Full text data of PFN1
PFN1
[Confidence: low (only semi-automatic identification from reviews)]
Profilin-1 (Epididymis tissue protein Li 184a; Profilin I)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Profilin-1 (Epididymis tissue protein Li 184a; Profilin I)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P07737
ID PROF1_HUMAN Reviewed; 140 AA.
AC P07737; Q53Y44;
DT 01-AUG-1988, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 2.
DT 22-JAN-2014, entry version 156.
DE RecName: Full=Profilin-1;
DE AltName: Full=Epididymis tissue protein Li 184a;
DE AltName: Full=Profilin I;
GN Name=PFN1;
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].
RX PubMed=3356709;
RA Kwiatkowski D.J., Bruns G.A.P.;
RT "Human profilin. Molecular cloning, sequence comparison, and
RT chromosomal analysis.";
RL J. Biol. Chem. 263:5910-5915(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RC TISSUE=Epididymis;
RX PubMed=20736409; DOI=10.1074/mcp.M110.001719;
RA Li J., Liu F., Wang H., Liu X., Liu J., Li N., Wan F., Wang W.,
RA Zhang C., Jin S., Liu J., Zhu P., Liu Y.;
RT "Systematic mapping and functional analysis of a family of human
RT epididymal secretory sperm-located proteins.";
RL Mol. Cell. Proteomics 9:2517-2528(2010).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 (MAY-2004) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Colon, Lung, Pancreas, and 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 PROTEIN SEQUENCE OF 2-140, AND ACETYLATION AT ALA-2.
RX PubMed=3342873; DOI=10.1016/0014-5793(88)80575-1;
RA Ampe C., Markey F., Lindberg U., Vandekerckhove J.;
RT "The primary structure of human platelet profilin: reinvestigation of
RT the calf spleen profilin sequence.";
RL FEBS Lett. 228:17-21(1988).
RN [9]
RP CHARACTERIZATION.
RX PubMed=7758455; DOI=10.1111/j.1432-1033.1995.tb20506.x;
RA Gieselmann R., Kwiatkowski D.J., Janmey P.A., Witke W.;
RT "Distinct biochemical characteristics of the two human profilin
RT isoforms.";
RL Eur. J. Biochem. 229:621-628(1995).
RN [10]
RP IDENTIFICATION IN A COMPLEX WITH RAN; ACTB AND XPO6.
RX PubMed=14592989; DOI=10.1093/emboj/cdg565;
RA Stueven T., Hartmann E., Goerlich D.;
RT "Exportin 6: a novel nuclear export receptor that is specific for
RT profilin.actin complexes.";
RL EMBO J. 22:5928-5940(2003).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-129, AND MASS
RP SPECTROMETRY.
RX PubMed=15592455; DOI=10.1038/nbt1046;
RA Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H.,
RA Zha X.-M., Polakiewicz R.D., Comb M.J.;
RT "Immunoaffinity profiling of tyrosine phosphorylation in cancer
RT cells.";
RL Nat. Biotechnol. 23:94-101(2005).
RN [12]
RP FUNCTION, INTERACTION WITH HTT, AND PHOSPHORYLATION AT SER-138.
RX PubMed=18573880; DOI=10.1128/MCB.00079-08;
RA Shao J., Welch W.J., Diprospero N.A., Diamond M.I.;
RT "Phosphorylation of profilin by ROCK1 regulates polyglutamine
RT aggregation.";
RL Mol. Cell. Biol. 28:5196-5208(2008).
RN [13]
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 [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-85, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [15]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-105 AND LYS-108, AND MASS
RP 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 [16]
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 [17]
RP STRUCTURE BY NMR.
RX PubMed=8268157; DOI=10.1021/bi00213a010;
RA Metzler W.J., Constantine K.L., Friedrichs M.S., Bell A.J.,
RA Ernst E.G., Lavoie T.B., Mueller L.;
RT "Characterization of the three-dimensional solution structure of human
RT profilin: 1H, 13C, and 15N NMR assignments and global folding
RT pattern.";
RL Biochemistry 32:13818-13829(1993).
RN [18]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS).
RA Fedorov A.A., Pollard T.D., Almo S.C.;
RL Submitted (APR-1996) to the PDB data bank.
RN [19]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF COMPLEX WITH POLY-PRO.
RX PubMed=9360613; DOI=10.1038/nsb1197-953;
RA Mahoney N.M., Janmey P.A., Almo S.C.;
RT "Structure of the profilin-poly-L-proline complex involved in
RT morphogenesis and cytoskeletal regulation.";
RL Nat. Struct. Biol. 4:953-960(1997).
RN [20]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF COMPLEX WITH POLY-PRO.
RX PubMed=10404225; DOI=10.1038/10722;
RA Mahoney N.M., Rozwarski D.A., Fedorov E., Fedorov A.A., Almo S.C.;
RT "Profilin binds proline-rich ligands in two distinct amide backbone
RT orientations.";
RL Nat. Struct. Biol. 6:666-671(1999).
RN [21]
RP X-RAY CRYSTALLOGRAPHY (1.5 ANGSTROMS) OF 2-140 IN COMPLEXES WITH VASP
RP AND MONOMERIC ACTIN, AND INTERACTION WITH VASP.
RX PubMed=17914456; DOI=10.1038/sj.emboj.7601874;
RA Ferron F., Rebowski G., Lee S.H., Dominguez R.;
RT "Structural basis for the recruitment of profilin-actin complexes
RT during filament elongation by Ena/VASP.";
RL EMBO J. 26:4597-4606(2007).
RN [22]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 2-140 IN COMPLEX WITH VASP
RP AND ACTIN.
RX PubMed=18689676; DOI=10.1073/pnas.0805852105;
RA Baek K., Liu X., Ferron F., Shu S., Korn E.D., Dominguez R.;
RT "Modulation of actin structure and function by phosphorylation of Tyr-
RT 53 and profilin binding.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:11748-11753(2008).
RN [23]
RP VARIANTS ALS18 GLY-71; THR-114; GLY-117 AND VAL-118, AND
RP CHARACTERIZATION OF VARIANTS ALS18 GLY-71; THR-114; GLY-117 AND
RP VAL-118.
RX PubMed=22801503; DOI=10.1038/nature11280;
RA Wu C.H., Fallini C., Ticozzi N., Keagle P.J., Sapp P.C.,
RA Piotrowska K., Lowe P., Koppers M., McKenna-Yasek D., Baron D.M.,
RA Kost J.E., Gonzalez-Perez P., Fox A.D., Adams J., Taroni F.,
RA Tiloca C., Leclerc A.L., Chafe S.C., Mangroo D., Moore M.J.,
RA Zitzewitz J.A., Xu Z.S., van den Berg L.H., Glass J.D., Siciliano G.,
RA Cirulli E.T., Goldstein D.B., Salachas F., Meininger V., Rossoll W.,
RA Ratti A., Gellera C., Bosco D.A., Bassell G.J., Silani V., Drory V.E.,
RA Brown R.H. Jr., Landers J.E.;
RT "Mutations in the profilin 1 gene cause familial amyotrophic lateral
RT sclerosis.";
RL Nature 488:499-503(2012).
CC -!- FUNCTION: Binds to actin and affects the structure of the
CC cytoskeleton. At high concentrations, profilin prevents the
CC polymerization of actin, whereas it enhances it at low
CC concentrations. By binding to PIP2, it inhibits the formation of
CC IP3 and DG. Inhibits androgen receptor (AR) and HTT aggregation
CC and binding of G-actin is essential for its inhibition of AR.
CC -!- SUBUNIT: Occurs in many kinds of cells as a complex with monomeric
CC actin in a 1:1 ratio. Found in a complex with XPO6, Ran, ACTB and
CC PFN1. Interacts with VASP. Interacts with HTT.
CC -!- INTERACTION:
CC Q92558:WASF1; NbExp=2; IntAct=EBI-713780, EBI-1548747;
CC O08816:Wasl (xeno); NbExp=4; IntAct=EBI-713780, EBI-6142604;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton.
CC -!- TISSUE SPECIFICITY: Expressed in epididymis (at protein level).
CC -!- PTM: Phosphorylation at Ser-138 reduces its affinity for G-actin
CC and blocks its interaction with HTT, reducing its ability to
CC inhibit androgen receptor (AR) and HTT aggregation.
CC -!- DISEASE: Amyotrophic lateral sclerosis 18 (ALS18) [MIM:614808]: A
CC neurodegenerative disorder affecting upper motor neurons in the
CC brain and lower motor neurons in the brain stem and spinal cord,
CC resulting in fatal paralysis. Sensory abnormalities are absent.
CC The pathologic hallmarks of the disease include pallor of the
CC corticospinal tract due to loss of motor neurons, presence of
CC ubiquitin-positive inclusions within surviving motor neurons, and
CC deposition of pathologic aggregates. The etiology of amyotrophic
CC lateral sclerosis is likely to be multifactorial, involving both
CC genetic and environmental factors. The disease is inherited in 5-
CC 10% of the cases. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the profilin family.
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DR EMBL; J03191; AAA36486.1; -; mRNA.
DR EMBL; GU727630; ADU87632.1; -; mRNA.
DR EMBL; BT007001; AAP35647.1; -; mRNA.
DR EMBL; AK312168; BAG35102.1; -; mRNA.
DR EMBL; CR407670; CAG28598.1; -; mRNA.
DR EMBL; CH471108; EAW90381.1; -; Genomic_DNA.
DR EMBL; CH471108; EAW90383.1; -; Genomic_DNA.
DR EMBL; CH471108; EAW90384.1; -; Genomic_DNA.
DR EMBL; BC002475; AAH02475.1; -; mRNA.
DR EMBL; BC006768; AAH06768.1; -; mRNA.
DR EMBL; BC013439; AAH13439.1; -; mRNA.
DR EMBL; BC015164; AAH15164.1; -; mRNA.
DR EMBL; BC057828; AAH57828.1; -; mRNA.
DR PIR; A28622; A28622.
DR RefSeq; NP_005013.1; NM_005022.3.
DR UniGene; Hs.494691; -.
DR PDB; 1AWI; X-ray; 2.20 A; A/B=3-140.
DR PDB; 1CF0; X-ray; 2.20 A; A/B=3-140.
DR PDB; 1CJF; X-ray; 2.30 A; A/B=2-140.
DR PDB; 1FIK; X-ray; 2.30 A; A=2-140.
DR PDB; 1FIL; X-ray; 2.00 A; A=2-140.
DR PDB; 1PFL; NMR; -; A=2-140.
DR PDB; 2PAV; X-ray; 1.80 A; P=2-140.
DR PDB; 2PBD; X-ray; 1.50 A; P=2-140.
DR PDB; 3CHW; X-ray; 2.30 A; P=2-140.
DR PDBsum; 1AWI; -.
DR PDBsum; 1CF0; -.
DR PDBsum; 1CJF; -.
DR PDBsum; 1FIK; -.
DR PDBsum; 1FIL; -.
DR PDBsum; 1PFL; -.
DR PDBsum; 2PAV; -.
DR PDBsum; 2PBD; -.
DR PDBsum; 3CHW; -.
DR ProteinModelPortal; P07737; -.
DR SMR; P07737; 2-140.
DR DIP; DIP-30N; -.
DR IntAct; P07737; 36.
DR MINT; MINT-1372667; -.
DR STRING; 9606.ENSP00000225655; -.
DR Allergome; 907; Hom s Profilin.
DR PhosphoSite; P07737; -.
DR DMDM; 130979; -.
DR DOSAC-COBS-2DPAGE; P07737; -.
DR OGP; P07737; -.
DR REPRODUCTION-2DPAGE; IPI00216691; -.
DR UCD-2DPAGE; P07737; -.
DR PaxDb; P07737; -.
DR PeptideAtlas; P07737; -.
DR PRIDE; P07737; -.
DR DNASU; 5216; -.
DR Ensembl; ENST00000225655; ENSP00000225655; ENSG00000108518.
DR GeneID; 5216; -.
DR KEGG; hsa:5216; -.
DR UCSC; uc002gaa.4; human.
DR CTD; 5216; -.
DR GeneCards; GC17M004848; -.
DR HGNC; HGNC:8881; PFN1.
DR HPA; CAB037140; -.
DR MIM; 176610; gene.
DR MIM; 614808; phenotype.
DR neXtProt; NX_P07737; -.
DR Orphanet; 803; Amyotrophic lateral sclerosis.
DR PharmGKB; PA33219; -.
DR eggNOG; NOG269129; -.
DR HOGENOM; HOG000171592; -.
DR HOVERGEN; HBG053683; -.
DR InParanoid; P07737; -.
DR KO; K05759; -.
DR OMA; HLRRAQY; -.
DR OrthoDB; EOG7JMGGT; -.
DR PhylomeDB; P07737; -.
DR Reactome; REACT_111045; Developmental Biology.
DR Reactome; REACT_604; Hemostasis.
DR ChiTaRS; PFN1; human.
DR EvolutionaryTrace; P07737; -.
DR GeneWiki; Profilin_1; -.
DR GenomeRNAi; 5216; -.
DR NextBio; 20172; -.
DR PMAP-CutDB; P07737; -.
DR PRO; PR:P07737; -.
DR ArrayExpress; P07737; -.
DR Bgee; P07737; -.
DR CleanEx; HS_PFN1; -.
DR Genevestigator; P07737; -.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-KW.
DR GO; GO:0005856; C:cytoskeleton; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IEA:Ensembl.
DR GO; GO:0030036; P:actin cytoskeleton organization; IEA:InterPro.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
DR GO; GO:0001843; P:neural tube closure; IEA:Ensembl.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0002576; P:platelet degranulation; TAS:Reactome.
DR GO; GO:0006357; P:regulation of transcription from RNA polymerase II promoter; IEA:Ensembl.
DR InterPro; IPR005454; Profilin_chordates.
DR InterPro; IPR027310; Profilin_CS.
DR InterPro; IPR005455; Profilin_eukaryotes/bac.
DR Pfam; PF00235; Profilin; 1.
DR PRINTS; PR01639; PROFILINMAML.
DR SMART; SM00392; PROF; 1.
DR SUPFAM; SSF55770; SSF55770; 1.
DR PROSITE; PS00414; PROFILIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Actin-binding;
KW Amyotrophic lateral sclerosis; Complete proteome; Cytoplasm;
KW Cytoskeleton; Direct protein sequencing; Disease mutation;
KW Isopeptide bond; Neurodegeneration; Phosphoprotein;
KW Reference proteome; Ubl conjugation.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 140 Profilin-1.
FT /FTId=PRO_0000199571.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 85 85 Phosphoserine.
FT MOD_RES 105 105 N6-acetyllysine.
FT MOD_RES 108 108 N6-acetyllysine.
FT MOD_RES 129 129 Phosphotyrosine.
FT MOD_RES 138 138 Phosphoserine; by ROCK1.
FT CROSSLNK 54 54 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin).
FT VARIANT 71 71 C -> G (in ALS18; the mutant protein is
FT detected in the insoluble fraction of
FT cells).
FT /FTId=VAR_068925.
FT VARIANT 114 114 M -> T (in ALS18; the mutant protein is
FT detected in the insoluble fraction of
FT cells).
FT /FTId=VAR_068926.
FT VARIANT 117 117 E -> G (in ALS18; unknown pathological
FT significance; like the wild-type the
FT mutant protein is detected in the soluble
FT fraction of cells; dbSNP:rs140547520).
FT /FTId=VAR_068927.
FT VARIANT 118 118 G -> V (in ALS18; the mutant protein is
FT detected in the insoluble fraction of
FT cells).
FT /FTId=VAR_068928.
FT HELIX 5 12
FT STRAND 14 16
FT STRAND 17 28
FT STRAND 30 34
FT HELIX 40 42
FT HELIX 45 52
FT HELIX 58 60
FT STRAND 64 66
FT STRAND 69 77
FT STRAND 78 80
FT TURN 81 83
FT STRAND 85 90
FT STRAND 93 96
FT STRAND 100 105
FT STRAND 107 115
FT HELIX 121 137
SQ SEQUENCE 140 AA; 15054 MW; F725119E55A289EB CRC64;
MAGWNAYIDN LMADGTCQDA AIVGYKDSPS VWAAVPGKTF VNITPAEVGV LVGKDRSSFY
VNGLTLGGQK CSVIRDSLLQ DGEFSMDLRT KSTGGAPTFN VTVTKTDKTL VLLMGKEGVH
GGLINKKCYE MASHLRRSQY
//
ID PROF1_HUMAN Reviewed; 140 AA.
AC P07737; Q53Y44;
DT 01-AUG-1988, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 2.
DT 22-JAN-2014, entry version 156.
DE RecName: Full=Profilin-1;
DE AltName: Full=Epididymis tissue protein Li 184a;
DE AltName: Full=Profilin I;
GN Name=PFN1;
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].
RX PubMed=3356709;
RA Kwiatkowski D.J., Bruns G.A.P.;
RT "Human profilin. Molecular cloning, sequence comparison, and
RT chromosomal analysis.";
RL J. Biol. Chem. 263:5910-5915(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RC TISSUE=Epididymis;
RX PubMed=20736409; DOI=10.1074/mcp.M110.001719;
RA Li J., Liu F., Wang H., Liu X., Liu J., Li N., Wan F., Wang W.,
RA Zhang C., Jin S., Liu J., Zhu P., Liu Y.;
RT "Systematic mapping and functional analysis of a family of human
RT epididymal secretory sperm-located proteins.";
RL Mol. Cell. Proteomics 9:2517-2528(2010).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 (MAY-2004) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Colon, Lung, Pancreas, and 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 PROTEIN SEQUENCE OF 2-140, AND ACETYLATION AT ALA-2.
RX PubMed=3342873; DOI=10.1016/0014-5793(88)80575-1;
RA Ampe C., Markey F., Lindberg U., Vandekerckhove J.;
RT "The primary structure of human platelet profilin: reinvestigation of
RT the calf spleen profilin sequence.";
RL FEBS Lett. 228:17-21(1988).
RN [9]
RP CHARACTERIZATION.
RX PubMed=7758455; DOI=10.1111/j.1432-1033.1995.tb20506.x;
RA Gieselmann R., Kwiatkowski D.J., Janmey P.A., Witke W.;
RT "Distinct biochemical characteristics of the two human profilin
RT isoforms.";
RL Eur. J. Biochem. 229:621-628(1995).
RN [10]
RP IDENTIFICATION IN A COMPLEX WITH RAN; ACTB AND XPO6.
RX PubMed=14592989; DOI=10.1093/emboj/cdg565;
RA Stueven T., Hartmann E., Goerlich D.;
RT "Exportin 6: a novel nuclear export receptor that is specific for
RT profilin.actin complexes.";
RL EMBO J. 22:5928-5940(2003).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-129, AND MASS
RP SPECTROMETRY.
RX PubMed=15592455; DOI=10.1038/nbt1046;
RA Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H.,
RA Zha X.-M., Polakiewicz R.D., Comb M.J.;
RT "Immunoaffinity profiling of tyrosine phosphorylation in cancer
RT cells.";
RL Nat. Biotechnol. 23:94-101(2005).
RN [12]
RP FUNCTION, INTERACTION WITH HTT, AND PHOSPHORYLATION AT SER-138.
RX PubMed=18573880; DOI=10.1128/MCB.00079-08;
RA Shao J., Welch W.J., Diprospero N.A., Diamond M.I.;
RT "Phosphorylation of profilin by ROCK1 regulates polyglutamine
RT aggregation.";
RL Mol. Cell. Biol. 28:5196-5208(2008).
RN [13]
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 [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-85, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [15]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-105 AND LYS-108, AND MASS
RP 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 [16]
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 [17]
RP STRUCTURE BY NMR.
RX PubMed=8268157; DOI=10.1021/bi00213a010;
RA Metzler W.J., Constantine K.L., Friedrichs M.S., Bell A.J.,
RA Ernst E.G., Lavoie T.B., Mueller L.;
RT "Characterization of the three-dimensional solution structure of human
RT profilin: 1H, 13C, and 15N NMR assignments and global folding
RT pattern.";
RL Biochemistry 32:13818-13829(1993).
RN [18]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS).
RA Fedorov A.A., Pollard T.D., Almo S.C.;
RL Submitted (APR-1996) to the PDB data bank.
RN [19]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF COMPLEX WITH POLY-PRO.
RX PubMed=9360613; DOI=10.1038/nsb1197-953;
RA Mahoney N.M., Janmey P.A., Almo S.C.;
RT "Structure of the profilin-poly-L-proline complex involved in
RT morphogenesis and cytoskeletal regulation.";
RL Nat. Struct. Biol. 4:953-960(1997).
RN [20]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF COMPLEX WITH POLY-PRO.
RX PubMed=10404225; DOI=10.1038/10722;
RA Mahoney N.M., Rozwarski D.A., Fedorov E., Fedorov A.A., Almo S.C.;
RT "Profilin binds proline-rich ligands in two distinct amide backbone
RT orientations.";
RL Nat. Struct. Biol. 6:666-671(1999).
RN [21]
RP X-RAY CRYSTALLOGRAPHY (1.5 ANGSTROMS) OF 2-140 IN COMPLEXES WITH VASP
RP AND MONOMERIC ACTIN, AND INTERACTION WITH VASP.
RX PubMed=17914456; DOI=10.1038/sj.emboj.7601874;
RA Ferron F., Rebowski G., Lee S.H., Dominguez R.;
RT "Structural basis for the recruitment of profilin-actin complexes
RT during filament elongation by Ena/VASP.";
RL EMBO J. 26:4597-4606(2007).
RN [22]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 2-140 IN COMPLEX WITH VASP
RP AND ACTIN.
RX PubMed=18689676; DOI=10.1073/pnas.0805852105;
RA Baek K., Liu X., Ferron F., Shu S., Korn E.D., Dominguez R.;
RT "Modulation of actin structure and function by phosphorylation of Tyr-
RT 53 and profilin binding.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:11748-11753(2008).
RN [23]
RP VARIANTS ALS18 GLY-71; THR-114; GLY-117 AND VAL-118, AND
RP CHARACTERIZATION OF VARIANTS ALS18 GLY-71; THR-114; GLY-117 AND
RP VAL-118.
RX PubMed=22801503; DOI=10.1038/nature11280;
RA Wu C.H., Fallini C., Ticozzi N., Keagle P.J., Sapp P.C.,
RA Piotrowska K., Lowe P., Koppers M., McKenna-Yasek D., Baron D.M.,
RA Kost J.E., Gonzalez-Perez P., Fox A.D., Adams J., Taroni F.,
RA Tiloca C., Leclerc A.L., Chafe S.C., Mangroo D., Moore M.J.,
RA Zitzewitz J.A., Xu Z.S., van den Berg L.H., Glass J.D., Siciliano G.,
RA Cirulli E.T., Goldstein D.B., Salachas F., Meininger V., Rossoll W.,
RA Ratti A., Gellera C., Bosco D.A., Bassell G.J., Silani V., Drory V.E.,
RA Brown R.H. Jr., Landers J.E.;
RT "Mutations in the profilin 1 gene cause familial amyotrophic lateral
RT sclerosis.";
RL Nature 488:499-503(2012).
CC -!- FUNCTION: Binds to actin and affects the structure of the
CC cytoskeleton. At high concentrations, profilin prevents the
CC polymerization of actin, whereas it enhances it at low
CC concentrations. By binding to PIP2, it inhibits the formation of
CC IP3 and DG. Inhibits androgen receptor (AR) and HTT aggregation
CC and binding of G-actin is essential for its inhibition of AR.
CC -!- SUBUNIT: Occurs in many kinds of cells as a complex with monomeric
CC actin in a 1:1 ratio. Found in a complex with XPO6, Ran, ACTB and
CC PFN1. Interacts with VASP. Interacts with HTT.
CC -!- INTERACTION:
CC Q92558:WASF1; NbExp=2; IntAct=EBI-713780, EBI-1548747;
CC O08816:Wasl (xeno); NbExp=4; IntAct=EBI-713780, EBI-6142604;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton.
CC -!- TISSUE SPECIFICITY: Expressed in epididymis (at protein level).
CC -!- PTM: Phosphorylation at Ser-138 reduces its affinity for G-actin
CC and blocks its interaction with HTT, reducing its ability to
CC inhibit androgen receptor (AR) and HTT aggregation.
CC -!- DISEASE: Amyotrophic lateral sclerosis 18 (ALS18) [MIM:614808]: A
CC neurodegenerative disorder affecting upper motor neurons in the
CC brain and lower motor neurons in the brain stem and spinal cord,
CC resulting in fatal paralysis. Sensory abnormalities are absent.
CC The pathologic hallmarks of the disease include pallor of the
CC corticospinal tract due to loss of motor neurons, presence of
CC ubiquitin-positive inclusions within surviving motor neurons, and
CC deposition of pathologic aggregates. The etiology of amyotrophic
CC lateral sclerosis is likely to be multifactorial, involving both
CC genetic and environmental factors. The disease is inherited in 5-
CC 10% of the cases. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the profilin family.
CC -----------------------------------------------------------------------
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DR EMBL; J03191; AAA36486.1; -; mRNA.
DR EMBL; GU727630; ADU87632.1; -; mRNA.
DR EMBL; BT007001; AAP35647.1; -; mRNA.
DR EMBL; AK312168; BAG35102.1; -; mRNA.
DR EMBL; CR407670; CAG28598.1; -; mRNA.
DR EMBL; CH471108; EAW90381.1; -; Genomic_DNA.
DR EMBL; CH471108; EAW90383.1; -; Genomic_DNA.
DR EMBL; CH471108; EAW90384.1; -; Genomic_DNA.
DR EMBL; BC002475; AAH02475.1; -; mRNA.
DR EMBL; BC006768; AAH06768.1; -; mRNA.
DR EMBL; BC013439; AAH13439.1; -; mRNA.
DR EMBL; BC015164; AAH15164.1; -; mRNA.
DR EMBL; BC057828; AAH57828.1; -; mRNA.
DR PIR; A28622; A28622.
DR RefSeq; NP_005013.1; NM_005022.3.
DR UniGene; Hs.494691; -.
DR PDB; 1AWI; X-ray; 2.20 A; A/B=3-140.
DR PDB; 1CF0; X-ray; 2.20 A; A/B=3-140.
DR PDB; 1CJF; X-ray; 2.30 A; A/B=2-140.
DR PDB; 1FIK; X-ray; 2.30 A; A=2-140.
DR PDB; 1FIL; X-ray; 2.00 A; A=2-140.
DR PDB; 1PFL; NMR; -; A=2-140.
DR PDB; 2PAV; X-ray; 1.80 A; P=2-140.
DR PDB; 2PBD; X-ray; 1.50 A; P=2-140.
DR PDB; 3CHW; X-ray; 2.30 A; P=2-140.
DR PDBsum; 1AWI; -.
DR PDBsum; 1CF0; -.
DR PDBsum; 1CJF; -.
DR PDBsum; 1FIK; -.
DR PDBsum; 1FIL; -.
DR PDBsum; 1PFL; -.
DR PDBsum; 2PAV; -.
DR PDBsum; 2PBD; -.
DR PDBsum; 3CHW; -.
DR ProteinModelPortal; P07737; -.
DR SMR; P07737; 2-140.
DR DIP; DIP-30N; -.
DR IntAct; P07737; 36.
DR MINT; MINT-1372667; -.
DR STRING; 9606.ENSP00000225655; -.
DR Allergome; 907; Hom s Profilin.
DR PhosphoSite; P07737; -.
DR DMDM; 130979; -.
DR DOSAC-COBS-2DPAGE; P07737; -.
DR OGP; P07737; -.
DR REPRODUCTION-2DPAGE; IPI00216691; -.
DR UCD-2DPAGE; P07737; -.
DR PaxDb; P07737; -.
DR PeptideAtlas; P07737; -.
DR PRIDE; P07737; -.
DR DNASU; 5216; -.
DR Ensembl; ENST00000225655; ENSP00000225655; ENSG00000108518.
DR GeneID; 5216; -.
DR KEGG; hsa:5216; -.
DR UCSC; uc002gaa.4; human.
DR CTD; 5216; -.
DR GeneCards; GC17M004848; -.
DR HGNC; HGNC:8881; PFN1.
DR HPA; CAB037140; -.
DR MIM; 176610; gene.
DR MIM; 614808; phenotype.
DR neXtProt; NX_P07737; -.
DR Orphanet; 803; Amyotrophic lateral sclerosis.
DR PharmGKB; PA33219; -.
DR eggNOG; NOG269129; -.
DR HOGENOM; HOG000171592; -.
DR HOVERGEN; HBG053683; -.
DR InParanoid; P07737; -.
DR KO; K05759; -.
DR OMA; HLRRAQY; -.
DR OrthoDB; EOG7JMGGT; -.
DR PhylomeDB; P07737; -.
DR Reactome; REACT_111045; Developmental Biology.
DR Reactome; REACT_604; Hemostasis.
DR ChiTaRS; PFN1; human.
DR EvolutionaryTrace; P07737; -.
DR GeneWiki; Profilin_1; -.
DR GenomeRNAi; 5216; -.
DR NextBio; 20172; -.
DR PMAP-CutDB; P07737; -.
DR PRO; PR:P07737; -.
DR ArrayExpress; P07737; -.
DR Bgee; P07737; -.
DR CleanEx; HS_PFN1; -.
DR Genevestigator; P07737; -.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-KW.
DR GO; GO:0005856; C:cytoskeleton; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IEA:Ensembl.
DR GO; GO:0030036; P:actin cytoskeleton organization; IEA:InterPro.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
DR GO; GO:0001843; P:neural tube closure; IEA:Ensembl.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0002576; P:platelet degranulation; TAS:Reactome.
DR GO; GO:0006357; P:regulation of transcription from RNA polymerase II promoter; IEA:Ensembl.
DR InterPro; IPR005454; Profilin_chordates.
DR InterPro; IPR027310; Profilin_CS.
DR InterPro; IPR005455; Profilin_eukaryotes/bac.
DR Pfam; PF00235; Profilin; 1.
DR PRINTS; PR01639; PROFILINMAML.
DR SMART; SM00392; PROF; 1.
DR SUPFAM; SSF55770; SSF55770; 1.
DR PROSITE; PS00414; PROFILIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Actin-binding;
KW Amyotrophic lateral sclerosis; Complete proteome; Cytoplasm;
KW Cytoskeleton; Direct protein sequencing; Disease mutation;
KW Isopeptide bond; Neurodegeneration; Phosphoprotein;
KW Reference proteome; Ubl conjugation.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 140 Profilin-1.
FT /FTId=PRO_0000199571.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 85 85 Phosphoserine.
FT MOD_RES 105 105 N6-acetyllysine.
FT MOD_RES 108 108 N6-acetyllysine.
FT MOD_RES 129 129 Phosphotyrosine.
FT MOD_RES 138 138 Phosphoserine; by ROCK1.
FT CROSSLNK 54 54 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin).
FT VARIANT 71 71 C -> G (in ALS18; the mutant protein is
FT detected in the insoluble fraction of
FT cells).
FT /FTId=VAR_068925.
FT VARIANT 114 114 M -> T (in ALS18; the mutant protein is
FT detected in the insoluble fraction of
FT cells).
FT /FTId=VAR_068926.
FT VARIANT 117 117 E -> G (in ALS18; unknown pathological
FT significance; like the wild-type the
FT mutant protein is detected in the soluble
FT fraction of cells; dbSNP:rs140547520).
FT /FTId=VAR_068927.
FT VARIANT 118 118 G -> V (in ALS18; the mutant protein is
FT detected in the insoluble fraction of
FT cells).
FT /FTId=VAR_068928.
FT HELIX 5 12
FT STRAND 14 16
FT STRAND 17 28
FT STRAND 30 34
FT HELIX 40 42
FT HELIX 45 52
FT HELIX 58 60
FT STRAND 64 66
FT STRAND 69 77
FT STRAND 78 80
FT TURN 81 83
FT STRAND 85 90
FT STRAND 93 96
FT STRAND 100 105
FT STRAND 107 115
FT HELIX 121 137
SQ SEQUENCE 140 AA; 15054 MW; F725119E55A289EB CRC64;
MAGWNAYIDN LMADGTCQDA AIVGYKDSPS VWAAVPGKTF VNITPAEVGV LVGKDRSSFY
VNGLTLGGQK CSVIRDSLLQ DGEFSMDLRT KSTGGAPTFN VTVTKTDKTL VLLMGKEGVH
GGLINKKCYE MASHLRRSQY
//
MIM
176610
*RECORD*
*FIELD* NO
176610
*FIELD* TI
*176610 PROFILIN 1; PFN1
*FIELD* TX
DESCRIPTION
Profilin-1 is a 140-amino acid protein and major growth regulator of
read morefilamentous (F)-actin through its binding of monomeric (G)-actin
(Mockrin and Korn, 1980).
CLONING
Profilin is a ubiquitous 12- to 15-kD protein which inhibits the
polymerization of actin. It is thought to function by complexing with
unpolymerized actin in vivo. Dissociation of the profilin-actin complex
is caused by binding of phosphatidylinositol 4,5-bisphosphate to
profilin. Ampe et al. (1988) described the amino acid sequence of human
platelet profilin and found it to have 95% homology to the sequence of
calf spleen profilin.
GENE FUNCTION
Goldschmidt-Clermont and Janmey (1991) reviewed the function of
profilin, partly on the basis of work in the S. cerevisiae, homolog, PFY
(Vojtek et al., 1991). Theriot and Mitchison (1993) reviewed the
multiple functions of profilin.
MAPPING
By Southern blot analysis of somatic cell hybrid DNA, Kwiatkowski and
Bruns (1988) found that at least 4 dispersed genetic loci in the human
genome hybridize with the profilin cDNA as well as the untranslated
region fragments, suggesting that several of these loci represent
pseudogenes of recent evolutionary origin. Chromosomes 1, 6, 13, and 17
were implicated. In addition, 5-prime and 3-prime untranslated regions
were found to be conserved between humans and rodents, implying a
functional role for these regions of the profilin gene. Kwiatkowski et
al. (1990) localized the functional profilin gene to 17p13 by analysis
of somatic cell hybrids and by in situ hybridization. By study of
patients with deletions and by use of somatic cell hybrids containing a
deleted chromosome 17, Kwiatkowski et al. (1990) sublocalized the PFN1
gene to 17p13.3. This is the same region as that deleted in the
Miller-Dieker syndrome (MDLS; 247200). They found that the gene indeed
was deleted in some patients with MDLS but that other patients had
smaller deletions not affecting the profilin locus. Thus, a single
allelic deletion of the profilin locus may contribute to the clinical
phenotype of MDLS in some patients but does not play a major role in the
essential phenotype.
In the mouse, Klingenspor et al. (1997) mapped the Pfn1 gene to
chromosome 11 and a profilin-1 related sequence to chromosome 15.
MOLECULAR GENETICS
Wu et al. (2012) identified 4 different mutations in the PFN1 gene in 7
of 274 familial ALS cases. One mutation (E117G; 176610.0004), was found
in 3 of 1,090 ALS cases and 3 of 7,560 controls. Wu et al. (2012)
performed in vitro assays and showed that mutant PFN1 produces
ubiquitinated, insoluble aggregates in transfected cells. In many cases
the aggregates contained the ALS-associated protein TDP43 (605078). The
E117G mutation (176610.0004) displayed a pattern more similar to
wildtype PFN1, with most of the expressed protein in the soluble
fraction. Wu et al. (2012) found that mutant PFN1 inhibited axon
outgrowth. Wu et al. (2012) concluded that mutations in the PFN1 gene
account for approximately 1 to 2% of familial ALS and suggested that
disruption of cytoskeletal pathways contribute importantly to ALS
pathogenicity.
ANIMAL MODEL
To examine the function of profilin-1 in vivo, Witke et al. (2001)
generated Pfn1 knockout mice. Homozygotes were not viable; they died as
early as the 2-cell stage, and no homozygous knockout blastocysts were
detectable. Adult heterozygotes showed a 50% reduction in profilin-1
expression with no apparent impairment of cell function. However,
heterozygous embryos had reduced survival during embryogenesis compared
with wildtype. Although weakly expressed in early embryos, profilin-2
(176590) could not compensate for lack of profilin-1. Their results
indicated that mouse profilin-1 is an essential protein that has
dosage-dependent effects on cell division and survival during
embryogenesis.
Yarovinsky et al. (2005) identified a profilin-like molecule from the
protozoan parasite Toxoplasma gondii that generates a potent IL12 (see
161560) response in murine dendritic cells that is dependent on MyD88
(602170). T. gondii profilin activates dendritic cells through TLR11
(606270) and is the first chemically defined ligand for this toll-like
receptor. Moreover, TLR11 is required in vivo for parasite-induced IL12
production and optimal resistance to infection, thereby establishing a
role for the receptor in host recognition of protozoan pathogens.
*FIELD* AV
.0001
AMYOTROPHIC LATERAL SCLEROSIS 18
PFN1, CYS71GLY
In 3 families segregating autosomal dominant ALS18 (614808), Wu et al.
(2012) identified a T-to-G transversion at nucleotide 347 of the PFN1
gene, resulting in a cysteine-to-glycine substitution at codon 71
(C71G). In family 1, all 4 affected members for which DNA was available
possessed the C71G variant. A single obligate carrier of the C71G
variant did not develop disease, but she died before the average age of
onset of this family (50.0 +/- 6.6 years). All unaffected family members
displayed the wildtype genotype. This mutation was subsequently
identified in 2 other families. In family 3, the mutation was detected
in 3 other affected family members. A single unaffected member of the
family whose age was in the mid-forties was found to be a mutation
carrier. The average age of onset in this family was 41.1 +/- 4.3 years
for those definitively affected. Haplotype analysis suggested that the
C71G variant derives from a single ancestral mutation. This mutation was
not observed among 7,560 control samples (15,120 alleles).
.0002
AMYOTROPHIC LATERAL SCLEROSIS 18
PFN1, MET114THR
In 2 families (families 2 and 4) segregating autosomal dominant ALS18
(614808), Wu et al. (2012) identified a T-to-C transition at nucleotide
477 of the PFN1 gene, resulting in a methionine-to-threonine
substitution at codon 114 (M114T). In family 2, all 8 affected members
for whom DNA was available carried the mutation, and on the basis of
genotype in spouse and progeny, Wu et al. (2012) were able to confirm
that a ninth affected family member also carried the mutation. Of 7
unaffected members, 5 did not carry the M114T variant. One unaffected
mutation carrier was aged in the mid-forties and a second obligate
carrier was asymptomatic into the seventies, suggesting high but
incomplete penetrance of this mutation. The average age of onset for
family 2 was 41.9 +/- 5.3 years and for family 4 it was 52.0 +/- 13.1
years. This mutation was not observed among 7,560 control samples
(15,120 alleles).
.0003
AMYOTROPHIC LATERAL SCLEROSIS 18
PFN1, GLY118VAL
In an individual from a family with a parent-child segregating autosomal
dominant ALS18 (614808), Wu et al. (2012) identified a G-to-T
transversion at nucleotide 489 of the PFN1 gene, resulting in a
glycine-to-valine substitution at codon 118 (G118V). This mutation was
not observed among 7,560 control samples (15,120 alleles). The glycine
at this position is invariant down to zebrafish.
.0004
AMYOTROPHIC LATERAL SCLEROSIS 18
PFN1, GLU117GLY
In one family with autosomal dominant ALS (ALS18; 614808) with
incomplete penetrance, Wu et al. (2012) identified a 2-basepair
substitution, AA to GT, at nucleotides 46 and 47 of the PFN1 gene,
resulting in a glutamic acid-to-glycine substitution at codon 117
(E117G). This mutation was subsequently identified in 2 sporadic ALS
patients among 816 sequenced. Overall, this mutation was identified in 3
of 1,090 ALS cases and 3 of 7,560 control samples (2.75 x 10(-3) vs 3.97
x 10(-4); P = 0.030, two-tailed Fisher's exact test). Wu et al. (2012)
suggested that, while it could be argued that the E117G variant is
nonpathogenic, more likely it is less pathogenic than the other 3
mutations (C71G; 176610.0001, M114T; 176610.0002, and G118V;
176610.0003) identified in the PFN1 gene to that time. While Western
blot analysis of the soluble and insoluble fractions of cells
transfected with wildtype and mutant PFN1 proteins detected a
considerable portion of the C71G, M114T, and G118V mutant proteins in
the insoluble fraction, the E117G mutation displayed a pattern more
similar to wildtype PFN1, with most of the expressed protein in the
soluble fraction. The glu at position 117 is invariant down to
zebrafish.
*FIELD* RF
1. Ampe, C.; Markey, F.; Lindberg, U.; Vandekerckhove, J.: The primary
structure of human platelet profilin: reinvestigation of the calf
spleen profilin sequence. FEBS Lett. 228: 17-21, 1988.
2. Goldschmidt-Clermont, P. J.; Janmey, P. A.: Profilin, a weak CAP
for actin and RAS. Cell 66: 419-421, 1991.
3. Klingenspor, M.; Bodnar, J.; Xia, Y.-R.; Welch, C.; Lusis, A. J.;
Reue, K.: Localization of profilin-1 (Pfn1) and a related sequence
(Pfn1-rs) to mouse chromosomes 11 and 15 respectively. Mammalian
Genome 8: 539-541, 1997.
4. Kwiatkowski, D. J.; Aklog, L.; Ledbetter, D. H.; Morton, C. C.
: Identification of the functional profilin gene, its localization
to chromosome subband 17p13.3, and demonstration of its deletion in
some patients with Miller-Dieker syndrome. Am. J. Hum. Genet. 46:
559-567, 1990.
5. Kwiatkowski, D. J.; Bruns, G. A. P.: Human profilin: molecular
cloning, sequence comparison, and chromosomal analysis. J. Biol.
Chem. 263: 5910-5915, 1988.
6. Mockrin, S. C.; Korn, E. D.: Acanthamoeba profilin interacts with
G-actin to increase the rate of exchange of actin-bound adenosine
5-prime-triphosphate. Biochemistry 19: 5359-5362, 1980.
7. Theriot, J. A.; Mitchison, T. J.: The three faces of profilin. Cell 75:
835-838, 1993.
8. Vojtek, A.; Haarer, B.; Field, J.; Gerst, J.; Pollard, T. D.; Brown,
S.; Wigler, M.: Evidence for a functional link between profilin and
CAP in the yeast S. cerevisiae. Cell 66: 497-505, 1991.
9. Witke, W.; Sutherland, J. D.; Sharpe, A.; Arai, M.; Kwiatkowski,
D. J.: Profilin I is essential for cell survival and cell division
in early mouse development. Proc. Nat. Acad. Sci. 98: 3832-3836,
2001.
10. Wu, C.-H.; Fallini, C.; Ticozzi, N.; Keagle, P. J.; Sapp, P. C.;
Piotrowska, K.; Lowe, P.; Koppers, M.; McKenna-Yasek, D.; Baron, D.
M.; Kost, J. E.; Gonzalez-Perez, P.; and 26 others: Mutations in
the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature 488:
499-503, 2012.
11. Yarovinsky, F.; Zhang, D.; Andersen, J. F.; Bannenberg, G. L.;
Serhan, C. N.; Hayden, M. S.; Hieny, S.; Sutterwala, F. S.; Flavell,
R. A.; Ghosh, S.; Sher, A.: TLR11 activation of dendritic cells by
a protozoan profilin-like protein. Science 308: 1626-1629, 2005.
*FIELD* CN
Ada Hamosh - updated: 9/5/2012
Ada Hamosh - updated: 2/6/2006
Victor A. McKusick - updated: 4/17/2001
Victor A. McKusick - updated: 8/18/1997
*FIELD* CD
Victor A. McKusick: 4/23/1988
*FIELD* ED
alopez: 09/06/2012
terry: 9/5/2012
alopez: 2/6/2006
mcapotos: 5/8/2001
mcapotos: 4/24/2001
terry: 4/17/2001
dkim: 7/24/1998
terry: 8/18/1997
mimadm: 2/25/1995
carol: 4/28/1994
warfield: 3/31/1994
carol: 12/16/1993
carol: 10/26/1993
supermim: 3/16/1992
*RECORD*
*FIELD* NO
176610
*FIELD* TI
*176610 PROFILIN 1; PFN1
*FIELD* TX
DESCRIPTION
Profilin-1 is a 140-amino acid protein and major growth regulator of
read morefilamentous (F)-actin through its binding of monomeric (G)-actin
(Mockrin and Korn, 1980).
CLONING
Profilin is a ubiquitous 12- to 15-kD protein which inhibits the
polymerization of actin. It is thought to function by complexing with
unpolymerized actin in vivo. Dissociation of the profilin-actin complex
is caused by binding of phosphatidylinositol 4,5-bisphosphate to
profilin. Ampe et al. (1988) described the amino acid sequence of human
platelet profilin and found it to have 95% homology to the sequence of
calf spleen profilin.
GENE FUNCTION
Goldschmidt-Clermont and Janmey (1991) reviewed the function of
profilin, partly on the basis of work in the S. cerevisiae, homolog, PFY
(Vojtek et al., 1991). Theriot and Mitchison (1993) reviewed the
multiple functions of profilin.
MAPPING
By Southern blot analysis of somatic cell hybrid DNA, Kwiatkowski and
Bruns (1988) found that at least 4 dispersed genetic loci in the human
genome hybridize with the profilin cDNA as well as the untranslated
region fragments, suggesting that several of these loci represent
pseudogenes of recent evolutionary origin. Chromosomes 1, 6, 13, and 17
were implicated. In addition, 5-prime and 3-prime untranslated regions
were found to be conserved between humans and rodents, implying a
functional role for these regions of the profilin gene. Kwiatkowski et
al. (1990) localized the functional profilin gene to 17p13 by analysis
of somatic cell hybrids and by in situ hybridization. By study of
patients with deletions and by use of somatic cell hybrids containing a
deleted chromosome 17, Kwiatkowski et al. (1990) sublocalized the PFN1
gene to 17p13.3. This is the same region as that deleted in the
Miller-Dieker syndrome (MDLS; 247200). They found that the gene indeed
was deleted in some patients with MDLS but that other patients had
smaller deletions not affecting the profilin locus. Thus, a single
allelic deletion of the profilin locus may contribute to the clinical
phenotype of MDLS in some patients but does not play a major role in the
essential phenotype.
In the mouse, Klingenspor et al. (1997) mapped the Pfn1 gene to
chromosome 11 and a profilin-1 related sequence to chromosome 15.
MOLECULAR GENETICS
Wu et al. (2012) identified 4 different mutations in the PFN1 gene in 7
of 274 familial ALS cases. One mutation (E117G; 176610.0004), was found
in 3 of 1,090 ALS cases and 3 of 7,560 controls. Wu et al. (2012)
performed in vitro assays and showed that mutant PFN1 produces
ubiquitinated, insoluble aggregates in transfected cells. In many cases
the aggregates contained the ALS-associated protein TDP43 (605078). The
E117G mutation (176610.0004) displayed a pattern more similar to
wildtype PFN1, with most of the expressed protein in the soluble
fraction. Wu et al. (2012) found that mutant PFN1 inhibited axon
outgrowth. Wu et al. (2012) concluded that mutations in the PFN1 gene
account for approximately 1 to 2% of familial ALS and suggested that
disruption of cytoskeletal pathways contribute importantly to ALS
pathogenicity.
ANIMAL MODEL
To examine the function of profilin-1 in vivo, Witke et al. (2001)
generated Pfn1 knockout mice. Homozygotes were not viable; they died as
early as the 2-cell stage, and no homozygous knockout blastocysts were
detectable. Adult heterozygotes showed a 50% reduction in profilin-1
expression with no apparent impairment of cell function. However,
heterozygous embryos had reduced survival during embryogenesis compared
with wildtype. Although weakly expressed in early embryos, profilin-2
(176590) could not compensate for lack of profilin-1. Their results
indicated that mouse profilin-1 is an essential protein that has
dosage-dependent effects on cell division and survival during
embryogenesis.
Yarovinsky et al. (2005) identified a profilin-like molecule from the
protozoan parasite Toxoplasma gondii that generates a potent IL12 (see
161560) response in murine dendritic cells that is dependent on MyD88
(602170). T. gondii profilin activates dendritic cells through TLR11
(606270) and is the first chemically defined ligand for this toll-like
receptor. Moreover, TLR11 is required in vivo for parasite-induced IL12
production and optimal resistance to infection, thereby establishing a
role for the receptor in host recognition of protozoan pathogens.
*FIELD* AV
.0001
AMYOTROPHIC LATERAL SCLEROSIS 18
PFN1, CYS71GLY
In 3 families segregating autosomal dominant ALS18 (614808), Wu et al.
(2012) identified a T-to-G transversion at nucleotide 347 of the PFN1
gene, resulting in a cysteine-to-glycine substitution at codon 71
(C71G). In family 1, all 4 affected members for which DNA was available
possessed the C71G variant. A single obligate carrier of the C71G
variant did not develop disease, but she died before the average age of
onset of this family (50.0 +/- 6.6 years). All unaffected family members
displayed the wildtype genotype. This mutation was subsequently
identified in 2 other families. In family 3, the mutation was detected
in 3 other affected family members. A single unaffected member of the
family whose age was in the mid-forties was found to be a mutation
carrier. The average age of onset in this family was 41.1 +/- 4.3 years
for those definitively affected. Haplotype analysis suggested that the
C71G variant derives from a single ancestral mutation. This mutation was
not observed among 7,560 control samples (15,120 alleles).
.0002
AMYOTROPHIC LATERAL SCLEROSIS 18
PFN1, MET114THR
In 2 families (families 2 and 4) segregating autosomal dominant ALS18
(614808), Wu et al. (2012) identified a T-to-C transition at nucleotide
477 of the PFN1 gene, resulting in a methionine-to-threonine
substitution at codon 114 (M114T). In family 2, all 8 affected members
for whom DNA was available carried the mutation, and on the basis of
genotype in spouse and progeny, Wu et al. (2012) were able to confirm
that a ninth affected family member also carried the mutation. Of 7
unaffected members, 5 did not carry the M114T variant. One unaffected
mutation carrier was aged in the mid-forties and a second obligate
carrier was asymptomatic into the seventies, suggesting high but
incomplete penetrance of this mutation. The average age of onset for
family 2 was 41.9 +/- 5.3 years and for family 4 it was 52.0 +/- 13.1
years. This mutation was not observed among 7,560 control samples
(15,120 alleles).
.0003
AMYOTROPHIC LATERAL SCLEROSIS 18
PFN1, GLY118VAL
In an individual from a family with a parent-child segregating autosomal
dominant ALS18 (614808), Wu et al. (2012) identified a G-to-T
transversion at nucleotide 489 of the PFN1 gene, resulting in a
glycine-to-valine substitution at codon 118 (G118V). This mutation was
not observed among 7,560 control samples (15,120 alleles). The glycine
at this position is invariant down to zebrafish.
.0004
AMYOTROPHIC LATERAL SCLEROSIS 18
PFN1, GLU117GLY
In one family with autosomal dominant ALS (ALS18; 614808) with
incomplete penetrance, Wu et al. (2012) identified a 2-basepair
substitution, AA to GT, at nucleotides 46 and 47 of the PFN1 gene,
resulting in a glutamic acid-to-glycine substitution at codon 117
(E117G). This mutation was subsequently identified in 2 sporadic ALS
patients among 816 sequenced. Overall, this mutation was identified in 3
of 1,090 ALS cases and 3 of 7,560 control samples (2.75 x 10(-3) vs 3.97
x 10(-4); P = 0.030, two-tailed Fisher's exact test). Wu et al. (2012)
suggested that, while it could be argued that the E117G variant is
nonpathogenic, more likely it is less pathogenic than the other 3
mutations (C71G; 176610.0001, M114T; 176610.0002, and G118V;
176610.0003) identified in the PFN1 gene to that time. While Western
blot analysis of the soluble and insoluble fractions of cells
transfected with wildtype and mutant PFN1 proteins detected a
considerable portion of the C71G, M114T, and G118V mutant proteins in
the insoluble fraction, the E117G mutation displayed a pattern more
similar to wildtype PFN1, with most of the expressed protein in the
soluble fraction. The glu at position 117 is invariant down to
zebrafish.
*FIELD* RF
1. Ampe, C.; Markey, F.; Lindberg, U.; Vandekerckhove, J.: The primary
structure of human platelet profilin: reinvestigation of the calf
spleen profilin sequence. FEBS Lett. 228: 17-21, 1988.
2. Goldschmidt-Clermont, P. J.; Janmey, P. A.: Profilin, a weak CAP
for actin and RAS. Cell 66: 419-421, 1991.
3. Klingenspor, M.; Bodnar, J.; Xia, Y.-R.; Welch, C.; Lusis, A. J.;
Reue, K.: Localization of profilin-1 (Pfn1) and a related sequence
(Pfn1-rs) to mouse chromosomes 11 and 15 respectively. Mammalian
Genome 8: 539-541, 1997.
4. Kwiatkowski, D. J.; Aklog, L.; Ledbetter, D. H.; Morton, C. C.
: Identification of the functional profilin gene, its localization
to chromosome subband 17p13.3, and demonstration of its deletion in
some patients with Miller-Dieker syndrome. Am. J. Hum. Genet. 46:
559-567, 1990.
5. Kwiatkowski, D. J.; Bruns, G. A. P.: Human profilin: molecular
cloning, sequence comparison, and chromosomal analysis. J. Biol.
Chem. 263: 5910-5915, 1988.
6. Mockrin, S. C.; Korn, E. D.: Acanthamoeba profilin interacts with
G-actin to increase the rate of exchange of actin-bound adenosine
5-prime-triphosphate. Biochemistry 19: 5359-5362, 1980.
7. Theriot, J. A.; Mitchison, T. J.: The three faces of profilin. Cell 75:
835-838, 1993.
8. Vojtek, A.; Haarer, B.; Field, J.; Gerst, J.; Pollard, T. D.; Brown,
S.; Wigler, M.: Evidence for a functional link between profilin and
CAP in the yeast S. cerevisiae. Cell 66: 497-505, 1991.
9. Witke, W.; Sutherland, J. D.; Sharpe, A.; Arai, M.; Kwiatkowski,
D. J.: Profilin I is essential for cell survival and cell division
in early mouse development. Proc. Nat. Acad. Sci. 98: 3832-3836,
2001.
10. Wu, C.-H.; Fallini, C.; Ticozzi, N.; Keagle, P. J.; Sapp, P. C.;
Piotrowska, K.; Lowe, P.; Koppers, M.; McKenna-Yasek, D.; Baron, D.
M.; Kost, J. E.; Gonzalez-Perez, P.; and 26 others: Mutations in
the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature 488:
499-503, 2012.
11. Yarovinsky, F.; Zhang, D.; Andersen, J. F.; Bannenberg, G. L.;
Serhan, C. N.; Hayden, M. S.; Hieny, S.; Sutterwala, F. S.; Flavell,
R. A.; Ghosh, S.; Sher, A.: TLR11 activation of dendritic cells by
a protozoan profilin-like protein. Science 308: 1626-1629, 2005.
*FIELD* CN
Ada Hamosh - updated: 9/5/2012
Ada Hamosh - updated: 2/6/2006
Victor A. McKusick - updated: 4/17/2001
Victor A. McKusick - updated: 8/18/1997
*FIELD* CD
Victor A. McKusick: 4/23/1988
*FIELD* ED
alopez: 09/06/2012
terry: 9/5/2012
alopez: 2/6/2006
mcapotos: 5/8/2001
mcapotos: 4/24/2001
terry: 4/17/2001
dkim: 7/24/1998
terry: 8/18/1997
mimadm: 2/25/1995
carol: 4/28/1994
warfield: 3/31/1994
carol: 12/16/1993
carol: 10/26/1993
supermim: 3/16/1992
MIM
614808
*RECORD*
*FIELD* NO
614808
*FIELD* TI
#614808 AMYOTROPHIC LATERAL SCLEROSIS 18; ALS18
*FIELD* TX
A number sign (#) is used with this entry because amyotrophic lateral
read moresclerosis-18 (ALS18) is caused by heterozygous mutation in the PFN1 gene
(176610) on chromosome 17p.
For a phenotypic description and a discussion of genetic heterogeneity
of amyotrophic lateral sclerosis (ALS), see ALS1 (105400).
CLINICAL FEATURES
Among 22 cases of ALS that resulted from mutations in PFN1 (ALS18), all
displayed limb onset. Given that bulbar onset represents approximately
25% of ALS cases, Wu et al. (2012) proposed that their observation
suggests a common clinical phenotype among patients with PFN1 mutations.
The age of onset for familial ALS18 cases was 44.8 +/- 7.4 years.
MAPPING
Wu et al. (2012) performed exome capture followed by deep sequencing on
2 large ALS families of Caucasian (family 1) and Sephardic Jewish
(family 2) origin. Both displayed a dominant inheritance mode and were
negative for known ALS-causing mutations. For each family, 2 affected
members with maximum genetic distance were selected for exome
sequencing. More than 150X coverage was achieved. Using a variety of
filters, Wu et al. (2012) were able to reduce the number of candidate
mutations to 2 within family 1 and 3 within family 2.
MOLECULAR GENETICS
Wu et al. (2012) identified 4 different missense mutations in 7 families
segregating autosomal dominant ALS. Sequencing of the PFN coding region
in 816 sporadic ALS samples identified 2 samples containing the E117G
mutation (176610.0004). In each of the mutations, the altered amino acid
was evolutionarily conserved down to the level of zebrafish.
*FIELD* RF
1. Wu, C.-H.; Fallini, C.; Ticozzi, N.; Keagle, P. J.; Sapp, P. C.;
Piotrowska, K.; Lowe, P.; Koppers, M.; McKenna-Yasek, D.; Baron, D.
M.; Kost, J. E.; Gonzalez-Perez, P.; and 26 others: Mutations in
the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature 488:
499-503, 2012.
*FIELD* CD
Ada Hamosh: 9/5/2012
*FIELD* ED
alopez: 09/06/2012
*RECORD*
*FIELD* NO
614808
*FIELD* TI
#614808 AMYOTROPHIC LATERAL SCLEROSIS 18; ALS18
*FIELD* TX
A number sign (#) is used with this entry because amyotrophic lateral
read moresclerosis-18 (ALS18) is caused by heterozygous mutation in the PFN1 gene
(176610) on chromosome 17p.
For a phenotypic description and a discussion of genetic heterogeneity
of amyotrophic lateral sclerosis (ALS), see ALS1 (105400).
CLINICAL FEATURES
Among 22 cases of ALS that resulted from mutations in PFN1 (ALS18), all
displayed limb onset. Given that bulbar onset represents approximately
25% of ALS cases, Wu et al. (2012) proposed that their observation
suggests a common clinical phenotype among patients with PFN1 mutations.
The age of onset for familial ALS18 cases was 44.8 +/- 7.4 years.
MAPPING
Wu et al. (2012) performed exome capture followed by deep sequencing on
2 large ALS families of Caucasian (family 1) and Sephardic Jewish
(family 2) origin. Both displayed a dominant inheritance mode and were
negative for known ALS-causing mutations. For each family, 2 affected
members with maximum genetic distance were selected for exome
sequencing. More than 150X coverage was achieved. Using a variety of
filters, Wu et al. (2012) were able to reduce the number of candidate
mutations to 2 within family 1 and 3 within family 2.
MOLECULAR GENETICS
Wu et al. (2012) identified 4 different missense mutations in 7 families
segregating autosomal dominant ALS. Sequencing of the PFN coding region
in 816 sporadic ALS samples identified 2 samples containing the E117G
mutation (176610.0004). In each of the mutations, the altered amino acid
was evolutionarily conserved down to the level of zebrafish.
*FIELD* RF
1. Wu, C.-H.; Fallini, C.; Ticozzi, N.; Keagle, P. J.; Sapp, P. C.;
Piotrowska, K.; Lowe, P.; Koppers, M.; McKenna-Yasek, D.; Baron, D.
M.; Kost, J. E.; Gonzalez-Perez, P.; and 26 others: Mutations in
the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature 488:
499-503, 2012.
*FIELD* CD
Ada Hamosh: 9/5/2012
*FIELD* ED
alopez: 09/06/2012