,
RA Zhang X.M.;
RT "Gankyrin plays an essential role in Ras-induced tumorigenesis through
RT regulation of the RhoA/ROCK pathway in mammalian cells.";
RL J. Clin. Invest. 120:2829-2841(2010).
RN [20]
RP FUNCTION, INTERACTION WITH RHOA AND RHOC, AND MUTAGENESIS OF ASP-45
RP AND ASP-185.
RX PubMed=20400958; DOI=10.1038/ncb2049;
RA Boulter E., Garcia-Mata R., Guilluy C., Dubash A., Rossi G.,
RA Brennwald P.J., Burridge K.;
RT "Regulation of Rho GTPase crosstalk, degradation and activity by
RT RhoGDI1.";
RL Nat. Cell Biol. 12:477-483(2010).
RN [21]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [22]
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 [23]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 59-204.
RX PubMed=9195882; DOI=10.1016/S0969-2126(97)00218-9;
RA Keep N.H., Barnes M., Barsukov I., Badii R., Lian L.-Y., Segal A.W.,
RA Moody P.C.E., Roberts G.C.K.;
RT "A modulator of rho family G proteins, rhoGDI, binds these G proteins
RT via an immunoglobulin-like domain and a flexible N-terminal arm.";
RL Structure 5:623-633(1997).
RN [24]
RP VARIANT NPHS8 ASP-185 DEL, CHARACTERIZATION OF VARIANT NPHS8 ASP-185
RP DEL, FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH RAC1; RHOA
RP AND CDC42.
RX PubMed=23434736; DOI=10.1136/jmedgenet-2012-101442;
RA Gupta I.R., Baldwin C., Auguste D., Ha K.C., El Andalousi J.,
RA Fahiminiya S., Bitzan M., Bernard C., Akbari M.R., Narod S.A.,
RA Rosenblatt D.S., Majewski J., Takano T.;
RT "ARHGDIA: a novel gene implicated in nephrotic syndrome.";
RL J. Med. Genet. 50:330-338(2013).
CC -!- FUNCTION: Controls Rho proteins homeostasis. Regulates the GDP/GTP
CC exchange reaction of the Rho proteins by inhibiting the
CC dissociation of GDP from them, and the subsequent binding of GTP
CC to them. Retains Rho proteins such as CDC42, RAC1 and RHOA in an
CC inactive cytosolic pool, regulating their stability and protecting
CC them from degradation. May shuttle Rho proteins from the
CC endoplasmic reticulum to their site of action at the cell
CC membrane. Through the modulation of Rho proteins, may play a role
CC in cell motility regulation. In glioma cells, inhibits cell
CC migration and invasion by mediating the signals of SEMA5A and
CC PLXNB3 that lead to inactivation of RAC1.
CC -!- SUBUNIT: Monomer. Forms a heterodimer with RAC1. Interacts with
CC PLXNB3 (By similarity). Interacts with FER. Interacts with PSMD10
CC and RHOA; the interaction with PSMD10 increases ARHGDIA
CC association with RHOA, leading to ARHGDIA-mediated inactivation of
CC RHOA and ROCK and prolonged AKT activation. Interacts with RHOC
CC and CDC42.
CC -!- INTERACTION:
CC P63000:RAC1; NbExp=6; IntAct=EBI-712693, EBI-413628;
CC P61586:RHOA; NbExp=2; IntAct=EBI-712693, EBI-446668;
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P52565-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P52565-2; Sequence=VSP_046699;
CC -!- DISEASE: Nephrotic syndrome 8 (NPHS8) [MIM:615244]: A form of
CC nephrotic syndrome, a renal disease clinically characterized by
CC progressive renal failure, severe proteinuria, hypoalbuminemia,
CC hyperlipidemia and edema. Kidney biopsies show diffuse mesangial
CC sclerosis, with small glomeruli, hypercellularity, increased
CC extracellular matrix, and contracted/collapsed glomerular tufts
CC surrounded by immature or abnormal podocytes. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the Rho GDI family.
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; X69550; CAA49281.1; -; mRNA.
DR EMBL; D13989; BAA03096.1; -; mRNA.
DR EMBL; M97579; AAA36566.1; -; mRNA.
DR EMBL; X63863; CAA45344.1; -; Genomic_DNA.
DR EMBL; AK300816; BAG62471.1; -; mRNA.
DR EMBL; AK312347; BAG35268.1; -; mRNA.
DR EMBL; AF498926; AAM21074.1; -; mRNA.
DR EMBL; BT006884; AAP35530.1; -; mRNA.
DR EMBL; CR456777; CAG33058.1; -; mRNA.
DR EMBL; AC145207; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471099; EAW89697.1; -; Genomic_DNA.
DR EMBL; BC005851; AAH05851.1; -; mRNA.
DR EMBL; BC005875; AAH05875.1; -; mRNA.
DR EMBL; BC008701; AAH08701.1; -; mRNA.
DR EMBL; BC009759; AAH09759.1; -; mRNA.
DR EMBL; BC016031; AAH16031.1; -; mRNA.
DR EMBL; BC016185; AAH16185.1; -; mRNA.
DR EMBL; BC024258; AAH24258.1; -; mRNA.
DR EMBL; BC027730; AAH27730.1; -; mRNA.
DR EMBL; BC075827; AAH75827.1; -; mRNA.
DR EMBL; BC106044; AAI06045.1; -; mRNA.
DR PIR; I38156; I38156.
DR RefSeq; NP_001172006.1; NM_001185077.1.
DR RefSeq; NP_001172007.1; NM_001185078.1.
DR RefSeq; NP_004300.1; NM_004309.4.
DR UniGene; Hs.159161; -.
DR PDB; 1CC0; X-ray; 5.00 A; E/F=1-204.
DR PDB; 1FSO; X-ray; 2.00 A; A=67-204.
DR PDB; 1FST; X-ray; 2.70 A; A/B=24-204.
DR PDB; 1FT0; X-ray; 2.60 A; A/B=67-204.
DR PDB; 1FT3; X-ray; 2.80 A; A/B=67-204.
DR PDB; 1HH4; X-ray; 2.70 A; D/E=1-204.
DR PDB; 1KMT; X-ray; 1.30 A; A/B=67-204.
DR PDB; 1QVY; X-ray; 1.60 A; A/B/C/D=67-204.
DR PDB; 1RHO; X-ray; 2.50 A; A/B/C=59-203.
DR PDB; 2BXW; X-ray; 2.40 A; A/B=67-204.
DR PDB; 2JHS; X-ray; 1.95 A; A=67-202.
DR PDB; 2JHT; X-ray; 1.88 A; A/B/C/D=67-202.
DR PDB; 2JHU; X-ray; 1.65 A; A/B=67-202.
DR PDB; 2JHV; X-ray; 2.07 A; A/B/C/D/E/F=67-202.
DR PDB; 2JHW; X-ray; 2.50 A; A/B=67-202.
DR PDB; 2JHX; X-ray; 1.60 A; A/B=67-202.
DR PDB; 2JHY; X-ray; 1.90 A; A=67-202.
DR PDB; 2JHZ; X-ray; 2.20 A; A/B=67-202.
DR PDB; 2JI0; X-ray; 2.10 A; A=67-202.
DR PDBsum; 1CC0; -.
DR PDBsum; 1FSO; -.
DR PDBsum; 1FST; -.
DR PDBsum; 1FT0; -.
DR PDBsum; 1FT3; -.
DR PDBsum; 1HH4; -.
DR PDBsum; 1KMT; -.
DR PDBsum; 1QVY; -.
DR PDBsum; 1RHO; -.
DR PDBsum; 2BXW; -.
DR PDBsum; 2JHS; -.
DR PDBsum; 2JHT; -.
DR PDBsum; 2JHU; -.
DR PDBsum; 2JHV; -.
DR PDBsum; 2JHW; -.
DR PDBsum; 2JHX; -.
DR PDBsum; 2JHY; -.
DR PDBsum; 2JHZ; -.
DR PDBsum; 2JI0; -.
DR ProteinModelPortal; P52565; -.
DR SMR; P52565; 23-202.
DR IntAct; P52565; 32.
DR MINT; MINT-93856; -.
DR STRING; 9606.ENSP00000269321; -.
DR PhosphoSite; P52565; -.
DR DMDM; 1707892; -.
DR DOSAC-COBS-2DPAGE; P52565; -.
DR OGP; P52565; -.
DR REPRODUCTION-2DPAGE; IPI00003815; -.
DR PaxDb; P52565; -.
DR PRIDE; P52565; -.
DR DNASU; 396; -.
DR Ensembl; ENST00000269321; ENSP00000269321; ENSG00000141522.
DR Ensembl; ENST00000400721; ENSP00000383556; ENSG00000141522.
DR Ensembl; ENST00000541078; ENSP00000441348; ENSG00000141522.
DR Ensembl; ENST00000580685; ENSP00000464205; ENSG00000141522.
DR GeneID; 396; -.
DR KEGG; hsa:396; -.
DR UCSC; uc021ufg.1; human.
DR CTD; 396; -.
DR GeneCards; GC17M079825; -.
DR HGNC; HGNC:678; ARHGDIA.
DR HPA; CAB004561; -.
DR HPA; CAB010005; -.
DR HPA; HPA021407; -.
DR MIM; 601925; gene.
DR MIM; 615244; phenotype.
DR neXtProt; NX_P52565; -.
DR Orphanet; 93217; Familial idiopathic steroid-resistant nephrotic syndrome with diffuse mesangial sclerosis.
DR PharmGKB; PA24963; -.
DR eggNOG; NOG289931; -.
DR HOGENOM; HOG000175765; -.
DR HOVERGEN; HBG000206; -.
DR InParanoid; P52565; -.
DR KO; K12462; -.
DR OMA; HLSWEWS; -.
DR OrthoDB; EOG72JWH9; -.
DR PhylomeDB; P52565; -.
DR Reactome; REACT_111102; Signal Transduction.
DR EvolutionaryTrace; P52565; -.
DR GeneWiki; ARHGDIA; -.
DR GenomeRNAi; 396; -.
DR NextBio; 1661; -.
DR PRO; PR:P52565; -.
DR ArrayExpress; P52565; -.
DR Bgee; P52565; -.
DR CleanEx; HS_ARHGDIA; -.
DR Genevestigator; P52565; -.
DR GO; GO:0005856; C:cytoskeleton; TAS:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0001772; C:immunological synapse; IEA:Ensembl.
DR GO; GO:0005096; F:GTPase activator activity; IEA:UniProtKB-KW.
DR GO; GO:0005094; F:Rho GDP-dissociation inhibitor activity; TAS:ProtInc.
DR GO; GO:0006928; P:cellular component movement; TAS:UniProtKB.
DR GO; GO:0043066; P:negative regulation of apoptotic process; TAS:UniProtKB.
DR GO; GO:0050771; P:negative regulation of axonogenesis; TAS:Reactome.
DR GO; GO:0007162; P:negative regulation of cell adhesion; TAS:ProtInc.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0050772; P:positive regulation of axonogenesis; TAS:Reactome.
DR GO; GO:0043547; P:positive regulation of GTPase activity; IEA:GOC.
DR GO; GO:0032880; P:regulation of protein localization; IEA:Ensembl.
DR GO; GO:0051056; P:regulation of small GTPase mediated signal transduction; TAS:Reactome.
DR GO; GO:0007266; P:Rho protein signal transduction; TAS:ProtInc.
DR Gene3D; 2.70.50.30; -; 1.
DR InterPro; IPR014756; Ig_E-set.
DR InterPro; IPR000406; Rho_GDI.
DR InterPro; IPR024792; RhoGDI_domain.
DR PANTHER; PTHR10980; PTHR10980; 1.
DR Pfam; PF02115; Rho_GDI; 1.
DR PRINTS; PR00492; RHOGDI.
DR SUPFAM; SSF81296; SSF81296; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Complete proteome;
KW Cytoplasm; Direct protein sequencing; Disease mutation;
KW GTPase activation; Phosphoprotein; Reference proteome.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 204 Rho GDP-dissociation inhibitor 1.
FT /FTId=PRO_0000219013.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 34 34 Phosphoserine (By similarity).
FT MOD_RES 105 105 N6-acetyllysine.
FT MOD_RES 127 127 N6-acetyllysine.
FT MOD_RES 141 141 N6-acetyllysine.
FT MOD_RES 178 178 N6-acetyllysine.
FT VAR_SEQ 139 183 IDKTDYMVGSYGPRAEEYEFLTPVEEAPKGMLARGSYSIKS
FT RFTD -> N (in isoform 2).
FT /FTId=VSP_046699.
FT VARIANT 185 185 Missing (in NPHS8; produces
FT mislocalization into the nucleus,
FT hyperactivation of Rho-GTPases RHOA, RAC1
FT and CDC42 and impaired cell motility).
FT /FTId=VAR_069814.
FT MUTAGEN 45 45 D->A: Loss of RHOA interaction; when
FT associated with A-185.
FT MUTAGEN 185 185 D->A: Loss of RHOA interaction; when
FT associated with A-45.
FT CONFLICT 139 139 I -> V (in Ref. 3; CAA45344 and 5;
FT BAG35268).
FT CONFLICT 188 188 D -> R (in Ref. 13; AA sequence).
FT HELIX 35 39
FT HELIX 46 56
FT STRAND 69 78
FT STRAND 82 84
FT STRAND 87 89
FT HELIX 94 99
FT STRAND 102 105
FT STRAND 109 118
FT STRAND 123 134
FT STRAND 137 149
FT STRAND 156 159
FT TURN 169 171
FT STRAND 173 182
FT STRAND 189 200
SQ SEQUENCE 204 AA; 23207 MW; 59CB6F42E3B3BCCA CRC64;
MAEQEPTAEQ LAQIAAENEE DEHSVNYKPP AQKSIQEIQE LDKDDESLRK YKEALLGRVA
VSADPNVPNV VVTGLTLVCS SAPGPLELDL TGDLESFKKQ SFVLKEGVEY RIKISFRVNR
EIVSGMKYIQ HTYRKGVKID KTDYMVGSYG PRAEEYEFLT PVEEAPKGML ARGSYSIKSR
FTDDDKTDHL SWEWNLTIKK DWKD
//
ID GDIR1_HUMAN Reviewed; 204 AA.
AC P52565; A8MXW0; B2R5X1; B4DDD3; B4DUV9; Q6IBM5;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 3.
DT 22-JAN-2014, entry version 139.
DE RecName: Full=Rho GDP-dissociation inhibitor 1;
DE Short=Rho GDI 1;
DE AltName: Full=Rho-GDI alpha;
GN Name=ARHGDIA; Synonyms=GDIA1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=8262133; DOI=10.1006/excr.1993.1298;
RA Leffers H., Nielsen M.S., Andersen A.H., Honore B., Madsen P.,
RA Vandekerckhove J., Celis J.E.;
RT "Identification of two human Rho GDP dissociation inhibitor proteins
RT whose overexpression leads to disruption of the actin cytoskeleton.";
RL Exp. Cell Res. 209:165-174(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Maeda A., Kaibuchi K., Takai Y.;
RT "Molecular cloning of human rho GDI.";
RL Submitted (APR-1993) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Chuang T.H., Bokoch G.M.;
RT "cDNA sequence of human rho GDP dissociation inhibitor.";
RL Submitted (JUL-1992) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1).
RA Mulheron J.G., Schwinn D.A., Caron M.G., Liggett S.B.;
RT "Genomic sequence of a human rho GDP dissociation inhibitor (GDI).";
RL Submitted (MAR-1992) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Brain cortex, and Neuroblastoma;
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RA Puhl H.L. III, Ikeda S.R., Aronstam R.S.;
RT "cDNA clones of human proteins involved in signal transduction
RT sequenced by the Guthrie cDNA resource center (www.cdna.org).";
RL Submitted (APR-2002) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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 [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16625196; DOI=10.1038/nature04689;
RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R.,
RA Gnerre S., Goldstein S., Grafham D.V., Grocock R., Hafez N.,
RA Hagopian D.S., Hart E., Norman C.H., Humphray S., Jaffe D.B.,
RA Jones M., Kamal M., Khodiyar V.K., LaButti K., Laird G., Lehoczky J.,
RA Liu X., Lokyitsang T., Loveland J., Lui A., Macdonald P., Major J.E.,
RA Matthews L., Mauceli E., McCarroll S.A., Mihalev A.H., Mudge J.,
RA Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., Schwartz D.C.,
RA Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT "DNA sequence of human chromosome 17 and analysis of rearrangement in
RT the human lineage.";
RL Nature 440:1045-1049(2006).
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Colon, Lung, Muscle, Skin, Tonsil, and Uterus;
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 [12]
RP PROTEIN SEQUENCE OF 2-42, CLEAVAGE OF INITIATOR METHIONINE,
RP ACETYLATION AT ALA-2, AND MASS SPECTROMETRY.
RC TISSUE=T-cell;
RA Bienvenut W.V., Kanor S., Tissot J.-D., Quadroni M.;
RL Submitted (MAY-2006) to UniProtKB.
RN [13]
RP PROTEIN SEQUENCE OF 34-50; 139-167 AND 181-199, AND MASS SPECTROMETRY.
RC TISSUE=Brain, Cajal-Retzius cell, and Fetal brain cortex;
RA Lubec G., Vishwanath V., Chen W.-Q., Sun Y.;
RL Submitted (DEC-2008) to UniProtKB.
RN [14]
RP PROTEIN SEQUENCE OF 34-37; 136-142 AND 181-199.
RC TISSUE=Neutrophil;
RX PubMed=8504089; DOI=10.1021/bi00072a029;
RA Kwong C.H., Malech H.L., Rotrosen D., Leto T.L.;
RT "Regulation of the human neutrophil NADPH oxidase by rho-related G-
RT proteins.";
RL Biochemistry 32:5711-5717(1993).
RN [15]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-141, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=16916647; DOI=10.1016/j.molcel.2006.06.026;
RA Kim S.C., Sprung R., Chen Y., Xu Y., Ball H., Pei J., Cheng T.,
RA Kho Y., Xiao H., Xiao L., Grishin N.V., White M., Yang X.-J., Zhao Y.;
RT "Substrate and functional diversity of lysine acetylation revealed by
RT a proteomics survey.";
RL Mol. Cell 23:607-618(2006).
RN [16]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [17]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-105; LYS-127; LYS-141 AND
RP LYS-178, 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 [18]
RP INTERACTION WITH FER.
RX PubMed=21122136; DOI=10.1186/1471-2091-11-48;
RA Fei F., Kweon S.M., Haataja L., De Sepulveda P., Groffen J.,
RA Heisterkamp N.;
RT "The Fer tyrosine kinase regulates interactions of Rho GDP-
RT Dissociation Inhibitor alpha with the small GTPase Rac.";
RL BMC Biochem. 11:48-48(2010).
RN [19]
RP INTERACTION WITH PSMD10 AND RHOA.
RX PubMed=20628200; DOI=10.1172/JCI42542;
RA Man J.H., Liang B., Gu Y.X., Zhou T., Li A.L., Li T., Jin B.F.,
RA Bai B., Zhang H.Y., Zhang W.N., Li W.H., Gong W.L., Li H.Y.,
RA Zhang X.M.;
RT "Gankyrin plays an essential role in Ras-induced tumorigenesis through
RT regulation of the RhoA/ROCK pathway in mammalian cells.";
RL J. Clin. Invest. 120:2829-2841(2010).
RN [20]
RP FUNCTION, INTERACTION WITH RHOA AND RHOC, AND MUTAGENESIS OF ASP-45
RP AND ASP-185.
RX PubMed=20400958; DOI=10.1038/ncb2049;
RA Boulter E., Garcia-Mata R., Guilluy C., Dubash A., Rossi G.,
RA Brennwald P.J., Burridge K.;
RT "Regulation of Rho GTPase crosstalk, degradation and activity by
RT RhoGDI1.";
RL Nat. Cell Biol. 12:477-483(2010).
RN [21]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [22]
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 [23]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 59-204.
RX PubMed=9195882; DOI=10.1016/S0969-2126(97)00218-9;
RA Keep N.H., Barnes M., Barsukov I., Badii R., Lian L.-Y., Segal A.W.,
RA Moody P.C.E., Roberts G.C.K.;
RT "A modulator of rho family G proteins, rhoGDI, binds these G proteins
RT via an immunoglobulin-like domain and a flexible N-terminal arm.";
RL Structure 5:623-633(1997).
RN [24]
RP VARIANT NPHS8 ASP-185 DEL, CHARACTERIZATION OF VARIANT NPHS8 ASP-185
RP DEL, FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH RAC1; RHOA
RP AND CDC42.
RX PubMed=23434736; DOI=10.1136/jmedgenet-2012-101442;
RA Gupta I.R., Baldwin C., Auguste D., Ha K.C., El Andalousi J.,
RA Fahiminiya S., Bitzan M., Bernard C., Akbari M.R., Narod S.A.,
RA Rosenblatt D.S., Majewski J., Takano T.;
RT "ARHGDIA: a novel gene implicated in nephrotic syndrome.";
RL J. Med. Genet. 50:330-338(2013).
CC -!- FUNCTION: Controls Rho proteins homeostasis. Regulates the GDP/GTP
CC exchange reaction of the Rho proteins by inhibiting the
CC dissociation of GDP from them, and the subsequent binding of GTP
CC to them. Retains Rho proteins such as CDC42, RAC1 and RHOA in an
CC inactive cytosolic pool, regulating their stability and protecting
CC them from degradation. May shuttle Rho proteins from the
CC endoplasmic reticulum to their site of action at the cell
CC membrane. Through the modulation of Rho proteins, may play a role
CC in cell motility regulation. In glioma cells, inhibits cell
CC migration and invasion by mediating the signals of SEMA5A and
CC PLXNB3 that lead to inactivation of RAC1.
CC -!- SUBUNIT: Monomer. Forms a heterodimer with RAC1. Interacts with
CC PLXNB3 (By similarity). Interacts with FER. Interacts with PSMD10
CC and RHOA; the interaction with PSMD10 increases ARHGDIA
CC association with RHOA, leading to ARHGDIA-mediated inactivation of
CC RHOA and ROCK and prolonged AKT activation. Interacts with RHOC
CC and CDC42.
CC -!- INTERACTION:
CC P63000:RAC1; NbExp=6; IntAct=EBI-712693, EBI-413628;
CC P61586:RHOA; NbExp=2; IntAct=EBI-712693, EBI-446668;
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P52565-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P52565-2; Sequence=VSP_046699;
CC -!- DISEASE: Nephrotic syndrome 8 (NPHS8) [MIM:615244]: A form of
CC nephrotic syndrome, a renal disease clinically characterized by
CC progressive renal failure, severe proteinuria, hypoalbuminemia,
CC hyperlipidemia and edema. Kidney biopsies show diffuse mesangial
CC sclerosis, with small glomeruli, hypercellularity, increased
CC extracellular matrix, and contracted/collapsed glomerular tufts
CC surrounded by immature or abnormal podocytes. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the Rho GDI family.
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; X69550; CAA49281.1; -; mRNA.
DR EMBL; D13989; BAA03096.1; -; mRNA.
DR EMBL; M97579; AAA36566.1; -; mRNA.
DR EMBL; X63863; CAA45344.1; -; Genomic_DNA.
DR EMBL; AK300816; BAG62471.1; -; mRNA.
DR EMBL; AK312347; BAG35268.1; -; mRNA.
DR EMBL; AF498926; AAM21074.1; -; mRNA.
DR EMBL; BT006884; AAP35530.1; -; mRNA.
DR EMBL; CR456777; CAG33058.1; -; mRNA.
DR EMBL; AC145207; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471099; EAW89697.1; -; Genomic_DNA.
DR EMBL; BC005851; AAH05851.1; -; mRNA.
DR EMBL; BC005875; AAH05875.1; -; mRNA.
DR EMBL; BC008701; AAH08701.1; -; mRNA.
DR EMBL; BC009759; AAH09759.1; -; mRNA.
DR EMBL; BC016031; AAH16031.1; -; mRNA.
DR EMBL; BC016185; AAH16185.1; -; mRNA.
DR EMBL; BC024258; AAH24258.1; -; mRNA.
DR EMBL; BC027730; AAH27730.1; -; mRNA.
DR EMBL; BC075827; AAH75827.1; -; mRNA.
DR EMBL; BC106044; AAI06045.1; -; mRNA.
DR PIR; I38156; I38156.
DR RefSeq; NP_001172006.1; NM_001185077.1.
DR RefSeq; NP_001172007.1; NM_001185078.1.
DR RefSeq; NP_004300.1; NM_004309.4.
DR UniGene; Hs.159161; -.
DR PDB; 1CC0; X-ray; 5.00 A; E/F=1-204.
DR PDB; 1FSO; X-ray; 2.00 A; A=67-204.
DR PDB; 1FST; X-ray; 2.70 A; A/B=24-204.
DR PDB; 1FT0; X-ray; 2.60 A; A/B=67-204.
DR PDB; 1FT3; X-ray; 2.80 A; A/B=67-204.
DR PDB; 1HH4; X-ray; 2.70 A; D/E=1-204.
DR PDB; 1KMT; X-ray; 1.30 A; A/B=67-204.
DR PDB; 1QVY; X-ray; 1.60 A; A/B/C/D=67-204.
DR PDB; 1RHO; X-ray; 2.50 A; A/B/C=59-203.
DR PDB; 2BXW; X-ray; 2.40 A; A/B=67-204.
DR PDB; 2JHS; X-ray; 1.95 A; A=67-202.
DR PDB; 2JHT; X-ray; 1.88 A; A/B/C/D=67-202.
DR PDB; 2JHU; X-ray; 1.65 A; A/B=67-202.
DR PDB; 2JHV; X-ray; 2.07 A; A/B/C/D/E/F=67-202.
DR PDB; 2JHW; X-ray; 2.50 A; A/B=67-202.
DR PDB; 2JHX; X-ray; 1.60 A; A/B=67-202.
DR PDB; 2JHY; X-ray; 1.90 A; A=67-202.
DR PDB; 2JHZ; X-ray; 2.20 A; A/B=67-202.
DR PDB; 2JI0; X-ray; 2.10 A; A=67-202.
DR PDBsum; 1CC0; -.
DR PDBsum; 1FSO; -.
DR PDBsum; 1FST; -.
DR PDBsum; 1FT0; -.
DR PDBsum; 1FT3; -.
DR PDBsum; 1HH4; -.
DR PDBsum; 1KMT; -.
DR PDBsum; 1QVY; -.
DR PDBsum; 1RHO; -.
DR PDBsum; 2BXW; -.
DR PDBsum; 2JHS; -.
DR PDBsum; 2JHT; -.
DR PDBsum; 2JHU; -.
DR PDBsum; 2JHV; -.
DR PDBsum; 2JHW; -.
DR PDBsum; 2JHX; -.
DR PDBsum; 2JHY; -.
DR PDBsum; 2JHZ; -.
DR PDBsum; 2JI0; -.
DR ProteinModelPortal; P52565; -.
DR SMR; P52565; 23-202.
DR IntAct; P52565; 32.
DR MINT; MINT-93856; -.
DR STRING; 9606.ENSP00000269321; -.
DR PhosphoSite; P52565; -.
DR DMDM; 1707892; -.
DR DOSAC-COBS-2DPAGE; P52565; -.
DR OGP; P52565; -.
DR REPRODUCTION-2DPAGE; IPI00003815; -.
DR PaxDb; P52565; -.
DR PRIDE; P52565; -.
DR DNASU; 396; -.
DR Ensembl; ENST00000269321; ENSP00000269321; ENSG00000141522.
DR Ensembl; ENST00000400721; ENSP00000383556; ENSG00000141522.
DR Ensembl; ENST00000541078; ENSP00000441348; ENSG00000141522.
DR Ensembl; ENST00000580685; ENSP00000464205; ENSG00000141522.
DR GeneID; 396; -.
DR KEGG; hsa:396; -.
DR UCSC; uc021ufg.1; human.
DR CTD; 396; -.
DR GeneCards; GC17M079825; -.
DR HGNC; HGNC:678; ARHGDIA.
DR HPA; CAB004561; -.
DR HPA; CAB010005; -.
DR HPA; HPA021407; -.
DR MIM; 601925; gene.
DR MIM; 615244; phenotype.
DR neXtProt; NX_P52565; -.
DR Orphanet; 93217; Familial idiopathic steroid-resistant nephrotic syndrome with diffuse mesangial sclerosis.
DR PharmGKB; PA24963; -.
DR eggNOG; NOG289931; -.
DR HOGENOM; HOG000175765; -.
DR HOVERGEN; HBG000206; -.
DR InParanoid; P52565; -.
DR KO; K12462; -.
DR OMA; HLSWEWS; -.
DR OrthoDB; EOG72JWH9; -.
DR PhylomeDB; P52565; -.
DR Reactome; REACT_111102; Signal Transduction.
DR EvolutionaryTrace; P52565; -.
DR GeneWiki; ARHGDIA; -.
DR GenomeRNAi; 396; -.
DR NextBio; 1661; -.
DR PRO; PR:P52565; -.
DR ArrayExpress; P52565; -.
DR Bgee; P52565; -.
DR CleanEx; HS_ARHGDIA; -.
DR Genevestigator; P52565; -.
DR GO; GO:0005856; C:cytoskeleton; TAS:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0001772; C:immunological synapse; IEA:Ensembl.
DR GO; GO:0005096; F:GTPase activator activity; IEA:UniProtKB-KW.
DR GO; GO:0005094; F:Rho GDP-dissociation inhibitor activity; TAS:ProtInc.
DR GO; GO:0006928; P:cellular component movement; TAS:UniProtKB.
DR GO; GO:0043066; P:negative regulation of apoptotic process; TAS:UniProtKB.
DR GO; GO:0050771; P:negative regulation of axonogenesis; TAS:Reactome.
DR GO; GO:0007162; P:negative regulation of cell adhesion; TAS:ProtInc.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0050772; P:positive regulation of axonogenesis; TAS:Reactome.
DR GO; GO:0043547; P:positive regulation of GTPase activity; IEA:GOC.
DR GO; GO:0032880; P:regulation of protein localization; IEA:Ensembl.
DR GO; GO:0051056; P:regulation of small GTPase mediated signal transduction; TAS:Reactome.
DR GO; GO:0007266; P:Rho protein signal transduction; TAS:ProtInc.
DR Gene3D; 2.70.50.30; -; 1.
DR InterPro; IPR014756; Ig_E-set.
DR InterPro; IPR000406; Rho_GDI.
DR InterPro; IPR024792; RhoGDI_domain.
DR PANTHER; PTHR10980; PTHR10980; 1.
DR Pfam; PF02115; Rho_GDI; 1.
DR PRINTS; PR00492; RHOGDI.
DR SUPFAM; SSF81296; SSF81296; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Complete proteome;
KW Cytoplasm; Direct protein sequencing; Disease mutation;
KW GTPase activation; Phosphoprotein; Reference proteome.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 204 Rho GDP-dissociation inhibitor 1.
FT /FTId=PRO_0000219013.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 34 34 Phosphoserine (By similarity).
FT MOD_RES 105 105 N6-acetyllysine.
FT MOD_RES 127 127 N6-acetyllysine.
FT MOD_RES 141 141 N6-acetyllysine.
FT MOD_RES 178 178 N6-acetyllysine.
FT VAR_SEQ 139 183 IDKTDYMVGSYGPRAEEYEFLTPVEEAPKGMLARGSYSIKS
FT RFTD -> N (in isoform 2).
FT /FTId=VSP_046699.
FT VARIANT 185 185 Missing (in NPHS8; produces
FT mislocalization into the nucleus,
FT hyperactivation of Rho-GTPases RHOA, RAC1
FT and CDC42 and impaired cell motility).
FT /FTId=VAR_069814.
FT MUTAGEN 45 45 D->A: Loss of RHOA interaction; when
FT associated with A-185.
FT MUTAGEN 185 185 D->A: Loss of RHOA interaction; when
FT associated with A-45.
FT CONFLICT 139 139 I -> V (in Ref. 3; CAA45344 and 5;
FT BAG35268).
FT CONFLICT 188 188 D -> R (in Ref. 13; AA sequence).
FT HELIX 35 39
FT HELIX 46 56
FT STRAND 69 78
FT STRAND 82 84
FT STRAND 87 89
FT HELIX 94 99
FT STRAND 102 105
FT STRAND 109 118
FT STRAND 123 134
FT STRAND 137 149
FT STRAND 156 159
FT TURN 169 171
FT STRAND 173 182
FT STRAND 189 200
SQ SEQUENCE 204 AA; 23207 MW; 59CB6F42E3B3BCCA CRC64;
MAEQEPTAEQ LAQIAAENEE DEHSVNYKPP AQKSIQEIQE LDKDDESLRK YKEALLGRVA
VSADPNVPNV VVTGLTLVCS SAPGPLELDL TGDLESFKKQ SFVLKEGVEY RIKISFRVNR
EIVSGMKYIQ HTYRKGVKID KTDYMVGSYG PRAEEYEFLT PVEEAPKGML ARGSYSIKSR
FTDDDKTDHL SWEWNLTIKK DWKD
//
MIM
601925
*RECORD*
*FIELD* NO
601925
*FIELD* TI
*601925 RHO GDP-DISSOCIATION INHIBITOR ALPHA; ARHGDIA
;;RHOGDI;;
GDP-DISSOCIATION INHIBITOR, APLYSIA RAS-RELATED 1; GDIA1
read more*FIELD* TX
DESCRIPTION
The ARHGDIA gene encodes the Rho-GDP dissociation inhibitor-alpha, which
sequesters Rho-GTPases in an inactive state in the cytosol (summary by
Gupta et al., 2013). Aplysia Ras-related homologs (ARHs), also called
Rho genes, belong to the RAS gene superfamily encoding small guanine
nucleotide exchange (GTP/GDP) factors. The ARH proteins may be kept in
the inactive, GDP-bound state by interaction with GDP dissociation
inhibitors, such as ARHGDIA (Leffers et al., 1993).
CLONING
By screening a transformed amnion cell library with an ARHGDIB (602843)
cDNA, Leffers et al. (1993) isolated cDNAs encoding ARHGDIA. They found
that ARHGDIA corresponded to a protein in the keratinocyte
2-dimensional-gel protein database known as IEF (isoelectric focusing)
8118. By 2-dimensional gel electrophoresis, the predicted 204-amino acid
protein had a pI of 4.74 and migrated at 29 kD. The amino acid sequences
of human and bovine ARHGDIA are 97% identical. Northern blot analysis
revealed that ARHGDIA was expressed in all cell lines and tissues
tested.
GENE STRUCTURE
Leffers et al. (1993) found that the ARHGDIA gene contains 6 exons.
MAPPING
Wagner et al. (1997) demonstrated by fluorescence in situ hybridization
that the ARHGDIA gene maps to chromosome 17q25.3. The assignment was
confirmed by the use of a new somatic cell hybrid panel for chromosome
17q.
GENE FUNCTION
Leffers et al. (1993) found that overexpression of ARHGDIB in mammalian
cells caused them to 'round up' and disrupted the actin cytoskeleton,
mimicking the phenotypic changes associated with inactivation of Rho
proteins.
Using immunohistochemistry, Gupta et al. (2013) found that the Arhgdia
protein was highly expressed in the glomerulus of the adult mouse
kidney, where it localized to podocytes. The protein was also detected
in mesangial cells. Mouse podocytes with knockdown of the Arhgdia gene
using shRNA showed higher levels of activated RhoA (165390), Rac1
(602048), and Cdc42 (116952) compared to control cells. These findings
demonstrated that those Rho-GTPases were no longer maintained in their
inactive state in the absence of functional Arhgdia. Further studies
showed that these cells had impaired cell motility, as demonstrated by
impaired wound healing, likely due to altered actin dynamics.
MOLECULAR GENETICS
In 2 sisters, born of consanguineous Pakistani parents, with congenital
nephrotic syndrome type 8 (NPHS8; 615244), Gupta et al. (2013)
identified a homozygous 3-bp in-frame deletion in the ARHGDIA gene
(601925.0001). The mutation was found by whole-exome sequencing and
confirmed by Sanger sequencing. In vitro functional studies and studies
of patient fibroblasts showed that the mutation resulted in the
hyperactivation of 3 Rho-GTPases due to loss of ARHGDIA function and
impaired cell motility. Both girls presented in the first weeks of life
with severe nephrotic syndrome, resulting in death in one. Renal biopsy
of 1 patient showed diffuse mesangial sclerosis. The findings suggested
that the mutation caused an imbalance in the active and inactive forms
of Rho-GTPases, leading to derangements in the actin cytoskeleton within
podocytes and subsequent nephrotic syndrome. Gupta et al. (2013) noted
that Arhgdia-null mice also develop proteinuria and progressive renal
failure.
ANIMAL MODEL
Shibata et al. (2008) found that Arhgdia -/- mice developed progressive
renal disease characterized by heavy albuminuria and podocyte damage.
These renal changes were associated with increased Rac1 (602048) and
mineralocorticoid receptor (NR3C2; 600983) signaling in the kidney
without alteration in systemic aldosterone status. Pharmacologic
intervention with a Rac-specific small molecule inhibitor diminished
mineralocorticoid receptor overactivity and renal damage. Furthermore,
mineralocorticoid receptor blockade suppressed albuminuria and
histologic changes in Arhgdia -/- mice. Shibata et al. (2008) concluded
that RAC1 modulates mineralocorticoid receptor activity, and that
activation of the RAC1-mineralocorticoid receptor pathway has a major
role in the pathogenesis of renal damage.
*FIELD* AV
.0001
NEPHROTIC SYNDROME, TYPE 8 (1 family)
ARHGDIA, 3-BP DEL, 553GAC
In 2 sisters, born of consanguineous Pakistani parents, with congenital
nephrotic syndrome type 8 (NPHS8; 615244), Gupta et al. (2013)
identified a homozygous 3-bp in-frame deletion (c.553_555delGAC) in exon
6 of the ARHGDIA gene, resulting in the deletion of a highly conserved
residue (asp185) at the interface where ARHGDIA interacts with
Rho-GTPases. The mutation, which was found by whole-exome sequencing and
confirmed by Sanger sequencing, was present in heterozygous state in the
unaffected mother and was not found in several large control databases
or in 96 ethnically matched controls. In vitro functional expression
studies in HEK293T cells showed that the mutant protein was unable to
bind to several Rho-GTPases, consistent with a loss of function. Patient
fibroblasts showed mislocalization of mutant ARHGDIA to the nucleus,
hyperactivation of 3 Rho-GTPases due to loss of ARHGDIA function, and
impaired cell motility. The findings suggested that the mutation caused
an imbalance in the active and inactive forms of Rho-GTPases, leading to
derangements in the actin cytoskeleton within podocytes and subsequent
nephrotic syndrome. Gupta et al. (2013) noted that Arhgdia-null mice
also develop proteinuria and progressive renal failure.
*FIELD* RF
1. Gupta, I. R.; Baldwin, C.; Auguste, D.; Ha, K. C. H.; El Andalousi,
J.; Fahiminiya, S.; Bitzan, M.; Bernard, C.; Akbari, M. R.; Narod,
S. A.; Rosenblatt, D. S.; Majewski, J.; Takano, T.: ARHGDIA: a novel
gene implicated in nephrotic syndrome. J. Med. Genet. 50: 330-338,
2013.
2. Leffers, H.; Nielsen, M. S.; Andersen, A. H.; Honore, B.; Madsen,
P.; Vandekerckhove, J.; Celis, J. E.: Identification of two human
rho GDP dissociation inhibitor proteins whose overexpression leads
to disruption of the actin cytoskeleton. Exp. Cell Res. 209: 165-174,
1993.
3. Shibata, S.; Nagase, M.; Yoshida, S.; Kawarazaki, W.; Kurihara,
H.; Tanaka, H.; Miyoshi, J.; Takai, Y.; Fujita, T.: Modification
of mineralocorticoid receptor function by Rac1 GTPase: implication
in proteinuric kidney disease. Nature Med. 14: 1370-1376, 2008.
4. Wagner, T.; Tommerup, N.; Wirth, J.; Leffers, H.; Zimmer, J.; Back,
E.; Weissenbach, J.; Scherer, G.: A somatic cell hybrid panel for
distal 17q: GDIA1 maps to 17q25.3. Cytogenet. Cell Genet. 76: 172-175,
1997.
*FIELD* CN
Cassandra L. Kniffin - updated: 5/22/2013
Patricia A. Hartz - updated: 12/19/2008
Rebekah S. Rasooly - updated: 7/14/1998
*FIELD* CD
Victor A. McKusick: 7/25/1997
*FIELD* ED
carol: 05/23/2013
ckniffin: 5/22/2013
mgross: 1/5/2009
terry: 12/19/2008
alopez: 8/5/1999
alopez: 7/14/1998
alopez: 8/4/1997
terry: 7/25/1997
*RECORD*
*FIELD* NO
601925
*FIELD* TI
*601925 RHO GDP-DISSOCIATION INHIBITOR ALPHA; ARHGDIA
;;RHOGDI;;
GDP-DISSOCIATION INHIBITOR, APLYSIA RAS-RELATED 1; GDIA1
read more*FIELD* TX
DESCRIPTION
The ARHGDIA gene encodes the Rho-GDP dissociation inhibitor-alpha, which
sequesters Rho-GTPases in an inactive state in the cytosol (summary by
Gupta et al., 2013). Aplysia Ras-related homologs (ARHs), also called
Rho genes, belong to the RAS gene superfamily encoding small guanine
nucleotide exchange (GTP/GDP) factors. The ARH proteins may be kept in
the inactive, GDP-bound state by interaction with GDP dissociation
inhibitors, such as ARHGDIA (Leffers et al., 1993).
CLONING
By screening a transformed amnion cell library with an ARHGDIB (602843)
cDNA, Leffers et al. (1993) isolated cDNAs encoding ARHGDIA. They found
that ARHGDIA corresponded to a protein in the keratinocyte
2-dimensional-gel protein database known as IEF (isoelectric focusing)
8118. By 2-dimensional gel electrophoresis, the predicted 204-amino acid
protein had a pI of 4.74 and migrated at 29 kD. The amino acid sequences
of human and bovine ARHGDIA are 97% identical. Northern blot analysis
revealed that ARHGDIA was expressed in all cell lines and tissues
tested.
GENE STRUCTURE
Leffers et al. (1993) found that the ARHGDIA gene contains 6 exons.
MAPPING
Wagner et al. (1997) demonstrated by fluorescence in situ hybridization
that the ARHGDIA gene maps to chromosome 17q25.3. The assignment was
confirmed by the use of a new somatic cell hybrid panel for chromosome
17q.
GENE FUNCTION
Leffers et al. (1993) found that overexpression of ARHGDIB in mammalian
cells caused them to 'round up' and disrupted the actin cytoskeleton,
mimicking the phenotypic changes associated with inactivation of Rho
proteins.
Using immunohistochemistry, Gupta et al. (2013) found that the Arhgdia
protein was highly expressed in the glomerulus of the adult mouse
kidney, where it localized to podocytes. The protein was also detected
in mesangial cells. Mouse podocytes with knockdown of the Arhgdia gene
using shRNA showed higher levels of activated RhoA (165390), Rac1
(602048), and Cdc42 (116952) compared to control cells. These findings
demonstrated that those Rho-GTPases were no longer maintained in their
inactive state in the absence of functional Arhgdia. Further studies
showed that these cells had impaired cell motility, as demonstrated by
impaired wound healing, likely due to altered actin dynamics.
MOLECULAR GENETICS
In 2 sisters, born of consanguineous Pakistani parents, with congenital
nephrotic syndrome type 8 (NPHS8; 615244), Gupta et al. (2013)
identified a homozygous 3-bp in-frame deletion in the ARHGDIA gene
(601925.0001). The mutation was found by whole-exome sequencing and
confirmed by Sanger sequencing. In vitro functional studies and studies
of patient fibroblasts showed that the mutation resulted in the
hyperactivation of 3 Rho-GTPases due to loss of ARHGDIA function and
impaired cell motility. Both girls presented in the first weeks of life
with severe nephrotic syndrome, resulting in death in one. Renal biopsy
of 1 patient showed diffuse mesangial sclerosis. The findings suggested
that the mutation caused an imbalance in the active and inactive forms
of Rho-GTPases, leading to derangements in the actin cytoskeleton within
podocytes and subsequent nephrotic syndrome. Gupta et al. (2013) noted
that Arhgdia-null mice also develop proteinuria and progressive renal
failure.
ANIMAL MODEL
Shibata et al. (2008) found that Arhgdia -/- mice developed progressive
renal disease characterized by heavy albuminuria and podocyte damage.
These renal changes were associated with increased Rac1 (602048) and
mineralocorticoid receptor (NR3C2; 600983) signaling in the kidney
without alteration in systemic aldosterone status. Pharmacologic
intervention with a Rac-specific small molecule inhibitor diminished
mineralocorticoid receptor overactivity and renal damage. Furthermore,
mineralocorticoid receptor blockade suppressed albuminuria and
histologic changes in Arhgdia -/- mice. Shibata et al. (2008) concluded
that RAC1 modulates mineralocorticoid receptor activity, and that
activation of the RAC1-mineralocorticoid receptor pathway has a major
role in the pathogenesis of renal damage.
*FIELD* AV
.0001
NEPHROTIC SYNDROME, TYPE 8 (1 family)
ARHGDIA, 3-BP DEL, 553GAC
In 2 sisters, born of consanguineous Pakistani parents, with congenital
nephrotic syndrome type 8 (NPHS8; 615244), Gupta et al. (2013)
identified a homozygous 3-bp in-frame deletion (c.553_555delGAC) in exon
6 of the ARHGDIA gene, resulting in the deletion of a highly conserved
residue (asp185) at the interface where ARHGDIA interacts with
Rho-GTPases. The mutation, which was found by whole-exome sequencing and
confirmed by Sanger sequencing, was present in heterozygous state in the
unaffected mother and was not found in several large control databases
or in 96 ethnically matched controls. In vitro functional expression
studies in HEK293T cells showed that the mutant protein was unable to
bind to several Rho-GTPases, consistent with a loss of function. Patient
fibroblasts showed mislocalization of mutant ARHGDIA to the nucleus,
hyperactivation of 3 Rho-GTPases due to loss of ARHGDIA function, and
impaired cell motility. The findings suggested that the mutation caused
an imbalance in the active and inactive forms of Rho-GTPases, leading to
derangements in the actin cytoskeleton within podocytes and subsequent
nephrotic syndrome. Gupta et al. (2013) noted that Arhgdia-null mice
also develop proteinuria and progressive renal failure.
*FIELD* RF
1. Gupta, I. R.; Baldwin, C.; Auguste, D.; Ha, K. C. H.; El Andalousi,
J.; Fahiminiya, S.; Bitzan, M.; Bernard, C.; Akbari, M. R.; Narod,
S. A.; Rosenblatt, D. S.; Majewski, J.; Takano, T.: ARHGDIA: a novel
gene implicated in nephrotic syndrome. J. Med. Genet. 50: 330-338,
2013.
2. Leffers, H.; Nielsen, M. S.; Andersen, A. H.; Honore, B.; Madsen,
P.; Vandekerckhove, J.; Celis, J. E.: Identification of two human
rho GDP dissociation inhibitor proteins whose overexpression leads
to disruption of the actin cytoskeleton. Exp. Cell Res. 209: 165-174,
1993.
3. Shibata, S.; Nagase, M.; Yoshida, S.; Kawarazaki, W.; Kurihara,
H.; Tanaka, H.; Miyoshi, J.; Takai, Y.; Fujita, T.: Modification
of mineralocorticoid receptor function by Rac1 GTPase: implication
in proteinuric kidney disease. Nature Med. 14: 1370-1376, 2008.
4. Wagner, T.; Tommerup, N.; Wirth, J.; Leffers, H.; Zimmer, J.; Back,
E.; Weissenbach, J.; Scherer, G.: A somatic cell hybrid panel for
distal 17q: GDIA1 maps to 17q25.3. Cytogenet. Cell Genet. 76: 172-175,
1997.
*FIELD* CN
Cassandra L. Kniffin - updated: 5/22/2013
Patricia A. Hartz - updated: 12/19/2008
Rebekah S. Rasooly - updated: 7/14/1998
*FIELD* CD
Victor A. McKusick: 7/25/1997
*FIELD* ED
carol: 05/23/2013
ckniffin: 5/22/2013
mgross: 1/5/2009
terry: 12/19/2008
alopez: 8/5/1999
alopez: 7/14/1998
alopez: 8/4/1997
terry: 7/25/1997
MIM
615244
*RECORD*
*FIELD* NO
615244
*FIELD* TI
#615244 NEPHROTIC SYNDROME, TYPE 8; NPHS8
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read morenephrotic syndrome type 8 (NPHS8) is caused by homozygous mutation in
the ARHGDIA gene (601925) on chromosome 17q25. One such family has been
reported.
For a general phenotypic description and a discussion of genetic
heterogeneity of nephrotic syndrome, see NPHS1 (256300).
CLINICAL FEATURES
Gupta et al. (2013) reported 2 sisters, born of consanguineous Pakistani
parents, with congenital nephrotic syndrome. Both girls presented in the
first weeks of life with severe proteinuria, hypoalbuminemia, and
generalized edema. Renal biopsy of 1 patient showed diffuse mesangial
sclerosis, with small glomeruli, hypercellularity, increased
extracellular matrix, and contracted/collapsed glomerular tufts
surrounded by immature or abnormal podocytes. Electron microscopy showed
diffuse effacement of foot processes, thinning of the glomerular
basement membrane, and swollen endothelial cells. One patient underwent
renal transplant at age 2 years, but the graft never functioned due to
venous thrombosis, and she remained on dialysis. The second child died
at age 2 months without treatment.
INHERITANCE
The transmission pattern in the family with congenital nephrotic
syndrome reported by Gupta et al. (2013) was consistent with autosomal
recessive inheritance.
MOLECULAR GENETICS
In 2 sisters, born of consanguineous Pakistani parents, with congenital
nephrotic syndrome type 8, Gupta et al. (2013) identified a homozygous
3-bp in-frame deletion in the ARHGDIA gene (601925.0001). The mutation
was found by whole-exome sequencing, confirmed by Sanger sequencing, and
not found in multiple controls. In vitro functional studies and studies
of patient fibroblasts showed that the mutation resulted in the
hyperactivation of 3 Rho-GTPases due to loss of ARHGDIA function and
caused impaired cell motility. The findings suggested that the mutation
caused an imbalance in the active and inactive forms of Rho-GTPases,
leading to derangements in the actin cytoskeleton within podocytes and
subsequent nephrotic syndrome. Gupta et al. (2013) noted that
Arhgdia-null mice also develop proteinuria and progressive renal
failure.
ANIMAL MODEL
Shibata et al. (2008) found that Arhgdia -/- mice developed progressive
renal disease characterized by heavy albuminuria and podocyte damage.
*FIELD* RF
1. Gupta, I. R.; Baldwin, C.; Auguste, D.; Ha, K. C. H.; El Andalousi,
J.; Fahiminiya, S.; Bitzan, M.; Bernard, C.; Akbari, M. R.; Narod,
S. A.; Rosenblatt, D. S.; Majewski, J.; Takano, T.: ARHGDIA: a novel
gene implicated in nephrotic syndrome. J. Med. Genet. 50: 330-338,
2013.
2. Shibata, S.; Nagase, M.; Yoshida, S.; Kawarazaki, W.; Kurihara,
H.; Tanaka, H.; Miyoshi, J.; Takai, Y.; Fujita, T.: Modification
of mineralocorticoid receptor function by Rac1 GTPase: implication
in proteinuric kidney disease. Nature Med. 14: 1370-1376, 2008.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GENITOURINARY:
[Kidneys];
Nephrotic syndrome;
Renal failure, progressive;
Abnormal glomeruli seen on biopsy;
Diffuse mesangial sclerosis;
Hypercellularity;
Immature podocytes;
Foot process effacement;
Thinning of the glomerular basement membrane;
Swollen endothelial cells
MUSCLE, SOFT TISSUE:
Edema
LABORATORY ABNORMALITIES:
Proteinuria;
Hypoalbuminemia
MISCELLANEOUS:
Onset in first weeks of life;
Rapidly progressive;
Fatal if renal transplant is not performed;
One family has been reported (last curated May 2013)
MOLECULAR BASIS:
Caused by mutation in the Rho GDP-dissociation inhibitor alpha gene
(ARHGDIA, 601925.0001)
*FIELD* CD
Cassandra L. Kniffin: 5/22/2013
*FIELD* ED
joanna: 05/30/2013
ckniffin: 5/22/2013
*FIELD* CD
Cassandra L. Kniffin: 5/22/2013
*FIELD* ED
carol: 05/23/2013
ckniffin: 5/22/2013
*RECORD*
*FIELD* NO
615244
*FIELD* TI
#615244 NEPHROTIC SYNDROME, TYPE 8; NPHS8
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read morenephrotic syndrome type 8 (NPHS8) is caused by homozygous mutation in
the ARHGDIA gene (601925) on chromosome 17q25. One such family has been
reported.
For a general phenotypic description and a discussion of genetic
heterogeneity of nephrotic syndrome, see NPHS1 (256300).
CLINICAL FEATURES
Gupta et al. (2013) reported 2 sisters, born of consanguineous Pakistani
parents, with congenital nephrotic syndrome. Both girls presented in the
first weeks of life with severe proteinuria, hypoalbuminemia, and
generalized edema. Renal biopsy of 1 patient showed diffuse mesangial
sclerosis, with small glomeruli, hypercellularity, increased
extracellular matrix, and contracted/collapsed glomerular tufts
surrounded by immature or abnormal podocytes. Electron microscopy showed
diffuse effacement of foot processes, thinning of the glomerular
basement membrane, and swollen endothelial cells. One patient underwent
renal transplant at age 2 years, but the graft never functioned due to
venous thrombosis, and she remained on dialysis. The second child died
at age 2 months without treatment.
INHERITANCE
The transmission pattern in the family with congenital nephrotic
syndrome reported by Gupta et al. (2013) was consistent with autosomal
recessive inheritance.
MOLECULAR GENETICS
In 2 sisters, born of consanguineous Pakistani parents, with congenital
nephrotic syndrome type 8, Gupta et al. (2013) identified a homozygous
3-bp in-frame deletion in the ARHGDIA gene (601925.0001). The mutation
was found by whole-exome sequencing, confirmed by Sanger sequencing, and
not found in multiple controls. In vitro functional studies and studies
of patient fibroblasts showed that the mutation resulted in the
hyperactivation of 3 Rho-GTPases due to loss of ARHGDIA function and
caused impaired cell motility. The findings suggested that the mutation
caused an imbalance in the active and inactive forms of Rho-GTPases,
leading to derangements in the actin cytoskeleton within podocytes and
subsequent nephrotic syndrome. Gupta et al. (2013) noted that
Arhgdia-null mice also develop proteinuria and progressive renal
failure.
ANIMAL MODEL
Shibata et al. (2008) found that Arhgdia -/- mice developed progressive
renal disease characterized by heavy albuminuria and podocyte damage.
*FIELD* RF
1. Gupta, I. R.; Baldwin, C.; Auguste, D.; Ha, K. C. H.; El Andalousi,
J.; Fahiminiya, S.; Bitzan, M.; Bernard, C.; Akbari, M. R.; Narod,
S. A.; Rosenblatt, D. S.; Majewski, J.; Takano, T.: ARHGDIA: a novel
gene implicated in nephrotic syndrome. J. Med. Genet. 50: 330-338,
2013.
2. Shibata, S.; Nagase, M.; Yoshida, S.; Kawarazaki, W.; Kurihara,
H.; Tanaka, H.; Miyoshi, J.; Takai, Y.; Fujita, T.: Modification
of mineralocorticoid receptor function by Rac1 GTPase: implication
in proteinuric kidney disease. Nature Med. 14: 1370-1376, 2008.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GENITOURINARY:
[Kidneys];
Nephrotic syndrome;
Renal failure, progressive;
Abnormal glomeruli seen on biopsy;
Diffuse mesangial sclerosis;
Hypercellularity;
Immature podocytes;
Foot process effacement;
Thinning of the glomerular basement membrane;
Swollen endothelial cells
MUSCLE, SOFT TISSUE:
Edema
LABORATORY ABNORMALITIES:
Proteinuria;
Hypoalbuminemia
MISCELLANEOUS:
Onset in first weeks of life;
Rapidly progressive;
Fatal if renal transplant is not performed;
One family has been reported (last curated May 2013)
MOLECULAR BASIS:
Caused by mutation in the Rho GDP-dissociation inhibitor alpha gene
(ARHGDIA, 601925.0001)
*FIELD* CD
Cassandra L. Kniffin: 5/22/2013
*FIELD* ED
joanna: 05/30/2013
ckniffin: 5/22/2013
*FIELD* CD
Cassandra L. Kniffin: 5/22/2013
*FIELD* ED
carol: 05/23/2013
ckniffin: 5/22/2013