Full text data of ACTN4
ACTN4
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Alpha-actinin-4 (F-actin cross-linking protein; Non-muscle alpha-actinin 4)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Alpha-actinin-4 (F-actin cross-linking protein; Non-muscle alpha-actinin 4)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
hRBCD
IPI00013808
IPI00013808 Alpha-actinin 4 Alpha-actinin 4 membrane n/a n/a n/a n/a n/a n/a n/a n/a 2 n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic, connected to cytoskeleton n/a found at its expected molecular weight found at molecular weight
IPI00013808 Alpha-actinin 4 Alpha-actinin 4 membrane n/a n/a n/a n/a n/a n/a n/a n/a 2 n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic, connected to cytoskeleton n/a found at its expected molecular weight found at molecular weight
UniProt
O43707
ID ACTN4_HUMAN Reviewed; 911 AA.
AC O43707; A4K467; D6PXK4; O76048;
DT 21-FEB-2001, integrated into UniProtKB/Swiss-Prot.
read moreDT 21-FEB-2001, sequence version 2.
DT 22-JAN-2014, entry version 165.
DE RecName: Full=Alpha-actinin-4;
DE AltName: Full=F-actin cross-linking protein;
DE AltName: Full=Non-muscle alpha-actinin 4;
GN Name=ACTN4;
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] OF 4-911 (ISOFORM 1).
RX PubMed=9508771; DOI=10.1083/jcb.140.6.1383;
RA Honda K., Yamada T., Endo R., Ino Y., Gotoh M., Tsuda H., Yamada Y.,
RA Chiba H., Hirohashi S.;
RT "Actinin-4, a novel actin-bundling protein associated with cell
RT motility and cancer invasion.";
RL J. Cell Biol. 140:1383-1393(1998).
RN [2]
RP ERRATUM.
RA Honda K., Yamada T., Endo R., Ino Y., Gotoh M., Tsuda H., Yamada Y.,
RA Chiba H., Hirohashi S.;
RL J. Cell Biol. 143:276-276(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Neuroblastoma;
RX PubMed=10656685; DOI=10.1038/sj.onc.1203310;
RA Nikolopoulos S.N., Spengler B.A., Kisselbach K., Evans A.E.,
RA Biedler J.L., Ross R.A.;
RT "The human non-muscle alpha-actinin protein encoded by the ACTN4 gene
RT suppresses tumorigenicity of human neuroblastoma cells.";
RL Oncogene 19:380-386(2000).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM ACTN4ISO), SUBCELLULAR LOCATION,
RP AND ALTERNATIVE SPLICING.
RX PubMed=22567897;
RA Aksenova V.I.U., Khotin M.G., Turoverova L.V., Iudintseva N.M.,
RA Magnusson K.E., Pinaev G.P., Tentler D.G.;
RT "Novel splicing isoform of actin-binding protein alpha-actinin 4 in
RT epidermoid carcinoma cells A431.";
RL Tsitologiia 54:25-32(2012).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RA Chakraborty S., Cheng X., Lam M., Reineke E.L., Li X., Liu Y., Gao C.,
RA Khurana S., Kao H.-Y.;
RT "Actinin alpha4, an actin binding protein, is a transcriptional
RT coactivator that antagonizes class II HDAC activity.";
RL Submitted (MAR-2006) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J.,
RA Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M.,
RA Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E.,
RA Caenepeel S., Carrano A.V., Caoile C., Chan Y.M., Christensen M.,
RA Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C.,
RA Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M.,
RA Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H.,
RA Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S.,
RA Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J.,
RA Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M.,
RA Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J.,
RA Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D.,
RA Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A.,
RA Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I.,
RA Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Placenta;
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 [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-170 (ISOFORM 1).
RC TISSUE=Uterus;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-218 (ISOFORM 1).
RX PubMed=16344560; DOI=10.1101/gr.4039406;
RA Kimura K., Wakamatsu A., Suzuki Y., Ota T., Nishikawa T.,
RA Yamashita R., Yamamoto J., Sekine M., Tsuritani K., Wakaguri H.,
RA Ishii S., Sugiyama T., Saito K., Isono Y., Irie R., Kushida N.,
RA Yoneyama T., Otsuka R., Kanda K., Yokoi T., Kondo H., Wagatsuma M.,
RA Murakawa K., Ishida S., Ishibashi T., Takahashi-Fujii A., Tanase T.,
RA Nagai K., Kikuchi H., Nakai K., Isogai T., Sugano S.;
RT "Diversification of transcriptional modulation: large-scale
RT identification and characterization of putative alternative promoters
RT of human genes.";
RL Genome Res. 16:55-65(2006).
RN [10]
RP INTERACTION WITH BAIAP1.
RX PubMed=12042308; DOI=10.1074/jbc.M203072200;
RA Patrie K.M., Drescher A.J., Welihinda A., Mundel P., Margolis B.;
RT "Interaction of two actin-binding proteins, synaptopodin and alpha-
RT actinin-4, with the tight junction protein MAGI-1.";
RL J. Biol. Chem. 277:30183-30190(2002).
RN [11]
RP IDENTIFICATION IN THE CART COMPLEX.
RX PubMed=15772161; DOI=10.1091/mbc.E04-11-1014;
RA Yan Q., Sun W., Kujala P., Lotfi Y., Vida T.A., Bean A.J.;
RT "CART: an Hrs/actinin-4/BERP/myosin V protein complex required for
RT efficient receptor recycling.";
RL Mol. Biol. Cell 16:2470-2482(2005).
RN [12]
RP IDENTIFICATION IN A MRNP GRANULE COMPLEX, IDENTIFICATION BY MASS
RP SPECTROMETRY, AND SUBCELLULAR LOCATION.
RX PubMed=17289661; DOI=10.1074/mcp.M600346-MCP200;
RA Joeson L., Vikesaa J., Krogh A., Nielsen L.K., Hansen T., Borup R.,
RA Johnsen A.H., Christiansen J., Nielsen F.C.;
RT "Molecular composition of IMP1 ribonucleoprotein granules.";
RL Mol. Cell. Proteomics 6:798-811(2007).
RN [13]
RP UBIQUITINATION [LARGE SCALE ANALYSIS] AT LYS-378, AND MASS
RP SPECTROMETRY.
RC TISSUE=Mammary cancer;
RX PubMed=17370265; DOI=10.1002/pmic.200600410;
RA Denis N.J., Vasilescu J., Lambert J.-P., Smith J.C., Figeys D.;
RT "Tryptic digestion of ubiquitin standards reveals an improved strategy
RT for identifying ubiquitinated proteins by mass spectrometry.";
RL Proteomics 7:868-874(2007).
RN [14]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-114; LYS-592 AND LYS-625,
RP 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 [15]
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 [16]
RP VARIANTS FSGS1 GLU-255; ILE-259 AND PRO-262.
RC TISSUE=Lymphocyte;
RX PubMed=10700177; DOI=10.1038/73456;
RA Kaplan J.M., Kim S.H., North K.N., Rennke H., Correia L.A.,
RA Tong H.-Q., Mathis B.J., Rodriguez-Perez J.-C., Allen P.G.,
RA Beggs A.H., Pollak M.R.;
RT "Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal
RT segmental glomerulosclerosis.";
RL Nat. Genet. 24:251-256(2000).
CC -!- FUNCTION: F-actin cross-linking protein which is thought to anchor
CC actin to a variety of intracellular structures. This is a bundling
CC protein. Probably involved in vesicular trafficking via its
CC association with the CART complex. The CART complex is necessary
CC for efficient transferrin receptor recycling but not for EGFR
CC degradation. Involved in tight junction assembly in epithelial
CC cells probably through interaction with MICALL2. Links MICALL2 to
CC the actin cytoskeleton and recruits it to the tight junctions.
CC -!- SUBUNIT: Homodimer; antiparallel (By similarity). Binds TRIM3 at
CC the N-terminus (By similarity). Interacts with MICALL2
CC (preferentially in opened conformation); stimulated by RAB13
CC activation (By similarity). Identified in a complex with CASK,
CC IQGAP1, MAGI2, NPHS1, SPTAN1 and SPTBN1 (By similarity).
CC Identified in a IGF2BP1-dependent mRNP granule complex containing
CC untranslated mRNAs. Component of the CART complex, at least
CC composed of ACTN4, HGS/HRS, MYO5B and TRIM3. Interacts with BAIAP1
CC and PDLIM2.
CC -!- INTERACTION:
CC P35222:CTNNB1; NbExp=6; IntAct=EBI-351526, EBI-491549;
CC P46940:IQGAP1; NbExp=3; IntAct=EBI-351526, EBI-297509;
CC Q07157:TJP1; NbExp=4; IntAct=EBI-351526, EBI-79553;
CC -!- SUBCELLULAR LOCATION: Nucleus. Cytoplasm. Cell junction (By
CC similarity). Note=Localized in cytoplasmic mRNP granules
CC containing untranslated mRNAs. Colocalizes with actin stress
CC fibers. Nuclear translocation can be induced by the PI3 kinase
CC inhibitor wortmannin or by cytochalasin D. Exclusively localized
CC in the nucleus in a limited number of cell lines (breast cancer
CC cell line MCF-7, oral floor cancer IMC-2, and bladder cancer KU-
CC 7).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=O43707-1; Sequence=Displayed;
CC Name=ACTN4ISO;
CC IsoId=O43707-2; Sequence=VSP_047733;
CC Note=Does not colocalize with actin cytoskeleton structures;
CC Name=3;
CC IsoId=O43707-3; Sequence=VSP_053401;
CC -!- TISSUE SPECIFICITY: Widely expressed.
CC -!- DISEASE: Focal segmental glomerulosclerosis 1 (FSGS1)
CC [MIM:603278]: A renal pathology defined by the presence of
CC segmental sclerosis in glomeruli and resulting in proteinuria,
CC reduced glomerular filtration rate and progressive decline in
CC renal function. Renal insufficiency often progresses to end-stage
CC renal disease, a highly morbid state requiring either dialysis
CC therapy or kidney transplantation. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the alpha-actinin family.
CC -!- SIMILARITY: Contains 1 actin-binding domain.
CC -!- SIMILARITY: Contains 2 CH (calponin-homology) domains.
CC -!- SIMILARITY: Contains 2 EF-hand domains.
CC -!- SIMILARITY: Contains 4 spectrin repeats.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAC17470.1; Type=Frameshift; Positions=19, 26, 124, 130, 589, 594, 787, 806;
CC Sequence=BAA24447.1; Type=Erroneous initiation;
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/ACTN4";
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DR EMBL; D89980; BAA24447.1; ALT_INIT; mRNA.
DR EMBL; U48734; AAC17470.1; ALT_FRAME; mRNA.
DR EMBL; GU987085; ADG03678.1; -; mRNA.
DR EMBL; DQ431186; ABD96103.1; -; mRNA.
DR EMBL; AC008649; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC022144; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC005033; AAH05033.1; -; mRNA.
DR EMBL; AL047603; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AU118403; -; NOT_ANNOTATED_CDS; mRNA.
DR RefSeq; NP_004915.2; NM_004924.4.
DR RefSeq; XP_005259340.1; XM_005259283.1.
DR UniGene; Hs.270291; -.
DR PDB; 1WLX; NMR; -; A=519-645.
DR PDB; 1YDI; X-ray; 1.80 A; B=734-757.
DR PDB; 2R0O; X-ray; 2.20 A; A/B=47-271.
DR PDBsum; 1WLX; -.
DR PDBsum; 1YDI; -.
DR PDBsum; 2R0O; -.
DR ProteinModelPortal; O43707; -.
DR SMR; O43707; 47-271, 286-911.
DR DIP; DIP-33179N; -.
DR IntAct; O43707; 26.
DR MINT; MINT-4998602; -.
DR STRING; 9606.ENSP00000252699; -.
DR PhosphoSite; O43707; -.
DR REPRODUCTION-2DPAGE; O43707; -.
DR PaxDb; O43707; -.
DR PeptideAtlas; O43707; -.
DR PRIDE; O43707; -.
DR DNASU; 81; -.
DR Ensembl; ENST00000252699; ENSP00000252699; ENSG00000130402.
DR Ensembl; ENST00000390009; ENSP00000439497; ENSG00000130402.
DR GeneID; 81; -.
DR KEGG; hsa:81; -.
DR UCSC; uc021uug.1; human.
DR CTD; 81; -.
DR GeneCards; GC19P039138; -.
DR HGNC; HGNC:166; ACTN4.
DR HPA; HPA001873; -.
DR HPA; HPA006035; -.
DR MIM; 603278; phenotype.
DR MIM; 604638; gene.
DR neXtProt; NX_O43707; -.
DR Orphanet; 93213; Familial idiopathic steroid-resistant nephrotic syndrome with focal segmental hyalinosis.
DR PharmGKB; PA23; -.
DR eggNOG; COG5069; -.
DR HOGENOM; HOG000263418; -.
DR HOVERGEN; HBG050453; -.
DR InParanoid; O43707; -.
DR KO; K05699; -.
DR OMA; QANIVGP; -.
DR OrthoDB; EOG72C4ZJ; -.
DR PhylomeDB; O43707; -.
DR Reactome; REACT_111155; Cell-Cell communication.
DR Reactome; REACT_604; Hemostasis.
DR ChiTaRS; ACTN4; human.
DR EvolutionaryTrace; O43707; -.
DR GeneWiki; Actinin_alpha_4; -.
DR GenomeRNAi; 81; -.
DR NextBio; 303; -.
DR PMAP-CutDB; O43707; -.
DR PRO; PR:O43707; -.
DR ArrayExpress; O43707; -.
DR Bgee; O43707; -.
DR CleanEx; HS_ACTN4; -.
DR Genevestigator; O43707; -.
DR GO; GO:0030054; C:cell junction; IEA:UniProtKB-SubCell.
DR GO; GO:0030863; C:cortical cytoskeleton; IEA:Ensembl.
DR GO; GO:0070062; C:extracellular vesicular exosome; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
DR GO; GO:0031093; C:platelet alpha granule lumen; TAS:Reactome.
DR GO; GO:0043234; C:protein complex; IDA:UniProtKB.
DR GO; GO:0031143; C:pseudopodium; TAS:UniProtKB.
DR GO; GO:0030529; C:ribonucleoprotein complex; IDA:UniProtKB.
DR GO; GO:0001725; C:stress fiber; IEA:Ensembl.
DR GO; GO:0030018; C:Z disc; IEA:Ensembl.
DR GO; GO:0051015; F:actin filament binding; IDA:UniProtKB.
DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR GO; GO:0005178; F:integrin binding; TAS:UniProtKB.
DR GO; GO:0001882; F:nucleoside binding; IDA:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; TAS:UniProtKB.
DR GO; GO:0051271; P:negative regulation of cellular component movement; IEA:Ensembl.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0002576; P:platelet degranulation; TAS:Reactome.
DR GO; GO:0051272; P:positive regulation of cellular component movement; IDA:UniProtKB.
DR GO; GO:0048549; P:positive regulation of pinocytosis; IEA:Ensembl.
DR GO; GO:0032417; P:positive regulation of sodium:hydrogen antiporter activity; NAS:UniProtKB.
DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW.
DR GO; GO:0042981; P:regulation of apoptotic process; NAS:UniProtKB.
DR GO; GO:0001666; P:response to hypoxia; IEA:Ensembl.
DR Gene3D; 1.10.238.10; -; 2.
DR Gene3D; 1.10.418.10; -; 2.
DR InterPro; IPR001589; Actinin_actin-bd_CS.
DR InterPro; IPR001715; CH-domain.
DR InterPro; IPR011992; EF-hand-dom_pair.
DR InterPro; IPR014837; EF-hand_Ca_insen.
DR InterPro; IPR018247; EF_Hand_1_Ca_BS.
DR InterPro; IPR002048; EF_hand_dom.
DR InterPro; IPR018159; Spectrin/alpha-actinin.
DR InterPro; IPR002017; Spectrin_repeat.
DR Pfam; PF00307; CH; 2.
DR Pfam; PF13405; EF-hand_6; 1.
DR Pfam; PF08726; EFhand_Ca_insen; 1.
DR Pfam; PF00435; Spectrin; 4.
DR SMART; SM00033; CH; 2.
DR SMART; SM00054; EFh; 2.
DR SMART; SM00150; SPEC; 4.
DR SUPFAM; SSF47576; SSF47576; 1.
DR PROSITE; PS00019; ACTININ_1; 1.
DR PROSITE; PS00020; ACTININ_2; 1.
DR PROSITE; PS50021; CH; 2.
DR PROSITE; PS00018; EF_HAND_1; 1.
DR PROSITE; PS50222; EF_HAND_2; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Actin-binding; Alternative splicing;
KW Calcium; Cell junction; Complete proteome; Cytoplasm;
KW Disease mutation; Isopeptide bond; Metal-binding; Nucleus;
KW Protein transport; Reference proteome; Repeat; Transport;
KW Ubl conjugation.
FT CHAIN 1 911 Alpha-actinin-4.
FT /FTId=PRO_0000073440.
FT DOMAIN 1 269 Actin-binding.
FT DOMAIN 50 154 CH 1.
FT DOMAIN 163 269 CH 2.
FT REPEAT 293 403 Spectrin 1.
FT REPEAT 413 518 Spectrin 2.
FT REPEAT 528 639 Spectrin 3.
FT REPEAT 649 752 Spectrin 4.
FT DOMAIN 765 800 EF-hand 1.
FT DOMAIN 806 841 EF-hand 2.
FT CA_BIND 778 789 1 (Potential).
FT CA_BIND 819 830 2 (Potential).
FT REGION 177 192 Polyphosphoinositide (PIP2)-binding
FT (Potential).
FT REGION 736 911 Mediates interaction with MICALL2 (By
FT similarity).
FT COMPBIAS 19 26 Poly-Gly.
FT MOD_RES 114 114 N6-acetyllysine.
FT MOD_RES 592 592 N6-acetyllysine.
FT MOD_RES 625 625 N6-acetyllysine.
FT CROSSLNK 378 378 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin).
FT VAR_SEQ 54 272 Missing (in isoform ACTN4ISO).
FT /FTId=VSP_047733.
FT VAR_SEQ 89 478 Missing (in isoform 3).
FT /FTId=VSP_053401.
FT VARIANT 255 255 K -> E (in FSGS1; dbSNP:rs28939374).
FT /FTId=VAR_010378.
FT VARIANT 259 259 T -> I (in FSGS1; dbSNP:rs28939375).
FT /FTId=VAR_010379.
FT VARIANT 262 262 S -> P (in FSGS1; dbSNP:rs28939376).
FT /FTId=VAR_010380.
FT CONFLICT 60 60 C -> S (in Ref. 3; AAC17470).
FT CONFLICT 164 164 S -> L (in Ref. 7; AL047603/AU118403).
FT CONFLICT 276 276 T -> TET (in Ref. 3; AAC17470).
FT CONFLICT 292 294 EHL -> CSTS (in Ref. 3; AAC17470).
FT CONFLICT 359 360 TL -> SV (in Ref. 3; AAC17470).
FT CONFLICT 476 476 I -> S (in Ref. 3; AAC17470).
FT CONFLICT 526 526 I -> II (in Ref. 3; AAC17470).
FT CONFLICT 536 536 R -> P (in Ref. 3; AAC17470).
FT CONFLICT 645 645 Q -> QQ (in Ref. 3; AAC17470).
FT CONFLICT 673 674 GR -> A (in Ref. 3; AAC17470).
FT CONFLICT 850 850 A -> T (in Ref. 3; AAC17470).
FT CONFLICT 891 893 AVP -> GVR (in Ref. 3; AAC17470).
FT HELIX 47 64
FT HELIX 65 67
FT TURN 74 80
FT HELIX 82 92
FT HELIX 105 120
FT TURN 121 123
FT HELIX 131 135
FT HELIX 139 153
FT TURN 154 157
FT HELIX 165 177
FT STRAND 187 189
FT HELIX 190 192
FT HELIX 196 205
FT HELIX 207 209
FT HELIX 212 214
FT HELIX 220 234
FT HELIX 243 248
FT STRAND 249 251
FT HELIX 254 267
FT HELIX 519 552
FT HELIX 560 600
FT STRAND 606 608
FT HELIX 616 641
SQ SEQUENCE 911 AA; 104854 MW; 461580C3F22937D1 CRC64;
MVDYHAANQS YQYGPSSAGN GAGGGGSMGD YMAQEDDWDR DLLLDPAWEK QQRKTFTAWC
NSHLRKAGTQ IENIDEDFRD GLKLMLLLEV ISGERLPKPE RGKMRVHKIN NVNKALDFIA
SKGVKLVSIG AEEIVDGNAK MTLGMIWTII LRFAIQDISV EETSAKEGLL LWCQRKTAPY
KNVNVQNFHI SWKDGLAFNA LIHRHRPELI EYDKLRKDDP VTNLNNAFEV AEKYLDIPKM
LDAEDIVNTA RPDEKAIMTY VSSFYHAFSG AQKAETAANR ICKVLAVNQE NEHLMEDYEK
LASDLLEWIR RTIPWLEDRV PQKTIQEMQQ KLEDFRDYRR VHKPPKVQEK CQLEINFNTL
QTKLRLSNRP AFMPSEGKMV SDINNGWQHL EQAEKGYEEW LLNEIRRLER LDHLAEKFRQ
KASIHEAWTD GKEAMLKHRD YETATLSDIK ALIRKHEAFE SDLAAHQDRV EQIAAIAQEL
NELDYYDSHN VNTRCQKICD QWDALGSLTH SRREALEKTE KQLEAIDQLH LEYAKRAAPF
NNWMESAMED LQDMFIVHTI EEIEGLISAH DQFKSTLPDA DREREAILAI HKEAQRIAES
NHIKLSGSNP YTTVTPQIIN SKWEKVQQLV PKRDHALLEE QSKQQSNEHL RRQFASQANV
VGPWIQTKME EIGRISIEMN GTLEDQLSHL KQYERSIVDY KPNLDLLEQQ HQLIQEALIF
DNKHTNYTME HIRVGWEQLL TTIARTINEV ENQILTRDAK GISQEQMQEF RASFNHFDKD
HGGALGPEEF KACLISLGYD VENDRQGEAE FNRIMSLVDP NHSGLVTFQA FIDFMSRETT
DTDTADQVIA SFKVLAGDKN FITAEELRRE LPPDQAEYCI ARMAPYQGPD AVPGALDYKS
FSTALYGESD L
//
ID ACTN4_HUMAN Reviewed; 911 AA.
AC O43707; A4K467; D6PXK4; O76048;
DT 21-FEB-2001, integrated into UniProtKB/Swiss-Prot.
read moreDT 21-FEB-2001, sequence version 2.
DT 22-JAN-2014, entry version 165.
DE RecName: Full=Alpha-actinin-4;
DE AltName: Full=F-actin cross-linking protein;
DE AltName: Full=Non-muscle alpha-actinin 4;
GN Name=ACTN4;
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] OF 4-911 (ISOFORM 1).
RX PubMed=9508771; DOI=10.1083/jcb.140.6.1383;
RA Honda K., Yamada T., Endo R., Ino Y., Gotoh M., Tsuda H., Yamada Y.,
RA Chiba H., Hirohashi S.;
RT "Actinin-4, a novel actin-bundling protein associated with cell
RT motility and cancer invasion.";
RL J. Cell Biol. 140:1383-1393(1998).
RN [2]
RP ERRATUM.
RA Honda K., Yamada T., Endo R., Ino Y., Gotoh M., Tsuda H., Yamada Y.,
RA Chiba H., Hirohashi S.;
RL J. Cell Biol. 143:276-276(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Neuroblastoma;
RX PubMed=10656685; DOI=10.1038/sj.onc.1203310;
RA Nikolopoulos S.N., Spengler B.A., Kisselbach K., Evans A.E.,
RA Biedler J.L., Ross R.A.;
RT "The human non-muscle alpha-actinin protein encoded by the ACTN4 gene
RT suppresses tumorigenicity of human neuroblastoma cells.";
RL Oncogene 19:380-386(2000).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM ACTN4ISO), SUBCELLULAR LOCATION,
RP AND ALTERNATIVE SPLICING.
RX PubMed=22567897;
RA Aksenova V.I.U., Khotin M.G., Turoverova L.V., Iudintseva N.M.,
RA Magnusson K.E., Pinaev G.P., Tentler D.G.;
RT "Novel splicing isoform of actin-binding protein alpha-actinin 4 in
RT epidermoid carcinoma cells A431.";
RL Tsitologiia 54:25-32(2012).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RA Chakraborty S., Cheng X., Lam M., Reineke E.L., Li X., Liu Y., Gao C.,
RA Khurana S., Kao H.-Y.;
RT "Actinin alpha4, an actin binding protein, is a transcriptional
RT coactivator that antagonizes class II HDAC activity.";
RL Submitted (MAR-2006) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J.,
RA Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M.,
RA Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E.,
RA Caenepeel S., Carrano A.V., Caoile C., Chan Y.M., Christensen M.,
RA Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C.,
RA Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M.,
RA Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H.,
RA Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S.,
RA Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J.,
RA Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M.,
RA Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J.,
RA Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D.,
RA Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A.,
RA Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I.,
RA Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Placenta;
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 [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-170 (ISOFORM 1).
RC TISSUE=Uterus;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-218 (ISOFORM 1).
RX PubMed=16344560; DOI=10.1101/gr.4039406;
RA Kimura K., Wakamatsu A., Suzuki Y., Ota T., Nishikawa T.,
RA Yamashita R., Yamamoto J., Sekine M., Tsuritani K., Wakaguri H.,
RA Ishii S., Sugiyama T., Saito K., Isono Y., Irie R., Kushida N.,
RA Yoneyama T., Otsuka R., Kanda K., Yokoi T., Kondo H., Wagatsuma M.,
RA Murakawa K., Ishida S., Ishibashi T., Takahashi-Fujii A., Tanase T.,
RA Nagai K., Kikuchi H., Nakai K., Isogai T., Sugano S.;
RT "Diversification of transcriptional modulation: large-scale
RT identification and characterization of putative alternative promoters
RT of human genes.";
RL Genome Res. 16:55-65(2006).
RN [10]
RP INTERACTION WITH BAIAP1.
RX PubMed=12042308; DOI=10.1074/jbc.M203072200;
RA Patrie K.M., Drescher A.J., Welihinda A., Mundel P., Margolis B.;
RT "Interaction of two actin-binding proteins, synaptopodin and alpha-
RT actinin-4, with the tight junction protein MAGI-1.";
RL J. Biol. Chem. 277:30183-30190(2002).
RN [11]
RP IDENTIFICATION IN THE CART COMPLEX.
RX PubMed=15772161; DOI=10.1091/mbc.E04-11-1014;
RA Yan Q., Sun W., Kujala P., Lotfi Y., Vida T.A., Bean A.J.;
RT "CART: an Hrs/actinin-4/BERP/myosin V protein complex required for
RT efficient receptor recycling.";
RL Mol. Biol. Cell 16:2470-2482(2005).
RN [12]
RP IDENTIFICATION IN A MRNP GRANULE COMPLEX, IDENTIFICATION BY MASS
RP SPECTROMETRY, AND SUBCELLULAR LOCATION.
RX PubMed=17289661; DOI=10.1074/mcp.M600346-MCP200;
RA Joeson L., Vikesaa J., Krogh A., Nielsen L.K., Hansen T., Borup R.,
RA Johnsen A.H., Christiansen J., Nielsen F.C.;
RT "Molecular composition of IMP1 ribonucleoprotein granules.";
RL Mol. Cell. Proteomics 6:798-811(2007).
RN [13]
RP UBIQUITINATION [LARGE SCALE ANALYSIS] AT LYS-378, AND MASS
RP SPECTROMETRY.
RC TISSUE=Mammary cancer;
RX PubMed=17370265; DOI=10.1002/pmic.200600410;
RA Denis N.J., Vasilescu J., Lambert J.-P., Smith J.C., Figeys D.;
RT "Tryptic digestion of ubiquitin standards reveals an improved strategy
RT for identifying ubiquitinated proteins by mass spectrometry.";
RL Proteomics 7:868-874(2007).
RN [14]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-114; LYS-592 AND LYS-625,
RP 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 [15]
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 [16]
RP VARIANTS FSGS1 GLU-255; ILE-259 AND PRO-262.
RC TISSUE=Lymphocyte;
RX PubMed=10700177; DOI=10.1038/73456;
RA Kaplan J.M., Kim S.H., North K.N., Rennke H., Correia L.A.,
RA Tong H.-Q., Mathis B.J., Rodriguez-Perez J.-C., Allen P.G.,
RA Beggs A.H., Pollak M.R.;
RT "Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal
RT segmental glomerulosclerosis.";
RL Nat. Genet. 24:251-256(2000).
CC -!- FUNCTION: F-actin cross-linking protein which is thought to anchor
CC actin to a variety of intracellular structures. This is a bundling
CC protein. Probably involved in vesicular trafficking via its
CC association with the CART complex. The CART complex is necessary
CC for efficient transferrin receptor recycling but not for EGFR
CC degradation. Involved in tight junction assembly in epithelial
CC cells probably through interaction with MICALL2. Links MICALL2 to
CC the actin cytoskeleton and recruits it to the tight junctions.
CC -!- SUBUNIT: Homodimer; antiparallel (By similarity). Binds TRIM3 at
CC the N-terminus (By similarity). Interacts with MICALL2
CC (preferentially in opened conformation); stimulated by RAB13
CC activation (By similarity). Identified in a complex with CASK,
CC IQGAP1, MAGI2, NPHS1, SPTAN1 and SPTBN1 (By similarity).
CC Identified in a IGF2BP1-dependent mRNP granule complex containing
CC untranslated mRNAs. Component of the CART complex, at least
CC composed of ACTN4, HGS/HRS, MYO5B and TRIM3. Interacts with BAIAP1
CC and PDLIM2.
CC -!- INTERACTION:
CC P35222:CTNNB1; NbExp=6; IntAct=EBI-351526, EBI-491549;
CC P46940:IQGAP1; NbExp=3; IntAct=EBI-351526, EBI-297509;
CC Q07157:TJP1; NbExp=4; IntAct=EBI-351526, EBI-79553;
CC -!- SUBCELLULAR LOCATION: Nucleus. Cytoplasm. Cell junction (By
CC similarity). Note=Localized in cytoplasmic mRNP granules
CC containing untranslated mRNAs. Colocalizes with actin stress
CC fibers. Nuclear translocation can be induced by the PI3 kinase
CC inhibitor wortmannin or by cytochalasin D. Exclusively localized
CC in the nucleus in a limited number of cell lines (breast cancer
CC cell line MCF-7, oral floor cancer IMC-2, and bladder cancer KU-
CC 7).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=O43707-1; Sequence=Displayed;
CC Name=ACTN4ISO;
CC IsoId=O43707-2; Sequence=VSP_047733;
CC Note=Does not colocalize with actin cytoskeleton structures;
CC Name=3;
CC IsoId=O43707-3; Sequence=VSP_053401;
CC -!- TISSUE SPECIFICITY: Widely expressed.
CC -!- DISEASE: Focal segmental glomerulosclerosis 1 (FSGS1)
CC [MIM:603278]: A renal pathology defined by the presence of
CC segmental sclerosis in glomeruli and resulting in proteinuria,
CC reduced glomerular filtration rate and progressive decline in
CC renal function. Renal insufficiency often progresses to end-stage
CC renal disease, a highly morbid state requiring either dialysis
CC therapy or kidney transplantation. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the alpha-actinin family.
CC -!- SIMILARITY: Contains 1 actin-binding domain.
CC -!- SIMILARITY: Contains 2 CH (calponin-homology) domains.
CC -!- SIMILARITY: Contains 2 EF-hand domains.
CC -!- SIMILARITY: Contains 4 spectrin repeats.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAC17470.1; Type=Frameshift; Positions=19, 26, 124, 130, 589, 594, 787, 806;
CC Sequence=BAA24447.1; Type=Erroneous initiation;
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/ACTN4";
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DR EMBL; D89980; BAA24447.1; ALT_INIT; mRNA.
DR EMBL; U48734; AAC17470.1; ALT_FRAME; mRNA.
DR EMBL; GU987085; ADG03678.1; -; mRNA.
DR EMBL; DQ431186; ABD96103.1; -; mRNA.
DR EMBL; AC008649; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC022144; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC005033; AAH05033.1; -; mRNA.
DR EMBL; AL047603; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AU118403; -; NOT_ANNOTATED_CDS; mRNA.
DR RefSeq; NP_004915.2; NM_004924.4.
DR RefSeq; XP_005259340.1; XM_005259283.1.
DR UniGene; Hs.270291; -.
DR PDB; 1WLX; NMR; -; A=519-645.
DR PDB; 1YDI; X-ray; 1.80 A; B=734-757.
DR PDB; 2R0O; X-ray; 2.20 A; A/B=47-271.
DR PDBsum; 1WLX; -.
DR PDBsum; 1YDI; -.
DR PDBsum; 2R0O; -.
DR ProteinModelPortal; O43707; -.
DR SMR; O43707; 47-271, 286-911.
DR DIP; DIP-33179N; -.
DR IntAct; O43707; 26.
DR MINT; MINT-4998602; -.
DR STRING; 9606.ENSP00000252699; -.
DR PhosphoSite; O43707; -.
DR REPRODUCTION-2DPAGE; O43707; -.
DR PaxDb; O43707; -.
DR PeptideAtlas; O43707; -.
DR PRIDE; O43707; -.
DR DNASU; 81; -.
DR Ensembl; ENST00000252699; ENSP00000252699; ENSG00000130402.
DR Ensembl; ENST00000390009; ENSP00000439497; ENSG00000130402.
DR GeneID; 81; -.
DR KEGG; hsa:81; -.
DR UCSC; uc021uug.1; human.
DR CTD; 81; -.
DR GeneCards; GC19P039138; -.
DR HGNC; HGNC:166; ACTN4.
DR HPA; HPA001873; -.
DR HPA; HPA006035; -.
DR MIM; 603278; phenotype.
DR MIM; 604638; gene.
DR neXtProt; NX_O43707; -.
DR Orphanet; 93213; Familial idiopathic steroid-resistant nephrotic syndrome with focal segmental hyalinosis.
DR PharmGKB; PA23; -.
DR eggNOG; COG5069; -.
DR HOGENOM; HOG000263418; -.
DR HOVERGEN; HBG050453; -.
DR InParanoid; O43707; -.
DR KO; K05699; -.
DR OMA; QANIVGP; -.
DR OrthoDB; EOG72C4ZJ; -.
DR PhylomeDB; O43707; -.
DR Reactome; REACT_111155; Cell-Cell communication.
DR Reactome; REACT_604; Hemostasis.
DR ChiTaRS; ACTN4; human.
DR EvolutionaryTrace; O43707; -.
DR GeneWiki; Actinin_alpha_4; -.
DR GenomeRNAi; 81; -.
DR NextBio; 303; -.
DR PMAP-CutDB; O43707; -.
DR PRO; PR:O43707; -.
DR ArrayExpress; O43707; -.
DR Bgee; O43707; -.
DR CleanEx; HS_ACTN4; -.
DR Genevestigator; O43707; -.
DR GO; GO:0030054; C:cell junction; IEA:UniProtKB-SubCell.
DR GO; GO:0030863; C:cortical cytoskeleton; IEA:Ensembl.
DR GO; GO:0070062; C:extracellular vesicular exosome; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
DR GO; GO:0031093; C:platelet alpha granule lumen; TAS:Reactome.
DR GO; GO:0043234; C:protein complex; IDA:UniProtKB.
DR GO; GO:0031143; C:pseudopodium; TAS:UniProtKB.
DR GO; GO:0030529; C:ribonucleoprotein complex; IDA:UniProtKB.
DR GO; GO:0001725; C:stress fiber; IEA:Ensembl.
DR GO; GO:0030018; C:Z disc; IEA:Ensembl.
DR GO; GO:0051015; F:actin filament binding; IDA:UniProtKB.
DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR GO; GO:0005178; F:integrin binding; TAS:UniProtKB.
DR GO; GO:0001882; F:nucleoside binding; IDA:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; TAS:UniProtKB.
DR GO; GO:0051271; P:negative regulation of cellular component movement; IEA:Ensembl.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0002576; P:platelet degranulation; TAS:Reactome.
DR GO; GO:0051272; P:positive regulation of cellular component movement; IDA:UniProtKB.
DR GO; GO:0048549; P:positive regulation of pinocytosis; IEA:Ensembl.
DR GO; GO:0032417; P:positive regulation of sodium:hydrogen antiporter activity; NAS:UniProtKB.
DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW.
DR GO; GO:0042981; P:regulation of apoptotic process; NAS:UniProtKB.
DR GO; GO:0001666; P:response to hypoxia; IEA:Ensembl.
DR Gene3D; 1.10.238.10; -; 2.
DR Gene3D; 1.10.418.10; -; 2.
DR InterPro; IPR001589; Actinin_actin-bd_CS.
DR InterPro; IPR001715; CH-domain.
DR InterPro; IPR011992; EF-hand-dom_pair.
DR InterPro; IPR014837; EF-hand_Ca_insen.
DR InterPro; IPR018247; EF_Hand_1_Ca_BS.
DR InterPro; IPR002048; EF_hand_dom.
DR InterPro; IPR018159; Spectrin/alpha-actinin.
DR InterPro; IPR002017; Spectrin_repeat.
DR Pfam; PF00307; CH; 2.
DR Pfam; PF13405; EF-hand_6; 1.
DR Pfam; PF08726; EFhand_Ca_insen; 1.
DR Pfam; PF00435; Spectrin; 4.
DR SMART; SM00033; CH; 2.
DR SMART; SM00054; EFh; 2.
DR SMART; SM00150; SPEC; 4.
DR SUPFAM; SSF47576; SSF47576; 1.
DR PROSITE; PS00019; ACTININ_1; 1.
DR PROSITE; PS00020; ACTININ_2; 1.
DR PROSITE; PS50021; CH; 2.
DR PROSITE; PS00018; EF_HAND_1; 1.
DR PROSITE; PS50222; EF_HAND_2; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Actin-binding; Alternative splicing;
KW Calcium; Cell junction; Complete proteome; Cytoplasm;
KW Disease mutation; Isopeptide bond; Metal-binding; Nucleus;
KW Protein transport; Reference proteome; Repeat; Transport;
KW Ubl conjugation.
FT CHAIN 1 911 Alpha-actinin-4.
FT /FTId=PRO_0000073440.
FT DOMAIN 1 269 Actin-binding.
FT DOMAIN 50 154 CH 1.
FT DOMAIN 163 269 CH 2.
FT REPEAT 293 403 Spectrin 1.
FT REPEAT 413 518 Spectrin 2.
FT REPEAT 528 639 Spectrin 3.
FT REPEAT 649 752 Spectrin 4.
FT DOMAIN 765 800 EF-hand 1.
FT DOMAIN 806 841 EF-hand 2.
FT CA_BIND 778 789 1 (Potential).
FT CA_BIND 819 830 2 (Potential).
FT REGION 177 192 Polyphosphoinositide (PIP2)-binding
FT (Potential).
FT REGION 736 911 Mediates interaction with MICALL2 (By
FT similarity).
FT COMPBIAS 19 26 Poly-Gly.
FT MOD_RES 114 114 N6-acetyllysine.
FT MOD_RES 592 592 N6-acetyllysine.
FT MOD_RES 625 625 N6-acetyllysine.
FT CROSSLNK 378 378 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin).
FT VAR_SEQ 54 272 Missing (in isoform ACTN4ISO).
FT /FTId=VSP_047733.
FT VAR_SEQ 89 478 Missing (in isoform 3).
FT /FTId=VSP_053401.
FT VARIANT 255 255 K -> E (in FSGS1; dbSNP:rs28939374).
FT /FTId=VAR_010378.
FT VARIANT 259 259 T -> I (in FSGS1; dbSNP:rs28939375).
FT /FTId=VAR_010379.
FT VARIANT 262 262 S -> P (in FSGS1; dbSNP:rs28939376).
FT /FTId=VAR_010380.
FT CONFLICT 60 60 C -> S (in Ref. 3; AAC17470).
FT CONFLICT 164 164 S -> L (in Ref. 7; AL047603/AU118403).
FT CONFLICT 276 276 T -> TET (in Ref. 3; AAC17470).
FT CONFLICT 292 294 EHL -> CSTS (in Ref. 3; AAC17470).
FT CONFLICT 359 360 TL -> SV (in Ref. 3; AAC17470).
FT CONFLICT 476 476 I -> S (in Ref. 3; AAC17470).
FT CONFLICT 526 526 I -> II (in Ref. 3; AAC17470).
FT CONFLICT 536 536 R -> P (in Ref. 3; AAC17470).
FT CONFLICT 645 645 Q -> QQ (in Ref. 3; AAC17470).
FT CONFLICT 673 674 GR -> A (in Ref. 3; AAC17470).
FT CONFLICT 850 850 A -> T (in Ref. 3; AAC17470).
FT CONFLICT 891 893 AVP -> GVR (in Ref. 3; AAC17470).
FT HELIX 47 64
FT HELIX 65 67
FT TURN 74 80
FT HELIX 82 92
FT HELIX 105 120
FT TURN 121 123
FT HELIX 131 135
FT HELIX 139 153
FT TURN 154 157
FT HELIX 165 177
FT STRAND 187 189
FT HELIX 190 192
FT HELIX 196 205
FT HELIX 207 209
FT HELIX 212 214
FT HELIX 220 234
FT HELIX 243 248
FT STRAND 249 251
FT HELIX 254 267
FT HELIX 519 552
FT HELIX 560 600
FT STRAND 606 608
FT HELIX 616 641
SQ SEQUENCE 911 AA; 104854 MW; 461580C3F22937D1 CRC64;
MVDYHAANQS YQYGPSSAGN GAGGGGSMGD YMAQEDDWDR DLLLDPAWEK QQRKTFTAWC
NSHLRKAGTQ IENIDEDFRD GLKLMLLLEV ISGERLPKPE RGKMRVHKIN NVNKALDFIA
SKGVKLVSIG AEEIVDGNAK MTLGMIWTII LRFAIQDISV EETSAKEGLL LWCQRKTAPY
KNVNVQNFHI SWKDGLAFNA LIHRHRPELI EYDKLRKDDP VTNLNNAFEV AEKYLDIPKM
LDAEDIVNTA RPDEKAIMTY VSSFYHAFSG AQKAETAANR ICKVLAVNQE NEHLMEDYEK
LASDLLEWIR RTIPWLEDRV PQKTIQEMQQ KLEDFRDYRR VHKPPKVQEK CQLEINFNTL
QTKLRLSNRP AFMPSEGKMV SDINNGWQHL EQAEKGYEEW LLNEIRRLER LDHLAEKFRQ
KASIHEAWTD GKEAMLKHRD YETATLSDIK ALIRKHEAFE SDLAAHQDRV EQIAAIAQEL
NELDYYDSHN VNTRCQKICD QWDALGSLTH SRREALEKTE KQLEAIDQLH LEYAKRAAPF
NNWMESAMED LQDMFIVHTI EEIEGLISAH DQFKSTLPDA DREREAILAI HKEAQRIAES
NHIKLSGSNP YTTVTPQIIN SKWEKVQQLV PKRDHALLEE QSKQQSNEHL RRQFASQANV
VGPWIQTKME EIGRISIEMN GTLEDQLSHL KQYERSIVDY KPNLDLLEQQ HQLIQEALIF
DNKHTNYTME HIRVGWEQLL TTIARTINEV ENQILTRDAK GISQEQMQEF RASFNHFDKD
HGGALGPEEF KACLISLGYD VENDRQGEAE FNRIMSLVDP NHSGLVTFQA FIDFMSRETT
DTDTADQVIA SFKVLAGDKN FITAEELRRE LPPDQAEYCI ARMAPYQGPD AVPGALDYKS
FSTALYGESD L
//
MIM
603278
*RECORD*
*FIELD* NO
603278
*FIELD* TI
#603278 FOCAL SEGMENTAL GLOMERULOSCLEROSIS 1; FSGS1
;;GLOMERULOSCLEROSIS, FOCAL SEGMENTAL, 1
read more*FIELD* TX
A number sign (#) is used with this entry because this form of
progressive renal disease, referred to here as focal segmental
glomerulosclerosis-1 (FSGS1), is caused by heterozygous mutation in the
gene encoding alpha-actinin-4 (ACTN4; 604638) on chromosome 19q13.
DESCRIPTION
Focal segmental glomerulosclerosis (FSGS) is a pathologic finding in
several renal disorders that manifest clinically as proteinuria and
progressive decline in renal function. Some patients with FSGS develop
the clinical entity called 'nephrotic syndrome' (see NPHS1; 256300),
which includes massive proteinuria, hypoalbuminemia, hyperlipidemia, and
edema. However, patients with FSGS may have proteinuria in the nephrotic
range without other features of the nephrotic syndrome (summary by
D'Agati et al., 2004; Mathis et al., 1998).
D'Agati et al. (2011) provided a detailed review of FSGS, emphasizing
that the disorder results from defects of the podocyte.
Because of confusion in the literature regarding use of the terms
'nephrotic syndrome' and 'focal segmental glomerulosclerosis' (see
NOMENCLATURE section), these disorders in OMIM are classified as NPHS or
FSGS according to how they were first designated in the literature.
- Genetic Heterogeneity of Focal Segmental Glomerulosclerosis
and Nephrotic Syndrome
Focal segmental glomerulosclerosis and nephrotic syndrome are
genetically heterogeneous disorders representing a spectrum of
hereditary renal diseases. See also FSGS2 (603965), caused by mutation
in the TRPC6 gene (603652), and FSGS3 (607832), associated with
variation in the CD2AP gene (604241). FSGS4 (612551) has been mapped to
chromosome 22q12, FSGS5 (613237) is caused by mutation in the INF2 gene
(610982), and FSGS6 (614131) is caused by mutation in the MYO1E gene
(601479) on chromosome 15q21.
NPHS1 (256300) is caused by mutation in the NPHS1 gene (602716); NPHS2
(600995) by mutation in the podocin gene (604766); NPHS3 (610725) by
mutation in the PLCE1 gene (608414); and NPHS4 (256370) by mutation in
the WT1 gene (607102).
CLINICAL FEATURES
Mathis et al. (1992) reported a large family with variable expression of
a glomerular disease associated with asymptomatic proteinuria and normal
renal function (7 patients) or significant proteinuria leading to
progressive renal failure (11 patients). Histopathologic changes were
variable, but included focal segmental glomerulosclerosis and diffuse
glomerulosclerosis. Renal failure usually occurred in the fifth decade
of life. The most consistent clinical finding was proteinuria without
microscopic hematuria or other significant urinary sediment elements.
This disease differed from Alport syndrome (301050) and congenital
nephrotic syndrome (256300) in age of onset, urinary findings, and lack
of associated conditions, such as deafness.
Mathis et al. (1998) provided follow-up of the family reported by Mathis
et al. (1992). An individual was considered affected if he/she had (1)
renal biopsy evidence of FSGS; (2) end-stage renal disease without
another cause; or (3) elevated urine microalbumin excretion without
another cause. The authors noted that emphasized the great variability
in the phenotypic expression of the disease gene. They further stated
that 'although we have termed the pathologic condition in this family
inherited FSGS, this may be misleading,' since some family members
developed end-stage renal failure at a relatively young age, whereas
others showed only microalbuminuria, including 1 individual whose 2
daughters were severely affected.
INHERITANCE
The genetic contribution to FSGS etiology is indicated by reports of its
occurrence in multiple members of families (Conlon et al., 1995; Faubert
and Porush, 1997). Both autosomal dominant and recessive patterns of
inheritance have been proposed (Conlon et al., 1995).
The inheritance pattern in the family reported by Mathis et al. (1998)
was autosomal dominant with reduced penetrance and variable
expressivity.
PATHOGENESIS
D'Agati et al. (2004) proposed a pathologic classification of FSGS,
defining 5 morphologic variants based entirely on assessment of
glomerular light microscopic alterations: collapsing variant, tip
variant, cellular variant, perihilar variant, and 'not otherwise
specified,' with classification into a given category requiring that all
preceding categories, as listed, be excluded.
D'Agati et al. (2011) reviewed the pathogenesis of FSGS, with emphasis
on loss of the glomerular filtration barrier due to defects in the
podocyte.
MAPPING
In a large kindred with affected members in at least 5 generations,
Mathis et al. (1998) performed linkage analysis and demonstrated mapping
to chromosome 19q13; maximum 2-point lod score = 12.28. They narrowed
the critical region to approximately 7 cM.
MOLECULAR GENETICS
In 3 families with clear evidence of autosomal dominant inheritance of
FSGS, including the family reported by Mathis et al. (1992, 1998),
Kaplan et al. (2000) identified heterozygous mutations in the ACTN4 gene
(604638.0001-604638.0003). They also analyzed the NPHS1 gene (602716)
and found no mutations associated with this disorder.
- Associations Pending Confirmation
See 300319 for discussion of a possible association of FSGS with
mutation in the NXF5 gene.
See 300776 for discussion of a possible association of FSGS with
mutation in the ALG13 gene.
NOMENCLATURE
In the literature, use of the clinical term 'nephrotic syndrome' (NPHS)
and the pathologic term 'focal segmental glomerulosclerosis' (FSGS) to
refer to the same disease entity has generated confusion in the naming
and classification of similar disorders. In OMIM, these disorders are
classified as NPHS or FSGS according to how they were first designated
in the literature. It is important to recognize that FSGS is a
histologic pattern of renal injury: some patients with FSGS on biopsy
have nephrotic syndrome, whereas others have only mild proteinuria. NPHS
and FSGS represent a spectrum of hereditary renal diseases of the
podocyte (see reviews by Pollak, 2002; Meyrier, 2005; Caridi et al.,
2010; Hildebrandt, 2010).
*FIELD* SA
Tejani et al. (1983)
*FIELD* RF
1. Caridi, G.; Trivelli, A.; Sanna-Cherchi, S.; Perfumo, F.; Ghiggeri,
G. M.: Familial forms of nephrotic syndrome. Pediat. Nephrol. 25:
241-252, 2010.
2. Conlon, P. J.; Butterly, D.; Albers, F.; Rodby, R.; Gunnells, J.
C.; Howell, D. N.: Clinical and pathologic features of familial focal
segmental glomerulosclerosis. Am. J. Kidney Dis. 26: 34-40, 1995.
3. D'Agati, V. D.; Fogo, A. B.; Bruijn, J. A.; Jennette, J. C.: Pathologic
classification of focal segmental glomerulosclerosis: a working proposal. Am.
J. Kidney Dis. 43: 368-382, 2004.
4. D'Agati, V. D.; Kaskel, F. J.; Falk, R. J.: Focal segmental glomerulosclerosis. New
Eng. J. Med. 365: 2398-2411, 2011.
5. Faubert, P. F.; Porush, J. G.: Familial focal segmental glomerulosclerosis:
nine cases in four families and review of the literature. Am. J.
Kidney Dis. 30: 265-270, 1997.
6. Hildebrandt, F.: Genetic kidney diseases. Lancet 375: 1287-1295,
2010.
7. Kaplan, J. M.; Kim, S. H.; North, K. N.; Rennke, H.; Correia, L.
A.; Tong, H.-Q.; Mathis, B. J.; Rodriguez-Perez, J.-C.; Allen, P.
G.; Beggs, A. H.; Pollak, M. R.: Mutations in ACTN4, encoding alpha-actinin-4,
cause familial focal segmental glomerulosclerosis. Nature Genet. 24:
251-256, 2000.
8. Mathis, B. J.; Calabrese, K. E.; Slick, G. L.: Familial glomerular
disease with asymptomatic proteinuria and nephrotic syndrome: a new
clinical entity. J. Am. Osteopath. Assoc. 92: 875-880, 1992.
9. Mathis, B. J.; Kim, S. H.; Calabrese, K.; Haas, M.; Seidman, J.
G.; Seidman, C. E.; Pollak, M. R.: A locus for inherited focal segmental
glomerulosclerosis maps to chromosome 19q13. Kidney Int. 53: 282-286,
1998.
10. Meyrier, A.: Mechanisms of disease: focal segmental glomerulosclerosis. Nature
Clin. Prac. 1: 44-54, 2005.
11. Pollak, M. R.: Inherited podocytopathies: FSGS and nephrotic
syndrome from a genetic viewpoint. J. Am. Soc. Nephrol. 13: 3016-3023,
2002.
12. Tejani, A.; Nicastri, A.; Phadke, K.; Sen, D.; Adamson, O.; Dunn,
I.; Calderon, P.: Familial focal segmental glomerulosclerosis. Int.
J. Pediat. Nephrol. 4: 231-234, 1983.
*FIELD* CN
Cassandra L. Kniffin - updated: 1/30/2012
Cassandra L. Kniffin - updated: 10/8/2010
Marla J. F. O'Neill - updated: 1/29/2010
Victor A. McKusick - updated: 12/4/2006
Victor A. McKusick - updated: 6/27/2005
Victor A. McKusick - updated: 2/29/2000
*FIELD* CD
Victor A. McKusick: 11/11/1998
*FIELD* ED
carol: 11/07/2013
carol: 1/30/2012
ckniffin: 1/30/2012
wwang: 7/29/2011
ckniffin: 7/28/2011
carol: 10/25/2010
ckniffin: 10/8/2010
alopez: 1/29/2010
alopez: 1/22/2009
carol: 1/25/2007
carol: 12/4/2006
terry: 12/4/2006
alopez: 7/6/2005
terry: 6/27/2005
alopez: 5/28/2003
carol: 8/15/2002
terry: 10/5/2000
alopez: 3/1/2000
terry: 2/29/2000
carol: 7/23/1999
carol: 7/7/1999
terry: 6/16/1999
dkim: 11/13/1998
carol: 11/11/1998
*RECORD*
*FIELD* NO
603278
*FIELD* TI
#603278 FOCAL SEGMENTAL GLOMERULOSCLEROSIS 1; FSGS1
;;GLOMERULOSCLEROSIS, FOCAL SEGMENTAL, 1
read more*FIELD* TX
A number sign (#) is used with this entry because this form of
progressive renal disease, referred to here as focal segmental
glomerulosclerosis-1 (FSGS1), is caused by heterozygous mutation in the
gene encoding alpha-actinin-4 (ACTN4; 604638) on chromosome 19q13.
DESCRIPTION
Focal segmental glomerulosclerosis (FSGS) is a pathologic finding in
several renal disorders that manifest clinically as proteinuria and
progressive decline in renal function. Some patients with FSGS develop
the clinical entity called 'nephrotic syndrome' (see NPHS1; 256300),
which includes massive proteinuria, hypoalbuminemia, hyperlipidemia, and
edema. However, patients with FSGS may have proteinuria in the nephrotic
range without other features of the nephrotic syndrome (summary by
D'Agati et al., 2004; Mathis et al., 1998).
D'Agati et al. (2011) provided a detailed review of FSGS, emphasizing
that the disorder results from defects of the podocyte.
Because of confusion in the literature regarding use of the terms
'nephrotic syndrome' and 'focal segmental glomerulosclerosis' (see
NOMENCLATURE section), these disorders in OMIM are classified as NPHS or
FSGS according to how they were first designated in the literature.
- Genetic Heterogeneity of Focal Segmental Glomerulosclerosis
and Nephrotic Syndrome
Focal segmental glomerulosclerosis and nephrotic syndrome are
genetically heterogeneous disorders representing a spectrum of
hereditary renal diseases. See also FSGS2 (603965), caused by mutation
in the TRPC6 gene (603652), and FSGS3 (607832), associated with
variation in the CD2AP gene (604241). FSGS4 (612551) has been mapped to
chromosome 22q12, FSGS5 (613237) is caused by mutation in the INF2 gene
(610982), and FSGS6 (614131) is caused by mutation in the MYO1E gene
(601479) on chromosome 15q21.
NPHS1 (256300) is caused by mutation in the NPHS1 gene (602716); NPHS2
(600995) by mutation in the podocin gene (604766); NPHS3 (610725) by
mutation in the PLCE1 gene (608414); and NPHS4 (256370) by mutation in
the WT1 gene (607102).
CLINICAL FEATURES
Mathis et al. (1992) reported a large family with variable expression of
a glomerular disease associated with asymptomatic proteinuria and normal
renal function (7 patients) or significant proteinuria leading to
progressive renal failure (11 patients). Histopathologic changes were
variable, but included focal segmental glomerulosclerosis and diffuse
glomerulosclerosis. Renal failure usually occurred in the fifth decade
of life. The most consistent clinical finding was proteinuria without
microscopic hematuria or other significant urinary sediment elements.
This disease differed from Alport syndrome (301050) and congenital
nephrotic syndrome (256300) in age of onset, urinary findings, and lack
of associated conditions, such as deafness.
Mathis et al. (1998) provided follow-up of the family reported by Mathis
et al. (1992). An individual was considered affected if he/she had (1)
renal biopsy evidence of FSGS; (2) end-stage renal disease without
another cause; or (3) elevated urine microalbumin excretion without
another cause. The authors noted that emphasized the great variability
in the phenotypic expression of the disease gene. They further stated
that 'although we have termed the pathologic condition in this family
inherited FSGS, this may be misleading,' since some family members
developed end-stage renal failure at a relatively young age, whereas
others showed only microalbuminuria, including 1 individual whose 2
daughters were severely affected.
INHERITANCE
The genetic contribution to FSGS etiology is indicated by reports of its
occurrence in multiple members of families (Conlon et al., 1995; Faubert
and Porush, 1997). Both autosomal dominant and recessive patterns of
inheritance have been proposed (Conlon et al., 1995).
The inheritance pattern in the family reported by Mathis et al. (1998)
was autosomal dominant with reduced penetrance and variable
expressivity.
PATHOGENESIS
D'Agati et al. (2004) proposed a pathologic classification of FSGS,
defining 5 morphologic variants based entirely on assessment of
glomerular light microscopic alterations: collapsing variant, tip
variant, cellular variant, perihilar variant, and 'not otherwise
specified,' with classification into a given category requiring that all
preceding categories, as listed, be excluded.
D'Agati et al. (2011) reviewed the pathogenesis of FSGS, with emphasis
on loss of the glomerular filtration barrier due to defects in the
podocyte.
MAPPING
In a large kindred with affected members in at least 5 generations,
Mathis et al. (1998) performed linkage analysis and demonstrated mapping
to chromosome 19q13; maximum 2-point lod score = 12.28. They narrowed
the critical region to approximately 7 cM.
MOLECULAR GENETICS
In 3 families with clear evidence of autosomal dominant inheritance of
FSGS, including the family reported by Mathis et al. (1992, 1998),
Kaplan et al. (2000) identified heterozygous mutations in the ACTN4 gene
(604638.0001-604638.0003). They also analyzed the NPHS1 gene (602716)
and found no mutations associated with this disorder.
- Associations Pending Confirmation
See 300319 for discussion of a possible association of FSGS with
mutation in the NXF5 gene.
See 300776 for discussion of a possible association of FSGS with
mutation in the ALG13 gene.
NOMENCLATURE
In the literature, use of the clinical term 'nephrotic syndrome' (NPHS)
and the pathologic term 'focal segmental glomerulosclerosis' (FSGS) to
refer to the same disease entity has generated confusion in the naming
and classification of similar disorders. In OMIM, these disorders are
classified as NPHS or FSGS according to how they were first designated
in the literature. It is important to recognize that FSGS is a
histologic pattern of renal injury: some patients with FSGS on biopsy
have nephrotic syndrome, whereas others have only mild proteinuria. NPHS
and FSGS represent a spectrum of hereditary renal diseases of the
podocyte (see reviews by Pollak, 2002; Meyrier, 2005; Caridi et al.,
2010; Hildebrandt, 2010).
*FIELD* SA
Tejani et al. (1983)
*FIELD* RF
1. Caridi, G.; Trivelli, A.; Sanna-Cherchi, S.; Perfumo, F.; Ghiggeri,
G. M.: Familial forms of nephrotic syndrome. Pediat. Nephrol. 25:
241-252, 2010.
2. Conlon, P. J.; Butterly, D.; Albers, F.; Rodby, R.; Gunnells, J.
C.; Howell, D. N.: Clinical and pathologic features of familial focal
segmental glomerulosclerosis. Am. J. Kidney Dis. 26: 34-40, 1995.
3. D'Agati, V. D.; Fogo, A. B.; Bruijn, J. A.; Jennette, J. C.: Pathologic
classification of focal segmental glomerulosclerosis: a working proposal. Am.
J. Kidney Dis. 43: 368-382, 2004.
4. D'Agati, V. D.; Kaskel, F. J.; Falk, R. J.: Focal segmental glomerulosclerosis. New
Eng. J. Med. 365: 2398-2411, 2011.
5. Faubert, P. F.; Porush, J. G.: Familial focal segmental glomerulosclerosis:
nine cases in four families and review of the literature. Am. J.
Kidney Dis. 30: 265-270, 1997.
6. Hildebrandt, F.: Genetic kidney diseases. Lancet 375: 1287-1295,
2010.
7. Kaplan, J. M.; Kim, S. H.; North, K. N.; Rennke, H.; Correia, L.
A.; Tong, H.-Q.; Mathis, B. J.; Rodriguez-Perez, J.-C.; Allen, P.
G.; Beggs, A. H.; Pollak, M. R.: Mutations in ACTN4, encoding alpha-actinin-4,
cause familial focal segmental glomerulosclerosis. Nature Genet. 24:
251-256, 2000.
8. Mathis, B. J.; Calabrese, K. E.; Slick, G. L.: Familial glomerular
disease with asymptomatic proteinuria and nephrotic syndrome: a new
clinical entity. J. Am. Osteopath. Assoc. 92: 875-880, 1992.
9. Mathis, B. J.; Kim, S. H.; Calabrese, K.; Haas, M.; Seidman, J.
G.; Seidman, C. E.; Pollak, M. R.: A locus for inherited focal segmental
glomerulosclerosis maps to chromosome 19q13. Kidney Int. 53: 282-286,
1998.
10. Meyrier, A.: Mechanisms of disease: focal segmental glomerulosclerosis. Nature
Clin. Prac. 1: 44-54, 2005.
11. Pollak, M. R.: Inherited podocytopathies: FSGS and nephrotic
syndrome from a genetic viewpoint. J. Am. Soc. Nephrol. 13: 3016-3023,
2002.
12. Tejani, A.; Nicastri, A.; Phadke, K.; Sen, D.; Adamson, O.; Dunn,
I.; Calderon, P.: Familial focal segmental glomerulosclerosis. Int.
J. Pediat. Nephrol. 4: 231-234, 1983.
*FIELD* CN
Cassandra L. Kniffin - updated: 1/30/2012
Cassandra L. Kniffin - updated: 10/8/2010
Marla J. F. O'Neill - updated: 1/29/2010
Victor A. McKusick - updated: 12/4/2006
Victor A. McKusick - updated: 6/27/2005
Victor A. McKusick - updated: 2/29/2000
*FIELD* CD
Victor A. McKusick: 11/11/1998
*FIELD* ED
carol: 11/07/2013
carol: 1/30/2012
ckniffin: 1/30/2012
wwang: 7/29/2011
ckniffin: 7/28/2011
carol: 10/25/2010
ckniffin: 10/8/2010
alopez: 1/29/2010
alopez: 1/22/2009
carol: 1/25/2007
carol: 12/4/2006
terry: 12/4/2006
alopez: 7/6/2005
terry: 6/27/2005
alopez: 5/28/2003
carol: 8/15/2002
terry: 10/5/2000
alopez: 3/1/2000
terry: 2/29/2000
carol: 7/23/1999
carol: 7/7/1999
terry: 6/16/1999
dkim: 11/13/1998
carol: 11/11/1998
MIM
604638
*RECORD*
*FIELD* NO
604638
*FIELD* TI
*604638 ACTININ, ALPHA-4; ACTN4
;;ACTININ-4
*FIELD* TX
CLONING
Honda et al. (1998) identified a novel actin-bundling protein associated
read morewith cell motility and cancer invasion.
Using a yeast 2-hybrid screen for proteins that interact with RNF22
(605493), El-Husseini et al. (2000) isolated an ACTN4 cDNA from a rat
brain library. The rat ACTN4 sequence contained an additional N-terminal
27 amino acids compared with the human sequence reported by Honda et al.
(1998). The additional sequence is consistent with another human
sequence deposited in GenBank (GENBANK U48734), leading El-Husseini et
al. (2000) to conclude that there are multiple isoforms of ACTN4.
GENE FUNCTION
Using immunohistochemistry, El-Husseini et al. (2000) showed that rat
RNF22 and ACTN4 are expressed in a punctate pattern throughout the
cytoplasm and neuritic processes of differentiated PC12 cells. They
concluded that the isoform of ACTN4 they identified may act to anchor
microfilaments to various cellular structures.
Alpha-actinin is highly expressed in the glomerular podocyte, is
important in nonmuscle cytoskeletal function, and is upregulated early
in the course of some animal models of nephrotic syndrome (Kaplan et
al., 2000).
Using in vitro binding assays, Patrie et al. (2002) showed that the
fifth PDZ domain of mouse Magi1 (BAIAP1; 602625) interacted with the C
terminus of rat alpha-actinin-4. Exogenously expressed human
synaptopodin (608155) and rat alpha-actinin-4 colocalized with
endogenous Magi1 at tight junctions of canine kidney epithelial cells.
MAPPING
By sequence analysis, Kaplan et al. (2000) mapped the ACTN4 gene to
chromosome 19q13.
MOLECULAR GENETICS
Focal segmental glomerulosclerosis (FSGS; 603278) is a common,
nonspecific renal lesion. Although it is often secondary to other
disorders, including HIV infection, obesity, hypertension, and diabetes,
FSGS also appears as an isolated idiopathic condition which is inherited
as an autosomal dominant. The phenotype had been mapped to 19q13. FSGS
is characterized by increased urinary protein excretion and decreasing
kidney function. Often, renal insufficiency in affected patients
progresses to end-stage renal failure, a highly morbid state requiring
either dialysis therapy or kidney transplantation. Kaplan et al. (2000)
identified mutations in the gene encoding ACTN4
(604638.0001-604638.0004), an actin-filament crosslinking protein, as
the cause of the disorder in 3 families with an autosomal dominant form
of FSGS. They found that in vitro, mutant alpha-actinin-4 bound
filamentous actin more strongly than did wildtype alpha-actinin-4.
Regulation of the actin cytoskeleton of glomerular podocytes may be
altered in this group of patients. The results had implications for
understanding the role of the cytoskeleton in the pathophysiology of
kidney disease and may be relevant to an understanding of the genetic
basis of susceptibility to kidney damage.
Weins et al. (2007) stated that ACTN4 proteins with disease-causing
mutations form aggregates with F-actin in human and mouse podocytes.
Using knockin mice homozygous for a disease-causing mutation in human
ACTN4, lys255 to glu (K255E), they showed that these aggregates were
associated with the actin cytoskeleton. The mutation exposed a buried
actin-binding site in ACTN4 that increased its actin-binding affinity,
abolished its Ca(2+) regulation in vitro, and mislocalized it from actin
stress fibers and focal adhesions in vivo. In vitro, actin filaments
crosslinked by mutant ACTN4 exhibited changes of structural and
biomechanical properties compared with wildtype ACTN4.
Echchakir et al. (2001) identified an antigen recognized on a human
large cell carcinoma by an autologous tumor-specific cytolytic T
lymphocyte (CTL) clone that was derived from mononuclear cells
infiltrating the primary tumor in a lung cancer patient. The antigenic
peptide was presented by HLA-A2 molecules and was encoded by the ACTN4
gene, which is expressed ubiquitously. In the tumor cells, a point
mutation generated an amino acid change that is essential for
recognition by the CTLs. The mutation was not found in ACTN4 cDNA
sequences from about 50 lung carcinoma cell lines, suggesting that it
was unique to this patient. Although the patient did not receive
chemotherapy or radiotherapy, he remained without evidence of tumor
after resection of the primary lesion in 1996. Anti-alpha-actinin-4 CTLs
were derived from blood samples collected from the patient in 1998 and
2000. It is possible that these CTLs, recognizing a truly tumor-specific
antigen, played a role in the clinical evolution of this lung cancer
patient.
ANIMAL MODEL
Kos et al. (2003) developed Actn4-deficient mice which showed
progressive proteinuria, glomerular disease, and death by several months
of age. Light microscopy revealed extensive glomerular disease and
proteinaceous casts; electron microscopy showed focal areas of podocyte
foot-process effacement in young mice and diffuse effacement and
globally disrupted podocyte morphology in older mice. Histologic
examination showed abnormalities only in the kidneys. Cell motility, as
measured by lymphocyte chemotaxis assays, was increased in the absence
of Actn4. Kos et al. (2003) concluded that ACTN4 is required for normal
glomerular function and is involved in the regulation of cell movement.
They also noted that the nonsarcomeric forms of ACTN, ACTN1 (102575) and
ACTN4, both found in the kidney, are not functionally redundant.
*FIELD* AV
.0001
FOCAL SEGMENTAL GLOMERULOSCLEROSIS 1
ACTN4, LYS228GLU
In affected individuals in a family with focal segmental
glomerulosclerosis that mapped to 19q (603278), Kaplan et al. (2000)
found a lys228-to-gly (K228G) mutation caused by a 682A-G nucleotide
substitution in the ACTN4 RNA. The disease in this family, like that in
2 others studied, showed a mild increase in urine protein excretion
starting in the teenage years or later, slowly progressive renal
dysfunction, and the development of end-stage renal failure in some
affected individuals. Two individuals in this family carrying the
lys228-to-glu allele had no clinical symptoms.
.0002
FOCAL SEGMENTAL GLOMERULOSCLEROSIS 1
ACTN4, THR232ILE
Kaplan et al. (2000) found that affected members in their family with
focal segmental glomerulosclerosis mapping to 19q13 (603278) had a
thr232-to-ile (T232I) mutation in the ACTN4 gene, caused by a 695C-T
transition. The family contained 4 individuals carrying the
disease-associated allele who had no proteinuria.
.0003
FOCAL SEGMENTAL GLOMERULOSCLEROSIS 1
ACTN4, SER235PRO
Kaplan et al. (2000) studied a family in which affected members with
focal segmental glomerulosclerosis (603278) had a ser235-to-pro (S235P)
mutation due to a 703T-C transition in the ACTN4 gene.
*FIELD* RF
1. Echchakir, H.; Mami-Chouaib, F.; Vergnon, I.; Baurain, J.-F.; Karanikas,
V.; Chouaib, S.; Coulie, P. G.: A point mutation in the alpha-actinin-4
gene generates an antigenic peptide recognized by autologous cytolytic
T lymphocytes on a human lung carcinoma. Cancer Res. 61: 4078-4083,
2001.
2. El-Husseini, A. E.; Kwasnicka, D.; Yamada, T.; Hirohashi, S.; Vincent,
S. R.: BERP, a novel ring finger protein, binds to alpha-actinin-4. Biochem.
Biophys. Res. Commun. 267: 906-911, 2000.
3. Honda, K.; Yamada, T.; Endo, R.; Ino, Y.; Gotoh, M.; Tsuda, H.;
Yamada, Y.; Chiba, H.; Hirohashi, S.: Actinin-4, a novel actin-bundling
protein associated with cell motility and cancer invasion. J. Cell
Biol. 140: 1383-1393, 1998. Note: Erratum: J. Cell Biol. 143: 277
only, 1998.
4. Kaplan, J. M.; Kim, S. H.; North, K. N.; Rennke, H.; Correia, L.
A.; Tong, H.-Q.; Mathis, B. J.; Rodriguez-Perez, J.-C.; Allen, P.
G.; Beggs, A. H.; Pollak, M. R.: Mutations in ACTN4, encoding alpha-actinin-4,
cause familial focal segmental glomerulosclerosis. Nature Genet. 24:
251-256, 2000.
5. Kos, C. H.; Le, T. C.; Sinha, S.; Henderson, J. M.; Kim, S. H.;
Sugimoto, H.; Kalluri, R.; Gerszten, R. E.; Pollak, M. R.: Mice deficient
in alpha-actinin-4 have severe glomerular disease. J. Clin. Invest. 111:
1683-1690, 2003.
6. Patrie, K. M.; Drescher, A. J.; Welihinda, A.; Mundel, P.; Margolis,
B.: Interaction of two actin-binding proteins, synaptopodin and alpha-actinin-4,
with the tight junction protein MAGI-1. J. Biol. Chem. 277: 30183-30190,
2002.
7. Weins, A.; Schlondorff, J. S.; Nakamura, F.; Denker, B. M.; Hartwig,
J. H.; Stossel, T. P.; Pollak, M. R.: Disease-associated mutant alpha-actinin-4
reveals a mechanism for regulating its F-actin-binding affinity. Proc.
Nat. Acad. Sci. 104: 16080-16085, 2007.
*FIELD* CN
Patricia A. Hartz - updated: 11/7/2007
Marla J. F. O'Neill - updated: 3/17/2005
Patricia A. Hartz - updated: 10/8/2003
Victor A. McKusick - updated: 8/23/2001
*FIELD* CD
Victor A. McKusick: 3/1/2000
*FIELD* ED
carol: 10/25/2010
terry: 10/22/2010
alopez: 1/29/2010
mgross: 11/7/2007
carol: 6/3/2005
wwang: 3/17/2005
wwang: 3/16/2005
alopez: 7/12/2004
mgross: 10/8/2003
carol: 8/29/2001
mcapotos: 8/23/2001
mcapotos: 8/20/2001
mcapotos: 4/4/2001
carol: 12/26/2000
terry: 10/5/2000
alopez: 3/1/2000
*RECORD*
*FIELD* NO
604638
*FIELD* TI
*604638 ACTININ, ALPHA-4; ACTN4
;;ACTININ-4
*FIELD* TX
CLONING
Honda et al. (1998) identified a novel actin-bundling protein associated
read morewith cell motility and cancer invasion.
Using a yeast 2-hybrid screen for proteins that interact with RNF22
(605493), El-Husseini et al. (2000) isolated an ACTN4 cDNA from a rat
brain library. The rat ACTN4 sequence contained an additional N-terminal
27 amino acids compared with the human sequence reported by Honda et al.
(1998). The additional sequence is consistent with another human
sequence deposited in GenBank (GENBANK U48734), leading El-Husseini et
al. (2000) to conclude that there are multiple isoforms of ACTN4.
GENE FUNCTION
Using immunohistochemistry, El-Husseini et al. (2000) showed that rat
RNF22 and ACTN4 are expressed in a punctate pattern throughout the
cytoplasm and neuritic processes of differentiated PC12 cells. They
concluded that the isoform of ACTN4 they identified may act to anchor
microfilaments to various cellular structures.
Alpha-actinin is highly expressed in the glomerular podocyte, is
important in nonmuscle cytoskeletal function, and is upregulated early
in the course of some animal models of nephrotic syndrome (Kaplan et
al., 2000).
Using in vitro binding assays, Patrie et al. (2002) showed that the
fifth PDZ domain of mouse Magi1 (BAIAP1; 602625) interacted with the C
terminus of rat alpha-actinin-4. Exogenously expressed human
synaptopodin (608155) and rat alpha-actinin-4 colocalized with
endogenous Magi1 at tight junctions of canine kidney epithelial cells.
MAPPING
By sequence analysis, Kaplan et al. (2000) mapped the ACTN4 gene to
chromosome 19q13.
MOLECULAR GENETICS
Focal segmental glomerulosclerosis (FSGS; 603278) is a common,
nonspecific renal lesion. Although it is often secondary to other
disorders, including HIV infection, obesity, hypertension, and diabetes,
FSGS also appears as an isolated idiopathic condition which is inherited
as an autosomal dominant. The phenotype had been mapped to 19q13. FSGS
is characterized by increased urinary protein excretion and decreasing
kidney function. Often, renal insufficiency in affected patients
progresses to end-stage renal failure, a highly morbid state requiring
either dialysis therapy or kidney transplantation. Kaplan et al. (2000)
identified mutations in the gene encoding ACTN4
(604638.0001-604638.0004), an actin-filament crosslinking protein, as
the cause of the disorder in 3 families with an autosomal dominant form
of FSGS. They found that in vitro, mutant alpha-actinin-4 bound
filamentous actin more strongly than did wildtype alpha-actinin-4.
Regulation of the actin cytoskeleton of glomerular podocytes may be
altered in this group of patients. The results had implications for
understanding the role of the cytoskeleton in the pathophysiology of
kidney disease and may be relevant to an understanding of the genetic
basis of susceptibility to kidney damage.
Weins et al. (2007) stated that ACTN4 proteins with disease-causing
mutations form aggregates with F-actin in human and mouse podocytes.
Using knockin mice homozygous for a disease-causing mutation in human
ACTN4, lys255 to glu (K255E), they showed that these aggregates were
associated with the actin cytoskeleton. The mutation exposed a buried
actin-binding site in ACTN4 that increased its actin-binding affinity,
abolished its Ca(2+) regulation in vitro, and mislocalized it from actin
stress fibers and focal adhesions in vivo. In vitro, actin filaments
crosslinked by mutant ACTN4 exhibited changes of structural and
biomechanical properties compared with wildtype ACTN4.
Echchakir et al. (2001) identified an antigen recognized on a human
large cell carcinoma by an autologous tumor-specific cytolytic T
lymphocyte (CTL) clone that was derived from mononuclear cells
infiltrating the primary tumor in a lung cancer patient. The antigenic
peptide was presented by HLA-A2 molecules and was encoded by the ACTN4
gene, which is expressed ubiquitously. In the tumor cells, a point
mutation generated an amino acid change that is essential for
recognition by the CTLs. The mutation was not found in ACTN4 cDNA
sequences from about 50 lung carcinoma cell lines, suggesting that it
was unique to this patient. Although the patient did not receive
chemotherapy or radiotherapy, he remained without evidence of tumor
after resection of the primary lesion in 1996. Anti-alpha-actinin-4 CTLs
were derived from blood samples collected from the patient in 1998 and
2000. It is possible that these CTLs, recognizing a truly tumor-specific
antigen, played a role in the clinical evolution of this lung cancer
patient.
ANIMAL MODEL
Kos et al. (2003) developed Actn4-deficient mice which showed
progressive proteinuria, glomerular disease, and death by several months
of age. Light microscopy revealed extensive glomerular disease and
proteinaceous casts; electron microscopy showed focal areas of podocyte
foot-process effacement in young mice and diffuse effacement and
globally disrupted podocyte morphology in older mice. Histologic
examination showed abnormalities only in the kidneys. Cell motility, as
measured by lymphocyte chemotaxis assays, was increased in the absence
of Actn4. Kos et al. (2003) concluded that ACTN4 is required for normal
glomerular function and is involved in the regulation of cell movement.
They also noted that the nonsarcomeric forms of ACTN, ACTN1 (102575) and
ACTN4, both found in the kidney, are not functionally redundant.
*FIELD* AV
.0001
FOCAL SEGMENTAL GLOMERULOSCLEROSIS 1
ACTN4, LYS228GLU
In affected individuals in a family with focal segmental
glomerulosclerosis that mapped to 19q (603278), Kaplan et al. (2000)
found a lys228-to-gly (K228G) mutation caused by a 682A-G nucleotide
substitution in the ACTN4 RNA. The disease in this family, like that in
2 others studied, showed a mild increase in urine protein excretion
starting in the teenage years or later, slowly progressive renal
dysfunction, and the development of end-stage renal failure in some
affected individuals. Two individuals in this family carrying the
lys228-to-glu allele had no clinical symptoms.
.0002
FOCAL SEGMENTAL GLOMERULOSCLEROSIS 1
ACTN4, THR232ILE
Kaplan et al. (2000) found that affected members in their family with
focal segmental glomerulosclerosis mapping to 19q13 (603278) had a
thr232-to-ile (T232I) mutation in the ACTN4 gene, caused by a 695C-T
transition. The family contained 4 individuals carrying the
disease-associated allele who had no proteinuria.
.0003
FOCAL SEGMENTAL GLOMERULOSCLEROSIS 1
ACTN4, SER235PRO
Kaplan et al. (2000) studied a family in which affected members with
focal segmental glomerulosclerosis (603278) had a ser235-to-pro (S235P)
mutation due to a 703T-C transition in the ACTN4 gene.
*FIELD* RF
1. Echchakir, H.; Mami-Chouaib, F.; Vergnon, I.; Baurain, J.-F.; Karanikas,
V.; Chouaib, S.; Coulie, P. G.: A point mutation in the alpha-actinin-4
gene generates an antigenic peptide recognized by autologous cytolytic
T lymphocytes on a human lung carcinoma. Cancer Res. 61: 4078-4083,
2001.
2. El-Husseini, A. E.; Kwasnicka, D.; Yamada, T.; Hirohashi, S.; Vincent,
S. R.: BERP, a novel ring finger protein, binds to alpha-actinin-4. Biochem.
Biophys. Res. Commun. 267: 906-911, 2000.
3. Honda, K.; Yamada, T.; Endo, R.; Ino, Y.; Gotoh, M.; Tsuda, H.;
Yamada, Y.; Chiba, H.; Hirohashi, S.: Actinin-4, a novel actin-bundling
protein associated with cell motility and cancer invasion. J. Cell
Biol. 140: 1383-1393, 1998. Note: Erratum: J. Cell Biol. 143: 277
only, 1998.
4. Kaplan, J. M.; Kim, S. H.; North, K. N.; Rennke, H.; Correia, L.
A.; Tong, H.-Q.; Mathis, B. J.; Rodriguez-Perez, J.-C.; Allen, P.
G.; Beggs, A. H.; Pollak, M. R.: Mutations in ACTN4, encoding alpha-actinin-4,
cause familial focal segmental glomerulosclerosis. Nature Genet. 24:
251-256, 2000.
5. Kos, C. H.; Le, T. C.; Sinha, S.; Henderson, J. M.; Kim, S. H.;
Sugimoto, H.; Kalluri, R.; Gerszten, R. E.; Pollak, M. R.: Mice deficient
in alpha-actinin-4 have severe glomerular disease. J. Clin. Invest. 111:
1683-1690, 2003.
6. Patrie, K. M.; Drescher, A. J.; Welihinda, A.; Mundel, P.; Margolis,
B.: Interaction of two actin-binding proteins, synaptopodin and alpha-actinin-4,
with the tight junction protein MAGI-1. J. Biol. Chem. 277: 30183-30190,
2002.
7. Weins, A.; Schlondorff, J. S.; Nakamura, F.; Denker, B. M.; Hartwig,
J. H.; Stossel, T. P.; Pollak, M. R.: Disease-associated mutant alpha-actinin-4
reveals a mechanism for regulating its F-actin-binding affinity. Proc.
Nat. Acad. Sci. 104: 16080-16085, 2007.
*FIELD* CN
Patricia A. Hartz - updated: 11/7/2007
Marla J. F. O'Neill - updated: 3/17/2005
Patricia A. Hartz - updated: 10/8/2003
Victor A. McKusick - updated: 8/23/2001
*FIELD* CD
Victor A. McKusick: 3/1/2000
*FIELD* ED
carol: 10/25/2010
terry: 10/22/2010
alopez: 1/29/2010
mgross: 11/7/2007
carol: 6/3/2005
wwang: 3/17/2005
wwang: 3/16/2005
alopez: 7/12/2004
mgross: 10/8/2003
carol: 8/29/2001
mcapotos: 8/23/2001
mcapotos: 8/20/2001
mcapotos: 4/4/2001
carol: 12/26/2000
terry: 10/5/2000
alopez: 3/1/2000