Full text data of DIAPH1
DIAPH1
(DIAP1)
[Confidence: high (present in two of the MS resources)]
Protein diaphanous homolog 1 (Diaphanous-related formin-1; DRF1)
Protein diaphanous homolog 1 (Diaphanous-related formin-1; DRF1)
hRBCD
IPI00030876
IPI00030876 Diaphanous 1 actin binding, Rho GTPase binding, actin cytoskeleton organization and biogenesis, cell organization soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a found at its expected molecular weight found at molecular weight
IPI00030876 Diaphanous 1 actin binding, Rho GTPase binding, actin cytoskeleton organization and biogenesis, cell organization soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a found at its expected molecular weight found at molecular weight
UniProt
O60610
ID DIAP1_HUMAN Reviewed; 1272 AA.
AC O60610; A6NF18; B7ZKW2; E9PEZ2; Q17RN4; Q59FH8; Q9UC76;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
read moreDT 25-NOV-2008, sequence version 2.
DT 22-JAN-2014, entry version 137.
DE RecName: Full=Protein diaphanous homolog 1;
DE AltName: Full=Diaphanous-related formin-1;
DE Short=DRF1;
GN Name=DIAPH1; Synonyms=DIAP1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RX PubMed=9360932; DOI=10.1126/science.278.5341.1315;
RA Lynch E.D., Lee M.K., Morrow J.E., Welcsh P.L., Leon P.E., King M.-C.;
RT "Nonsyndromic deafness DFNA1 associated with mutation of a human
RT homolog of the Drosophila gene diaphanous.";
RL Science 278:1315-1318(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Brain;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.,
RA Ohara O., Nagase T., Kikuno R.F.;
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T.,
RA Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M.,
RA Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K.,
RA Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C.,
RA Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M.,
RA Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A.,
RA Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M.,
RA Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S.,
RA Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3).
RC TISSUE=Heart, and Lung;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 227-841 (ISOFORM 2).
RC TISSUE=Ovarian carcinoma;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP PROTEIN SEQUENCE OF 560-580 AND 855-869, AND INTERACTION WITH DCAF7.
RX PubMed=16887337; DOI=10.1016/j.jdermsci.2006.06.001;
RA Morita K., Lo Celso C., Spencer-Dene B., Zouboulis C.C., Watt F.M.;
RT "HAN11 binds mDia1 and controls GLI1 transcriptional activity.";
RL J. Dermatol. Sci. 44:11-20(2006).
RN [7]
RP PROTEIN SEQUENCE OF 742-801 AND 1145-1169.
RC TISSUE=Platelet;
RX PubMed=7737110;
RA Reinhard M., Giehl K., Abel K., Haffner C., Jarchau T., Hoppe V.,
RA Jockusch B.M., Walter U.;
RT "The proline-rich focal adhesion and microfilament protein VASP is a
RT ligand for profilins.";
RL EMBO J. 14:1583-1589(1995).
RN [8]
RP UBIQUITINATION [LARGE SCALE ANALYSIS] AT LYS-486, 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 [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-22, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-22, 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 [11]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-1057 AND LYS-1103, 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 [12]
RP FUNCTION.
RX PubMed=20937854; DOI=10.1073/pnas.1000975107;
RA Zaoui K., Benseddik K., Daou P., Salaun D., Badache A.;
RT "ErbB2 receptor controls microtubule capture by recruiting ACF7 to the
RT plasma membrane of migrating cells.";
RL Proc. Natl. Acad. Sci. U.S.A. 107:18517-18522(2010).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-22, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [14]
RP FUNCTION.
RX PubMed=21834987; DOI=10.1186/1741-7007-9-54;
RA Bai S.W., Herrera-Abreu M.T., Rohn J.L., Racine V., Tajadura V.,
RA Suryavanshi N., Bechtel S., Wiemann S., Baum B., Ridley A.J.;
RT "Identification and characterization of a set of conserved and new
RT regulators of cytoskeletal organisation, cell morphology and
RT migration.";
RL BMC Biol. 9:54-54(2011).
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 ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
CC -!- FUNCTION: Acts in a Rho-dependent manner to recruit PFY1 to the
CC membrane. Required for the assembly of F-actin structures, such as
CC actin cables and stress fibers. Nucleates actin filaments. Binds
CC to the barbed end of the actin filament and slows down actin
CC polymerization and depolymerization. Required for cytokinesis, and
CC transcriptional activation of the serum response factor. DFR
CC proteins couple Rho and Src tyrosine kinase during signaling and
CC the regulation of actin dynamics. Functions as a scaffold protein
CC for MAPRE1 and APC to stabilize microtubules and promote cell
CC migration (By similarity). Has neurite outgrowth promoting
CC activity (By similarity). In hear cells, it may play a role in the
CC regulation of actin polymerization in hair cells. The MEMO1-RHOA-
CC DIAPH1 signaling pathway plays an important role in ERBB2-
CC dependent stabilization of microtubules at the cell cortex. It
CC controls the localization of APC and CLASP2 to the cell membrane,
CC via the regulation of GSK3B activity. In turn, membrane-bound APC
CC allows the localization of the MACF1 to the cell membrane, which
CC is required for microtubule capture and stabilization. Plays a
CC role in the regulation of cell morphology and cytoskeletal
CC organization. Required in the control of cell shape.
CC -!- SUBUNIT: Homodimer. Interacts with the GTP-bound form of RHOA.
CC Interacts with RHOC, PFY1, MAPRE1, BAIAP2 and APC. Interacts with
CC SCAI (By similarity). Interacts with DCAF7, via FH2 domain.
CC Interacts with NCDN (By similarity).
CC -!- INTERACTION:
CC Q9Q2G4:ORF (xeno); NbExp=2; IntAct=EBI-3959709, EBI-6248094;
CC P49593:PPM1F; NbExp=3; IntAct=EBI-3959709, EBI-719945;
CC P61586:RHOA; NbExp=3; IntAct=EBI-3959709, EBI-446668;
CC -!- SUBCELLULAR LOCATION: Cell membrane. Cell projection, ruffle
CC membrane. Cytoplasm, cytoskeleton. Note=Membrane ruffles,
CC especially at the tip of ruffles, of motile cells.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=O60610-1; Sequence=Displayed;
CC Name=2;
CC IsoId=O60610-2; Sequence=VSP_035870, VSP_035871, VSP_035872;
CC Name=3;
CC IsoId=O60610-3; Sequence=VSP_035870;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Expressed in brain, heart, placenta, lung,
CC kidney, pancreas, liver, skeletal muscle and cochlea.
CC -!- DOMAIN: The DAD domain regulates activation via by an
CC autoinhibitory interaction with the GBD/FH3 domain. This
CC autoinhibition is released upon competitive binding of an
CC activated GTPase. The release of DAD allows the FH2 domain to then
CC nucleate and elongate nonbranched actin filaments (By similarity).
CC -!- DISEASE: Deafness, autosomal dominant, 1 (DFNA1) [MIM:124900]: A
CC form of non-syndromic sensorineural hearing loss. Sensorineural
CC deafness results from damage to the neural receptors of the inner
CC ear, the nerve pathways to the brain, or the area of the brain
CC that receives sound information. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the formin homology family. Diaphanous
CC subfamily.
CC -!- SIMILARITY: Contains 1 DAD (diaphanous autoregulatory) domain.
CC -!- SIMILARITY: Contains 1 FH1 (formin homology 1) domain.
CC -!- SIMILARITY: Contains 1 FH2 (formin homology 2) domain.
CC -!- SIMILARITY: Contains 1 GBD/FH3 (Rho GTPase-binding/formin homology
CC 3) domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAB14533.1; Type=Miscellaneous discrepancy; Note=Intron retention;
CC Sequence=BAD92719.1; Type=Erroneous initiation; Note=Translation N-terminally shortened;
CC -!- WEB RESOURCE: Name=Hereditary hearing loss homepage; Note=Gene
CC page;
CC URL="http://webhost.ua.ac.be/hhh/";
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DR EMBL; AF051782; AAC05373.1; -; mRNA.
DR EMBL; AB209482; BAD92719.1; ALT_INIT; mRNA.
DR EMBL; AC008781; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC117257; AAI17258.1; -; mRNA.
DR EMBL; BC143413; AAI43414.1; -; mRNA.
DR EMBL; AK023345; BAB14533.1; ALT_SEQ; mRNA.
DR RefSeq; NP_001073280.1; NM_001079812.2.
DR RefSeq; NP_005210.3; NM_005219.4.
DR UniGene; Hs.529451; -.
DR ProteinModelPortal; O60610; -.
DR SMR; O60610; 92-461, 762-1215.
DR IntAct; O60610; 18.
DR MINT; MINT-1198324; -.
DR STRING; 9606.ENSP00000381565; -.
DR PhosphoSite; O60610; -.
DR OGP; O60610; -.
DR PaxDb; O60610; -.
DR PRIDE; O60610; -.
DR DNASU; 1729; -.
DR Ensembl; ENST00000389057; ENSP00000373709; ENSG00000131504.
DR Ensembl; ENST00000398557; ENSP00000381565; ENSG00000131504.
DR GeneID; 1729; -.
DR KEGG; hsa:1729; -.
DR UCSC; uc003llb.4; human.
DR CTD; 1729; -.
DR GeneCards; GC05M140875; -.
DR HGNC; HGNC:2876; DIAPH1.
DR HPA; HPA004916; -.
DR MIM; 124900; phenotype.
DR MIM; 602121; gene.
DR neXtProt; NX_O60610; -.
DR Orphanet; 90635; Autosomal dominant nonsyndromic sensorineural deafness type DFNA.
DR PharmGKB; PA27333; -.
DR eggNOG; NOG149898; -.
DR HOGENOM; HOG000293231; -.
DR HOVERGEN; HBG051357; -.
DR KO; K05740; -.
DR ChiTaRS; DIAPH1; human.
DR GeneWiki; DIAPH1; -.
DR GenomeRNAi; 1729; -.
DR NextBio; 6997; -.
DR PRO; PR:O60610; -.
DR ArrayExpress; O60610; -.
DR Bgee; O60610; -.
DR CleanEx; HS_DIAPH1; -.
DR Genevestigator; O60610; -.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-KW.
DR GO; GO:0072686; C:mitotic spindle; IDA:BHF-UCL.
DR GO; GO:0043005; C:neuron projection; IEA:Ensembl.
DR GO; GO:0032587; C:ruffle membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005102; F:receptor binding; NAS:ProtInc.
DR GO; GO:0030041; P:actin filament polymerization; IEA:Ensembl.
DR GO; GO:0071420; P:cellular response to histamine; IMP:BHF-UCL.
DR GO; GO:0007010; P:cytoskeleton organization; IMP:UniProtKB.
DR GO; GO:0031175; P:neuron projection development; IEA:Ensembl.
DR GO; GO:0035372; P:protein localization to microtubule; IMP:BHF-UCL.
DR GO; GO:0008360; P:regulation of cell shape; IMP:UniProtKB.
DR GO; GO:0032886; P:regulation of microtubule-based process; IMP:UniProtKB.
DR GO; GO:0051279; P:regulation of release of sequestered calcium ion into cytosol; IMP:BHF-UCL.
DR GO; GO:0007605; P:sensory perception of sound; TAS:ProtInc.
DR InterPro; IPR016024; ARM-type_fold.
DR InterPro; IPR014767; Diaphanous_autoregulatory.
DR InterPro; IPR010465; Drf_DAD.
DR InterPro; IPR015425; FH2_Formin.
DR InterPro; IPR010472; FH3_dom.
DR InterPro; IPR027653; Formin_Diaph1.
DR InterPro; IPR009408; Formin_homology_1.
DR InterPro; IPR010473; GTPase-bd.
DR InterPro; IPR014768; GTPase-bd/formin_homology_3.
DR PANTHER; PTHR23213:SF17; PTHR23213:SF17; 1.
DR Pfam; PF06345; Drf_DAD; 1.
DR Pfam; PF06346; Drf_FH1; 1.
DR Pfam; PF06367; Drf_FH3; 1.
DR Pfam; PF06371; Drf_GBD; 1.
DR Pfam; PF02181; FH2; 1.
DR SMART; SM00498; FH2; 1.
DR SUPFAM; SSF48371; SSF48371; 1.
DR PROSITE; PS51231; DAD; 1.
DR PROSITE; PS51444; FH2; 1.
DR PROSITE; PS51232; GBD_FH3; 1.
PE 1: Evidence at protein level;
KW Acetylation; Actin-binding; Alternative splicing; Cell membrane;
KW Cell projection; Coiled coil; Complete proteome; Cytoplasm;
KW Cytoskeleton; Deafness; Direct protein sequencing; Hearing;
KW Isopeptide bond; Membrane; Non-syndromic deafness; Phosphoprotein;
KW Reference proteome; Repeat; Ubl conjugation.
FT CHAIN 1 1272 Protein diaphanous homolog 1.
FT /FTId=PRO_0000194893.
FT DOMAIN 84 449 GBD/FH3.
FT DOMAIN 583 764 FH1.
FT DOMAIN 769 1171 FH2.
FT DOMAIN 1194 1222 DAD.
FT COILED 468 572 Potential.
FT COILED 1039 1196 Potential.
FT COMPBIAS 1213 1216 Arg/Lys-rich (basic).
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 22 22 Phosphoserine.
FT MOD_RES 1057 1057 N6-acetyllysine.
FT MOD_RES 1103 1103 N6-acetyllysine.
FT MOD_RES 1121 1121 Phosphotyrosine (By similarity).
FT CROSSLNK 486 486 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin).
FT VAR_SEQ 40 48 Missing (in isoform 2 and isoform 3).
FT /FTId=VSP_035870.
FT VAR_SEQ 621 632 Missing (in isoform 2).
FT /FTId=VSP_035871.
FT VAR_SEQ 826 828 Missing (in isoform 2).
FT /FTId=VSP_035872.
FT CONFLICT 13 13 G -> E (in Ref. 1; AAC05373).
FT CONFLICT 609 609 Missing (in Ref. 4; AAI17258).
FT CONFLICT 1156 1156 R -> A (in Ref. 7; AA sequence).
FT CONFLICT 1157 1157 E -> K (in Ref. 1; AAC05373 and 7; AA
FT sequence).
SQ SEQUENCE 1272 AA; 141347 MW; 9C8273DE4748564F CRC64;
MEPPGGSLGP GRGTRDKKKG RSPDELPSAG GDGGKSKKFT LKRLMADELE RFTSMRIKKE
KEKPNSAHRN SSASYGDDPT AQSLQDVSDE QVLVLFEQML LDMNLNEEKQ QPLREKDIII
KREMVSQYLY TSKAGMSQKE SSKSAMMYIQ ELRSGLRDMP LLSCLESLRV SLNNNPVSWV
QTFGAEGLAS LLDILKRLHD EKEETAGSYD SRNKHEIIRC LKAFMNNKFG IKTMLETEEG
ILLLVRAMDP AVPNMMIDAA KLLSALCILP QPEDMNERVL EAMTERAEMD EVERFQPLLD
GLKSGTTIAL KVGCLQLINA LITPAEELDF RVHIRSELMR LGLHQVLQDL REIENEDMRV
QLNVFDEQGE EDSYDLKGRL DDIRMEMDDF NEVFQILLNT VKDSKAEPHF LSILQHLLLV
RNDYEARPQY YKLIEECISQ IVLHKNGADP DFKCRHLQIE IEGLIDQMID KTKVEKSEAK
AAELEKKLDS ELTARHELQV EMKKMESDFE QKLQDLQGEK DALHSEKQQI ATEKQDLEAE
VSQLTGEVAK LTKELEDAKK EMASLSAAAI TVPPSVPSRA PVPPAPPLPG DSGTIIPPPP
APGDSTTPPP PPPPPPPPPP LPGGVCISSP PSLPGGTAIS PPPPLSGDAT IPPPPPLPEG
VGIPSPSSLP GGTAIPPPPP LPGSARIPPP PPPLPGSAGI PPPPPPLPGE AGMPPPPPPL
PGGPGIPPPP PFPGGPGIPP PPPGMGMPPP PPFGFGVPAA PVLPFGLTPK KLYKPEVQLR
RPNWSKLVAE DLSQDCFWTK VKEDRFENNE LFAKLTLTFS AQTKTSKAKK DQEGGEEKKS
VQKKKVKELK VLDSKTAQNL SIFLGSFRMP YQEIKNVILE VNEAVLTESM IQNLIKQMPE
PEQLKMLSEL KDEYDDLAES EQFGVVMGTV PRLRPRLNAI LFKLQFSEQV ENIKPEIVSV
TAACEELRKS ESFSNLLEIT LLVGNYMNAG SRNAGAFGFN ISFLCKLRDT KSTDQKMTLL
HFLAELCEND YPDVLKFPDE LAHVEKASRV SAENLQKNLD QMKKQISDVE RDVQNFPAAT
DEKDKFVEKM TSFVKDAQEQ YNKLRMMHSN METLYKELGE YFLFDPKKLS VEEFFMDLHN
FRNMFLQAVK ENQKRRETEE KMRRAKLAKE KAEKERLEKQ QKREQLIDMN AEGDETGVMD
SLLEALQSGA AFRRKRGPRQ ANRKAGCAVT SLLASELTKD DAMAAVPAKV SKNSETFPTI
LEEAKELVGR AS
//
ID DIAP1_HUMAN Reviewed; 1272 AA.
AC O60610; A6NF18; B7ZKW2; E9PEZ2; Q17RN4; Q59FH8; Q9UC76;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
read moreDT 25-NOV-2008, sequence version 2.
DT 22-JAN-2014, entry version 137.
DE RecName: Full=Protein diaphanous homolog 1;
DE AltName: Full=Diaphanous-related formin-1;
DE Short=DRF1;
GN Name=DIAPH1; Synonyms=DIAP1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RX PubMed=9360932; DOI=10.1126/science.278.5341.1315;
RA Lynch E.D., Lee M.K., Morrow J.E., Welcsh P.L., Leon P.E., King M.-C.;
RT "Nonsyndromic deafness DFNA1 associated with mutation of a human
RT homolog of the Drosophila gene diaphanous.";
RL Science 278:1315-1318(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Brain;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.,
RA Ohara O., Nagase T., Kikuno R.F.;
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T.,
RA Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M.,
RA Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K.,
RA Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C.,
RA Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M.,
RA Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A.,
RA Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M.,
RA Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S.,
RA Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3).
RC TISSUE=Heart, and Lung;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 227-841 (ISOFORM 2).
RC TISSUE=Ovarian carcinoma;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP PROTEIN SEQUENCE OF 560-580 AND 855-869, AND INTERACTION WITH DCAF7.
RX PubMed=16887337; DOI=10.1016/j.jdermsci.2006.06.001;
RA Morita K., Lo Celso C., Spencer-Dene B., Zouboulis C.C., Watt F.M.;
RT "HAN11 binds mDia1 and controls GLI1 transcriptional activity.";
RL J. Dermatol. Sci. 44:11-20(2006).
RN [7]
RP PROTEIN SEQUENCE OF 742-801 AND 1145-1169.
RC TISSUE=Platelet;
RX PubMed=7737110;
RA Reinhard M., Giehl K., Abel K., Haffner C., Jarchau T., Hoppe V.,
RA Jockusch B.M., Walter U.;
RT "The proline-rich focal adhesion and microfilament protein VASP is a
RT ligand for profilins.";
RL EMBO J. 14:1583-1589(1995).
RN [8]
RP UBIQUITINATION [LARGE SCALE ANALYSIS] AT LYS-486, 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 [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-22, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-22, 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 [11]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-1057 AND LYS-1103, 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 [12]
RP FUNCTION.
RX PubMed=20937854; DOI=10.1073/pnas.1000975107;
RA Zaoui K., Benseddik K., Daou P., Salaun D., Badache A.;
RT "ErbB2 receptor controls microtubule capture by recruiting ACF7 to the
RT plasma membrane of migrating cells.";
RL Proc. Natl. Acad. Sci. U.S.A. 107:18517-18522(2010).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-22, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [14]
RP FUNCTION.
RX PubMed=21834987; DOI=10.1186/1741-7007-9-54;
RA Bai S.W., Herrera-Abreu M.T., Rohn J.L., Racine V., Tajadura V.,
RA Suryavanshi N., Bechtel S., Wiemann S., Baum B., Ridley A.J.;
RT "Identification and characterization of a set of conserved and new
RT regulators of cytoskeletal organisation, cell morphology and
RT migration.";
RL BMC Biol. 9:54-54(2011).
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 ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
CC -!- FUNCTION: Acts in a Rho-dependent manner to recruit PFY1 to the
CC membrane. Required for the assembly of F-actin structures, such as
CC actin cables and stress fibers. Nucleates actin filaments. Binds
CC to the barbed end of the actin filament and slows down actin
CC polymerization and depolymerization. Required for cytokinesis, and
CC transcriptional activation of the serum response factor. DFR
CC proteins couple Rho and Src tyrosine kinase during signaling and
CC the regulation of actin dynamics. Functions as a scaffold protein
CC for MAPRE1 and APC to stabilize microtubules and promote cell
CC migration (By similarity). Has neurite outgrowth promoting
CC activity (By similarity). In hear cells, it may play a role in the
CC regulation of actin polymerization in hair cells. The MEMO1-RHOA-
CC DIAPH1 signaling pathway plays an important role in ERBB2-
CC dependent stabilization of microtubules at the cell cortex. It
CC controls the localization of APC and CLASP2 to the cell membrane,
CC via the regulation of GSK3B activity. In turn, membrane-bound APC
CC allows the localization of the MACF1 to the cell membrane, which
CC is required for microtubule capture and stabilization. Plays a
CC role in the regulation of cell morphology and cytoskeletal
CC organization. Required in the control of cell shape.
CC -!- SUBUNIT: Homodimer. Interacts with the GTP-bound form of RHOA.
CC Interacts with RHOC, PFY1, MAPRE1, BAIAP2 and APC. Interacts with
CC SCAI (By similarity). Interacts with DCAF7, via FH2 domain.
CC Interacts with NCDN (By similarity).
CC -!- INTERACTION:
CC Q9Q2G4:ORF (xeno); NbExp=2; IntAct=EBI-3959709, EBI-6248094;
CC P49593:PPM1F; NbExp=3; IntAct=EBI-3959709, EBI-719945;
CC P61586:RHOA; NbExp=3; IntAct=EBI-3959709, EBI-446668;
CC -!- SUBCELLULAR LOCATION: Cell membrane. Cell projection, ruffle
CC membrane. Cytoplasm, cytoskeleton. Note=Membrane ruffles,
CC especially at the tip of ruffles, of motile cells.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=O60610-1; Sequence=Displayed;
CC Name=2;
CC IsoId=O60610-2; Sequence=VSP_035870, VSP_035871, VSP_035872;
CC Name=3;
CC IsoId=O60610-3; Sequence=VSP_035870;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Expressed in brain, heart, placenta, lung,
CC kidney, pancreas, liver, skeletal muscle and cochlea.
CC -!- DOMAIN: The DAD domain regulates activation via by an
CC autoinhibitory interaction with the GBD/FH3 domain. This
CC autoinhibition is released upon competitive binding of an
CC activated GTPase. The release of DAD allows the FH2 domain to then
CC nucleate and elongate nonbranched actin filaments (By similarity).
CC -!- DISEASE: Deafness, autosomal dominant, 1 (DFNA1) [MIM:124900]: A
CC form of non-syndromic sensorineural hearing loss. Sensorineural
CC deafness results from damage to the neural receptors of the inner
CC ear, the nerve pathways to the brain, or the area of the brain
CC that receives sound information. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the formin homology family. Diaphanous
CC subfamily.
CC -!- SIMILARITY: Contains 1 DAD (diaphanous autoregulatory) domain.
CC -!- SIMILARITY: Contains 1 FH1 (formin homology 1) domain.
CC -!- SIMILARITY: Contains 1 FH2 (formin homology 2) domain.
CC -!- SIMILARITY: Contains 1 GBD/FH3 (Rho GTPase-binding/formin homology
CC 3) domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAB14533.1; Type=Miscellaneous discrepancy; Note=Intron retention;
CC Sequence=BAD92719.1; Type=Erroneous initiation; Note=Translation N-terminally shortened;
CC -!- WEB RESOURCE: Name=Hereditary hearing loss homepage; Note=Gene
CC page;
CC URL="http://webhost.ua.ac.be/hhh/";
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DR EMBL; AF051782; AAC05373.1; -; mRNA.
DR EMBL; AB209482; BAD92719.1; ALT_INIT; mRNA.
DR EMBL; AC008781; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC117257; AAI17258.1; -; mRNA.
DR EMBL; BC143413; AAI43414.1; -; mRNA.
DR EMBL; AK023345; BAB14533.1; ALT_SEQ; mRNA.
DR RefSeq; NP_001073280.1; NM_001079812.2.
DR RefSeq; NP_005210.3; NM_005219.4.
DR UniGene; Hs.529451; -.
DR ProteinModelPortal; O60610; -.
DR SMR; O60610; 92-461, 762-1215.
DR IntAct; O60610; 18.
DR MINT; MINT-1198324; -.
DR STRING; 9606.ENSP00000381565; -.
DR PhosphoSite; O60610; -.
DR OGP; O60610; -.
DR PaxDb; O60610; -.
DR PRIDE; O60610; -.
DR DNASU; 1729; -.
DR Ensembl; ENST00000389057; ENSP00000373709; ENSG00000131504.
DR Ensembl; ENST00000398557; ENSP00000381565; ENSG00000131504.
DR GeneID; 1729; -.
DR KEGG; hsa:1729; -.
DR UCSC; uc003llb.4; human.
DR CTD; 1729; -.
DR GeneCards; GC05M140875; -.
DR HGNC; HGNC:2876; DIAPH1.
DR HPA; HPA004916; -.
DR MIM; 124900; phenotype.
DR MIM; 602121; gene.
DR neXtProt; NX_O60610; -.
DR Orphanet; 90635; Autosomal dominant nonsyndromic sensorineural deafness type DFNA.
DR PharmGKB; PA27333; -.
DR eggNOG; NOG149898; -.
DR HOGENOM; HOG000293231; -.
DR HOVERGEN; HBG051357; -.
DR KO; K05740; -.
DR ChiTaRS; DIAPH1; human.
DR GeneWiki; DIAPH1; -.
DR GenomeRNAi; 1729; -.
DR NextBio; 6997; -.
DR PRO; PR:O60610; -.
DR ArrayExpress; O60610; -.
DR Bgee; O60610; -.
DR CleanEx; HS_DIAPH1; -.
DR Genevestigator; O60610; -.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-KW.
DR GO; GO:0072686; C:mitotic spindle; IDA:BHF-UCL.
DR GO; GO:0043005; C:neuron projection; IEA:Ensembl.
DR GO; GO:0032587; C:ruffle membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005102; F:receptor binding; NAS:ProtInc.
DR GO; GO:0030041; P:actin filament polymerization; IEA:Ensembl.
DR GO; GO:0071420; P:cellular response to histamine; IMP:BHF-UCL.
DR GO; GO:0007010; P:cytoskeleton organization; IMP:UniProtKB.
DR GO; GO:0031175; P:neuron projection development; IEA:Ensembl.
DR GO; GO:0035372; P:protein localization to microtubule; IMP:BHF-UCL.
DR GO; GO:0008360; P:regulation of cell shape; IMP:UniProtKB.
DR GO; GO:0032886; P:regulation of microtubule-based process; IMP:UniProtKB.
DR GO; GO:0051279; P:regulation of release of sequestered calcium ion into cytosol; IMP:BHF-UCL.
DR GO; GO:0007605; P:sensory perception of sound; TAS:ProtInc.
DR InterPro; IPR016024; ARM-type_fold.
DR InterPro; IPR014767; Diaphanous_autoregulatory.
DR InterPro; IPR010465; Drf_DAD.
DR InterPro; IPR015425; FH2_Formin.
DR InterPro; IPR010472; FH3_dom.
DR InterPro; IPR027653; Formin_Diaph1.
DR InterPro; IPR009408; Formin_homology_1.
DR InterPro; IPR010473; GTPase-bd.
DR InterPro; IPR014768; GTPase-bd/formin_homology_3.
DR PANTHER; PTHR23213:SF17; PTHR23213:SF17; 1.
DR Pfam; PF06345; Drf_DAD; 1.
DR Pfam; PF06346; Drf_FH1; 1.
DR Pfam; PF06367; Drf_FH3; 1.
DR Pfam; PF06371; Drf_GBD; 1.
DR Pfam; PF02181; FH2; 1.
DR SMART; SM00498; FH2; 1.
DR SUPFAM; SSF48371; SSF48371; 1.
DR PROSITE; PS51231; DAD; 1.
DR PROSITE; PS51444; FH2; 1.
DR PROSITE; PS51232; GBD_FH3; 1.
PE 1: Evidence at protein level;
KW Acetylation; Actin-binding; Alternative splicing; Cell membrane;
KW Cell projection; Coiled coil; Complete proteome; Cytoplasm;
KW Cytoskeleton; Deafness; Direct protein sequencing; Hearing;
KW Isopeptide bond; Membrane; Non-syndromic deafness; Phosphoprotein;
KW Reference proteome; Repeat; Ubl conjugation.
FT CHAIN 1 1272 Protein diaphanous homolog 1.
FT /FTId=PRO_0000194893.
FT DOMAIN 84 449 GBD/FH3.
FT DOMAIN 583 764 FH1.
FT DOMAIN 769 1171 FH2.
FT DOMAIN 1194 1222 DAD.
FT COILED 468 572 Potential.
FT COILED 1039 1196 Potential.
FT COMPBIAS 1213 1216 Arg/Lys-rich (basic).
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 22 22 Phosphoserine.
FT MOD_RES 1057 1057 N6-acetyllysine.
FT MOD_RES 1103 1103 N6-acetyllysine.
FT MOD_RES 1121 1121 Phosphotyrosine (By similarity).
FT CROSSLNK 486 486 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin).
FT VAR_SEQ 40 48 Missing (in isoform 2 and isoform 3).
FT /FTId=VSP_035870.
FT VAR_SEQ 621 632 Missing (in isoform 2).
FT /FTId=VSP_035871.
FT VAR_SEQ 826 828 Missing (in isoform 2).
FT /FTId=VSP_035872.
FT CONFLICT 13 13 G -> E (in Ref. 1; AAC05373).
FT CONFLICT 609 609 Missing (in Ref. 4; AAI17258).
FT CONFLICT 1156 1156 R -> A (in Ref. 7; AA sequence).
FT CONFLICT 1157 1157 E -> K (in Ref. 1; AAC05373 and 7; AA
FT sequence).
SQ SEQUENCE 1272 AA; 141347 MW; 9C8273DE4748564F CRC64;
MEPPGGSLGP GRGTRDKKKG RSPDELPSAG GDGGKSKKFT LKRLMADELE RFTSMRIKKE
KEKPNSAHRN SSASYGDDPT AQSLQDVSDE QVLVLFEQML LDMNLNEEKQ QPLREKDIII
KREMVSQYLY TSKAGMSQKE SSKSAMMYIQ ELRSGLRDMP LLSCLESLRV SLNNNPVSWV
QTFGAEGLAS LLDILKRLHD EKEETAGSYD SRNKHEIIRC LKAFMNNKFG IKTMLETEEG
ILLLVRAMDP AVPNMMIDAA KLLSALCILP QPEDMNERVL EAMTERAEMD EVERFQPLLD
GLKSGTTIAL KVGCLQLINA LITPAEELDF RVHIRSELMR LGLHQVLQDL REIENEDMRV
QLNVFDEQGE EDSYDLKGRL DDIRMEMDDF NEVFQILLNT VKDSKAEPHF LSILQHLLLV
RNDYEARPQY YKLIEECISQ IVLHKNGADP DFKCRHLQIE IEGLIDQMID KTKVEKSEAK
AAELEKKLDS ELTARHELQV EMKKMESDFE QKLQDLQGEK DALHSEKQQI ATEKQDLEAE
VSQLTGEVAK LTKELEDAKK EMASLSAAAI TVPPSVPSRA PVPPAPPLPG DSGTIIPPPP
APGDSTTPPP PPPPPPPPPP LPGGVCISSP PSLPGGTAIS PPPPLSGDAT IPPPPPLPEG
VGIPSPSSLP GGTAIPPPPP LPGSARIPPP PPPLPGSAGI PPPPPPLPGE AGMPPPPPPL
PGGPGIPPPP PFPGGPGIPP PPPGMGMPPP PPFGFGVPAA PVLPFGLTPK KLYKPEVQLR
RPNWSKLVAE DLSQDCFWTK VKEDRFENNE LFAKLTLTFS AQTKTSKAKK DQEGGEEKKS
VQKKKVKELK VLDSKTAQNL SIFLGSFRMP YQEIKNVILE VNEAVLTESM IQNLIKQMPE
PEQLKMLSEL KDEYDDLAES EQFGVVMGTV PRLRPRLNAI LFKLQFSEQV ENIKPEIVSV
TAACEELRKS ESFSNLLEIT LLVGNYMNAG SRNAGAFGFN ISFLCKLRDT KSTDQKMTLL
HFLAELCEND YPDVLKFPDE LAHVEKASRV SAENLQKNLD QMKKQISDVE RDVQNFPAAT
DEKDKFVEKM TSFVKDAQEQ YNKLRMMHSN METLYKELGE YFLFDPKKLS VEEFFMDLHN
FRNMFLQAVK ENQKRRETEE KMRRAKLAKE KAEKERLEKQ QKREQLIDMN AEGDETGVMD
SLLEALQSGA AFRRKRGPRQ ANRKAGCAVT SLLASELTKD DAMAAVPAKV SKNSETFPTI
LEEAKELVGR AS
//
MIM
124900
*RECORD*
*FIELD* NO
124900
*FIELD* TI
#124900 DEAFNESS, AUTOSOMAL DOMINANT 1; DFNA1
;;HEREDITARY LOW FREQUENCY HEARING LOSS; LFHL1;;
read moreDEAFNESS, PROGRESSIVE LOW TONE;;
KONIGSMARK SYNDROME
*FIELD* TX
A number sign (#) is used with this entry because of evidence that the
disorder is caused by mutation in the human homolog of the Drosophila
diaphanous gene (DIAPH1; 602121) on chromosome 5q31.
Low frequency hearing loss is genetically heterogeneous; see, e.g.,
DFNA6 (600965), which is caused by mutation in the WFS1 gene (606201).
CLINICAL FEATURES
Konigsmark et al. (1971) studied 3 families with low frequency hearing
loss in an autosomal dominant pedigree pattern.
In a large Costa Rican family, Leon et al. (1981) described many cases
of low frequency autosomal dominant deafness which differed from that
previously reported in its earlier onset (first decade) and its
progression to more profound deafness. Although the audiometric results
indicated an apical initiation of the pathology, as might result from
endolymphatic hydrops, presumably produced by alterations in the stria
vascularis or from labyrinthine otosclerosis, no bone histology was
available to identify the precise structures affected. In later studies,
Leon et al. (1992) indicated that the deafness was primary (i.e.,
nonsyndromal) and postlingual (with onset at about age 10 years, after
language and speaking were learned). By age 30, intelligence, fertility,
and life expectancy were normal. The family traced its ancestry to an
affected founder by the name of Monge, who was born in Costa Rica in
1754.
Low frequency hearing loss is said to occur in several sensorineural
hearing disorders such as Meniere disease, myxedema, and inner ear
malformations, and in conductive hearing disorders resulting from either
fixation or partial disruption of the ossicular chain (Parving, 1984).
MAPPING
Leon et al. (1992) mapped the gene for the deafness in the Costa Rican
family described by Leon et al. (1981) to 5q31, between markers IL9
(146931) at 5q31-q32 and GRL (138040) at 5q31. The maximum lod score
with IL9 was 13.55 at theta = 0.06. They indicated that the IL9 and GRL
genes are separated by about 7 cM.
MOLECULAR GENETICS
The form of autosomal dominant, fully penetrant, nonsyndromic
sensorineural progressive hearing loss in the large Costa Rican kindred
studied by Leon et al. (1981, 1992) was designated DFNA1. Lynch et al.
(1997) mapped the DFNA1 gene in this kindred to a region of 1 cM on 5q31
by linkage analysis and constructed a complete 800-kb bacterial
artificial chromosome (BAC) contig of the linked region. They compared
the sequences of these BACs with known genes and expressed sequence tags
(ESTs) from all available databases. A previously unidentified human
gene homologous to the Drosophila gene 'diaphanous' and a mouse gene was
revealed by the genomic sequence of 3 BACs. The human diaphanous gene
(602121) was screened for mutations in members of the Costa Rican M
family by means of SSCP analysis. Sequencing of variant bands revealed a
guanine-to-thymine substitution in the splice donor of the penultimate
exon of DFNA1 in affected members of the M kindred (602121.0001). The
base substitution disrupted the canonical splice donor sequence
AAGgtaagt and resulted in insertion of 4 nucleotides in the transcript,
a frameshift, and loss of the C-terminal 32 amino acids of the protein.
All 78 affected members of the M kindred were heterozygous for the
mutation. The site was wildtype in 330 control individuals with normal
hearing (660 chromosomes) of the following ancestries: 12 Costa Ricans
unrelated to the M family, 94 Latin Americans from other countries, 32
Spanish, 154 Europeans (other than Spanish) and North Americans of
European ancestry, and 38 African Americans. By RT-PCR of cochlear RNA
using PCR primers that amplify the region of the gene that harbored the
mutation in family M, Lynch et al. (1997) confirmed expression of human
diaphanous in the cochlea. The authors speculated that the biologic role
of this human diaphanous homolog in hearing is likely to be the
regulation of actin polymerization in hair cells of the inner ear.
HISTORY
Parving (1984) suggested that Konigsmark syndrome is a sensorineural
disorder 'transmitted by a dominant gene with complete penetrance.' In
another group of patients, dominant inheritance with incomplete
penetrance was considered likely and the type of deafness--sensorineural
or conductive--could not be determined. Parving (1984) suggested that
these patients have a mixed form 'caused by an early arrest in the
embryological development of both the ossicles and the cochlea.' Of 6
patients of the latter type, a 'carrier state' was found in the mother
of 3, and in 3 others the father and a brother were affected.
*FIELD* SA
Willems (2000)
*FIELD* RF
1. Konigsmark, B. W.; Mengel, M. C.; Berlin, C. I.: Dominant low-frequency
hearing loss: report of three families. Laryngoscope 81: 759-771,
1971.
2. Leon, P. E.; Bonilla, J. A.; Sanchez, J. R.; Vanegas, R.; Villalobos,
M.; Torres, L.; Leon, F.; Howell, A. L.; Rodriguez, J. A.: Low frequency
hereditary deafness in man with childhood onset. Am. J. Hum. Genet. 33:
209-214, 1981.
3. Leon, P. E.; Raventos, H.; Lynch, E.; Morrow, J.; King, M.-C.:
The gene for an inherited form of deafness maps to chromosome 5q31. Proc.
Nat. Acad. Sci. 89: 5181-5184, 1992.
4. Lynch, E. D.; Lee, M. K.; Morrow, J. E.; Welcsh, P. L.; Leon, P.
E.; King, M.-C.: Nonsyndromic deafness DFNA1 associated with mutation
of the human homolog of the Drosophila gene diaphanous. Science 278:
1315-1318, 1997.
5. Parving, A.: Inherited low-frequency hearing loss: a new mixed
conductive/sensorineural entity? Scand. Audiol. 13: 47-56, 1984.
6. Willems, P. J.: Genetic causes of hearing loss. New Eng. J. Med. 342:
1101-1109, 2000.
*FIELD* CS
Ears:
Sensorineural hearing loss;
Progressive hearing loss;
Low-frequency hearing loss
Misc:
Childhood onset
Inheritance:
Autosomal dominant (5q31)
*FIELD* CN
Victor A. McKusick - updated: 11/11/2002
Victor A. McKusick - updated: 5/25/2000
Victor A. McKusick - updated: 11/13/1997
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
carol: 02/03/2011
terry: 12/2/2008
carol: 1/31/2008
terry: 6/23/2006
alopez: 11/13/2002
terry: 11/11/2002
carol: 5/25/2000
terry: 4/30/1999
dkim: 10/12/1998
carol: 5/9/1998
terry: 5/8/1998
mark: 11/13/1997
terry: 11/12/1997
alopez: 4/30/1997
carol: 6/22/1996
davew: 7/5/1994
mimadm: 6/25/1994
jason: 6/17/1994
pfoster: 2/16/1994
warfield: 2/15/1994
carol: 2/4/1994
*RECORD*
*FIELD* NO
124900
*FIELD* TI
#124900 DEAFNESS, AUTOSOMAL DOMINANT 1; DFNA1
;;HEREDITARY LOW FREQUENCY HEARING LOSS; LFHL1;;
read moreDEAFNESS, PROGRESSIVE LOW TONE;;
KONIGSMARK SYNDROME
*FIELD* TX
A number sign (#) is used with this entry because of evidence that the
disorder is caused by mutation in the human homolog of the Drosophila
diaphanous gene (DIAPH1; 602121) on chromosome 5q31.
Low frequency hearing loss is genetically heterogeneous; see, e.g.,
DFNA6 (600965), which is caused by mutation in the WFS1 gene (606201).
CLINICAL FEATURES
Konigsmark et al. (1971) studied 3 families with low frequency hearing
loss in an autosomal dominant pedigree pattern.
In a large Costa Rican family, Leon et al. (1981) described many cases
of low frequency autosomal dominant deafness which differed from that
previously reported in its earlier onset (first decade) and its
progression to more profound deafness. Although the audiometric results
indicated an apical initiation of the pathology, as might result from
endolymphatic hydrops, presumably produced by alterations in the stria
vascularis or from labyrinthine otosclerosis, no bone histology was
available to identify the precise structures affected. In later studies,
Leon et al. (1992) indicated that the deafness was primary (i.e.,
nonsyndromal) and postlingual (with onset at about age 10 years, after
language and speaking were learned). By age 30, intelligence, fertility,
and life expectancy were normal. The family traced its ancestry to an
affected founder by the name of Monge, who was born in Costa Rica in
1754.
Low frequency hearing loss is said to occur in several sensorineural
hearing disorders such as Meniere disease, myxedema, and inner ear
malformations, and in conductive hearing disorders resulting from either
fixation or partial disruption of the ossicular chain (Parving, 1984).
MAPPING
Leon et al. (1992) mapped the gene for the deafness in the Costa Rican
family described by Leon et al. (1981) to 5q31, between markers IL9
(146931) at 5q31-q32 and GRL (138040) at 5q31. The maximum lod score
with IL9 was 13.55 at theta = 0.06. They indicated that the IL9 and GRL
genes are separated by about 7 cM.
MOLECULAR GENETICS
The form of autosomal dominant, fully penetrant, nonsyndromic
sensorineural progressive hearing loss in the large Costa Rican kindred
studied by Leon et al. (1981, 1992) was designated DFNA1. Lynch et al.
(1997) mapped the DFNA1 gene in this kindred to a region of 1 cM on 5q31
by linkage analysis and constructed a complete 800-kb bacterial
artificial chromosome (BAC) contig of the linked region. They compared
the sequences of these BACs with known genes and expressed sequence tags
(ESTs) from all available databases. A previously unidentified human
gene homologous to the Drosophila gene 'diaphanous' and a mouse gene was
revealed by the genomic sequence of 3 BACs. The human diaphanous gene
(602121) was screened for mutations in members of the Costa Rican M
family by means of SSCP analysis. Sequencing of variant bands revealed a
guanine-to-thymine substitution in the splice donor of the penultimate
exon of DFNA1 in affected members of the M kindred (602121.0001). The
base substitution disrupted the canonical splice donor sequence
AAGgtaagt and resulted in insertion of 4 nucleotides in the transcript,
a frameshift, and loss of the C-terminal 32 amino acids of the protein.
All 78 affected members of the M kindred were heterozygous for the
mutation. The site was wildtype in 330 control individuals with normal
hearing (660 chromosomes) of the following ancestries: 12 Costa Ricans
unrelated to the M family, 94 Latin Americans from other countries, 32
Spanish, 154 Europeans (other than Spanish) and North Americans of
European ancestry, and 38 African Americans. By RT-PCR of cochlear RNA
using PCR primers that amplify the region of the gene that harbored the
mutation in family M, Lynch et al. (1997) confirmed expression of human
diaphanous in the cochlea. The authors speculated that the biologic role
of this human diaphanous homolog in hearing is likely to be the
regulation of actin polymerization in hair cells of the inner ear.
HISTORY
Parving (1984) suggested that Konigsmark syndrome is a sensorineural
disorder 'transmitted by a dominant gene with complete penetrance.' In
another group of patients, dominant inheritance with incomplete
penetrance was considered likely and the type of deafness--sensorineural
or conductive--could not be determined. Parving (1984) suggested that
these patients have a mixed form 'caused by an early arrest in the
embryological development of both the ossicles and the cochlea.' Of 6
patients of the latter type, a 'carrier state' was found in the mother
of 3, and in 3 others the father and a brother were affected.
*FIELD* SA
Willems (2000)
*FIELD* RF
1. Konigsmark, B. W.; Mengel, M. C.; Berlin, C. I.: Dominant low-frequency
hearing loss: report of three families. Laryngoscope 81: 759-771,
1971.
2. Leon, P. E.; Bonilla, J. A.; Sanchez, J. R.; Vanegas, R.; Villalobos,
M.; Torres, L.; Leon, F.; Howell, A. L.; Rodriguez, J. A.: Low frequency
hereditary deafness in man with childhood onset. Am. J. Hum. Genet. 33:
209-214, 1981.
3. Leon, P. E.; Raventos, H.; Lynch, E.; Morrow, J.; King, M.-C.:
The gene for an inherited form of deafness maps to chromosome 5q31. Proc.
Nat. Acad. Sci. 89: 5181-5184, 1992.
4. Lynch, E. D.; Lee, M. K.; Morrow, J. E.; Welcsh, P. L.; Leon, P.
E.; King, M.-C.: Nonsyndromic deafness DFNA1 associated with mutation
of the human homolog of the Drosophila gene diaphanous. Science 278:
1315-1318, 1997.
5. Parving, A.: Inherited low-frequency hearing loss: a new mixed
conductive/sensorineural entity? Scand. Audiol. 13: 47-56, 1984.
6. Willems, P. J.: Genetic causes of hearing loss. New Eng. J. Med. 342:
1101-1109, 2000.
*FIELD* CS
Ears:
Sensorineural hearing loss;
Progressive hearing loss;
Low-frequency hearing loss
Misc:
Childhood onset
Inheritance:
Autosomal dominant (5q31)
*FIELD* CN
Victor A. McKusick - updated: 11/11/2002
Victor A. McKusick - updated: 5/25/2000
Victor A. McKusick - updated: 11/13/1997
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
carol: 02/03/2011
terry: 12/2/2008
carol: 1/31/2008
terry: 6/23/2006
alopez: 11/13/2002
terry: 11/11/2002
carol: 5/25/2000
terry: 4/30/1999
dkim: 10/12/1998
carol: 5/9/1998
terry: 5/8/1998
mark: 11/13/1997
terry: 11/12/1997
alopez: 4/30/1997
carol: 6/22/1996
davew: 7/5/1994
mimadm: 6/25/1994
jason: 6/17/1994
pfoster: 2/16/1994
warfield: 2/15/1994
carol: 2/4/1994
MIM
602121
*RECORD*
*FIELD* NO
602121
*FIELD* TI
*602121 DIAPHANOUS, DROSOPHILA, HOMOLOG OF, 1; DIAPH1
;;DIA1
*FIELD* TX
CLONING
In a large Costa Rican kindred with autosomal dominant, fully penetrant,
read morenonsyndromic sensorineural progressive low-frequency hearing loss
(DFNA1; 124900), Lynch et al. (1997) mapped the disease gene to a region
on chromosome 5q31 by linkage analysis. They constructed a complete
800-kb bacterial artificial chromosome (BAC) contig of the linked region
and identified DIAPH1, a human gene homologous to the Drosophila gene
'diaphanous.' This human homolog of diaphanous has approximately 3,800
bp of coding sequence and a 3-prime untranslated region (UTR) of 918 or
1,891 bp. Lynch et al. (1997) found that the human gene is expressed in
brain, heart, placenta, lung, kidney, pancreas, liver, and skeletal
muscle. A single transcript of 4.7 kb was observed in all tissues, with
highest expression in skeletal muscle. They confirmed expression of the
diaphanous homolog in the cochlea by RT-PCR of cochlear RNA. In the
course of cloning the DIAPH1 gene, Lynch et al. (1997) identified a
second human homolog of the Drosophila diaphanous gene, DIAPH2 (300108),
which maps to Xq22.
GENE FUNCTION
Actin polymerization involves proteins known to interact with diaphanous
protein in Drosophila and mouse. Lynch et al. (1997) speculated that the
biologic role of DIAPH1 in hearing is likely to be the regulation of
actin polymerization in hair cells of the inner ear. Given that human
DIAPH1 appears to be ubiquitously expressed, and that the only observed
phenotype in the Costa Rican family with a DIAPH1 mutation (see
MOLECULAR GENETICS) is hearing loss, it seemed likely to Lynch et al.
(1997) that the hair cells of the cochlea are particularly sensitive to
proper maintenance of the actin cytoskeleton.
Geneste et al. (2002) found that LIM domain kinase-1 (LIMK1; 601329) and
diaphanous cooperated to regulate serum response factor (SRF; 600589)
and actin dynamics in a rat neural precursor cell line.
Using human melanocytes and melanoma cell lines, Carreira et al. (2006)
identified MITF (156845) as a regulator of DIAPH1. Since DIAPH1 also
regulates SKP2 (601436), an F-box protein that promotes degradation of
p27(Kip1) (CDKN1B; 600778), depletion of MITF led to downregulation of
DIAPH1, followed by p27(Kip1)-dependent G1 arrest, reorganization of the
actin cytoskeleton, and increased cellular invasiveness. In contrast,
increased MITF expression promoted proliferation. Carreira et al. (2006)
concluded that variations in environmental cues that determine MITF
activity dictate the differentiation, proliferative, and
invasive/migratory potential of melanoma cells.
BIOCHEMICAL FEATURES
- Crystal Structure
Rose et al. (2005) presented the crystal structure of RhoC (165380) in
complex with the regulatory N terminus of mouse Diaph1 containing the
GBD/FH3 region, an all-helical structure with armadillo repeats. Rho
uses its 'switch' regions for interacting with 2 subdomains of GBD/FH3.
Rose et al. (2005) showed that the FH3 domain of Diaph1 forms a stable
dimer and identified the diaphanous autoregulatory domain (DAD)-binding
site. Although binding of Rho and DAD on the N-terminal fragment of
Diaph1 are mutually exclusive, their binding sites are only partially
overlapping.
GENE STRUCTURE
Lynch et al. (1997) determined that the DIAPH1 gene contains at least 18
exons.
MAPPING
By BAC analysis, Lynch et al. (1997) mapped the DIAPH1 gene to
chromosome 5q31.
MOLECULAR GENETICS
In a large Costa Rican kindred with DFNA1, Lynch et al. (1997)
identified a splice donor mutation in the penultimate exon of the DIAPH1
gene (602121.0001).
*FIELD* AV
.0001
DEAFNESS, AUTOSOMAL DOMINANT 1
DIAPH1, IVS17DS, G-T, +1
In members of a large kindred of Costa Rica affected with DFNA1
(124900), Lynch et al. (1997) demonstrated a guanine-to-thymine
transversion in the splice donor of the penultimate exon of the human
diaphanous homolog on chromosome 5q31. The substitution disrupted the
canonical splice donor sequence AAGgtaagt and resulted in insertion of 4
nucleotides in the gene transcript of affected individuals. The
mechanism for the insertion was splicing at a cryptic site 4 bp 3-prime
of the wildtype site. The insertion leads to a frameshift, encoding 21
aberrant amino acids, followed by protein termination that truncated 32
amino acids from the mature protein. The sequence of the RT-PCR product
from cochlear RNA was wildtype. Hence, if alternate splice forms of the
gene exist, normal cochlear transcripts include the region of the gene
that is improperly spliced in affected members of the kindred. Lynch et
al. (1997) noted that the DFNA1 mutation in the Costa Rican family is
relatively subtle, in that it affects only the C-terminal 52 amino acids
of a protein that must have more than 1,200 amino acid residues. The
mutation may represent a partial loss of function of the gene.
*FIELD* RF
1. Carreira, S.; Goodall, J.; Denat, L.; Rodriguez, M.; Nuciforo,
P.; Hoek, K. S.; Testori, A.; Larue, L.; Goding, C. R.: Mitf regulation
of Dia1 controls melanoma proliferation and invasiveness. Genes Dev. 20:
3426-3439, 2006.
2. Geneste, O.; Copeland, J. W.; Treisman, R.: LIM kinase and Diaphanous
cooperate to regulate serum response factor and actin dynamics. J.
Cell Biol. 157: 831-838, 2002.
3. Lynch, E. D.; Lee, M. K.; Morrow, J. E.; Welcsh, P. L.; Leon, P.
E.; King, M.-C.: Nonsyndromic deafness DFNA1 associated with mutation
of the human homolog of the Drosophila gene diaphanous. Science 278:
1315-1318, 1997.
4. Rose, R.; Weyand, M.; Lammers, M.; Ishizaki, T.; Ahmadian, M. R.;
Wittinghofer, A.: Structural and mechanistic insights into the interaction
between Rho and mammalian Dia. (Letter) Nature 435: 513-518, 2005.
*FIELD* CN
Patricia A. Hartz - updated: 3/2/2007
Patricia A. Hartz - updated: 9/16/2005
Ada Hamosh - updated: 6/15/2005
*FIELD* CD
Victor A. McKusick: 11/13/1997
*FIELD* ED
carol: 07/08/2009
carol: 6/19/2009
terry: 12/2/2008
mgross: 3/2/2007
mgross: 9/16/2005
alopez: 6/17/2005
terry: 6/15/2005
carol: 6/3/1998
joanna: 5/15/1998
alopez: 4/7/1998
alopez: 3/11/1998
terry: 3/9/1998
mark: 11/13/1997
*RECORD*
*FIELD* NO
602121
*FIELD* TI
*602121 DIAPHANOUS, DROSOPHILA, HOMOLOG OF, 1; DIAPH1
;;DIA1
*FIELD* TX
CLONING
In a large Costa Rican kindred with autosomal dominant, fully penetrant,
read morenonsyndromic sensorineural progressive low-frequency hearing loss
(DFNA1; 124900), Lynch et al. (1997) mapped the disease gene to a region
on chromosome 5q31 by linkage analysis. They constructed a complete
800-kb bacterial artificial chromosome (BAC) contig of the linked region
and identified DIAPH1, a human gene homologous to the Drosophila gene
'diaphanous.' This human homolog of diaphanous has approximately 3,800
bp of coding sequence and a 3-prime untranslated region (UTR) of 918 or
1,891 bp. Lynch et al. (1997) found that the human gene is expressed in
brain, heart, placenta, lung, kidney, pancreas, liver, and skeletal
muscle. A single transcript of 4.7 kb was observed in all tissues, with
highest expression in skeletal muscle. They confirmed expression of the
diaphanous homolog in the cochlea by RT-PCR of cochlear RNA. In the
course of cloning the DIAPH1 gene, Lynch et al. (1997) identified a
second human homolog of the Drosophila diaphanous gene, DIAPH2 (300108),
which maps to Xq22.
GENE FUNCTION
Actin polymerization involves proteins known to interact with diaphanous
protein in Drosophila and mouse. Lynch et al. (1997) speculated that the
biologic role of DIAPH1 in hearing is likely to be the regulation of
actin polymerization in hair cells of the inner ear. Given that human
DIAPH1 appears to be ubiquitously expressed, and that the only observed
phenotype in the Costa Rican family with a DIAPH1 mutation (see
MOLECULAR GENETICS) is hearing loss, it seemed likely to Lynch et al.
(1997) that the hair cells of the cochlea are particularly sensitive to
proper maintenance of the actin cytoskeleton.
Geneste et al. (2002) found that LIM domain kinase-1 (LIMK1; 601329) and
diaphanous cooperated to regulate serum response factor (SRF; 600589)
and actin dynamics in a rat neural precursor cell line.
Using human melanocytes and melanoma cell lines, Carreira et al. (2006)
identified MITF (156845) as a regulator of DIAPH1. Since DIAPH1 also
regulates SKP2 (601436), an F-box protein that promotes degradation of
p27(Kip1) (CDKN1B; 600778), depletion of MITF led to downregulation of
DIAPH1, followed by p27(Kip1)-dependent G1 arrest, reorganization of the
actin cytoskeleton, and increased cellular invasiveness. In contrast,
increased MITF expression promoted proliferation. Carreira et al. (2006)
concluded that variations in environmental cues that determine MITF
activity dictate the differentiation, proliferative, and
invasive/migratory potential of melanoma cells.
BIOCHEMICAL FEATURES
- Crystal Structure
Rose et al. (2005) presented the crystal structure of RhoC (165380) in
complex with the regulatory N terminus of mouse Diaph1 containing the
GBD/FH3 region, an all-helical structure with armadillo repeats. Rho
uses its 'switch' regions for interacting with 2 subdomains of GBD/FH3.
Rose et al. (2005) showed that the FH3 domain of Diaph1 forms a stable
dimer and identified the diaphanous autoregulatory domain (DAD)-binding
site. Although binding of Rho and DAD on the N-terminal fragment of
Diaph1 are mutually exclusive, their binding sites are only partially
overlapping.
GENE STRUCTURE
Lynch et al. (1997) determined that the DIAPH1 gene contains at least 18
exons.
MAPPING
By BAC analysis, Lynch et al. (1997) mapped the DIAPH1 gene to
chromosome 5q31.
MOLECULAR GENETICS
In a large Costa Rican kindred with DFNA1, Lynch et al. (1997)
identified a splice donor mutation in the penultimate exon of the DIAPH1
gene (602121.0001).
*FIELD* AV
.0001
DEAFNESS, AUTOSOMAL DOMINANT 1
DIAPH1, IVS17DS, G-T, +1
In members of a large kindred of Costa Rica affected with DFNA1
(124900), Lynch et al. (1997) demonstrated a guanine-to-thymine
transversion in the splice donor of the penultimate exon of the human
diaphanous homolog on chromosome 5q31. The substitution disrupted the
canonical splice donor sequence AAGgtaagt and resulted in insertion of 4
nucleotides in the gene transcript of affected individuals. The
mechanism for the insertion was splicing at a cryptic site 4 bp 3-prime
of the wildtype site. The insertion leads to a frameshift, encoding 21
aberrant amino acids, followed by protein termination that truncated 32
amino acids from the mature protein. The sequence of the RT-PCR product
from cochlear RNA was wildtype. Hence, if alternate splice forms of the
gene exist, normal cochlear transcripts include the region of the gene
that is improperly spliced in affected members of the kindred. Lynch et
al. (1997) noted that the DFNA1 mutation in the Costa Rican family is
relatively subtle, in that it affects only the C-terminal 52 amino acids
of a protein that must have more than 1,200 amino acid residues. The
mutation may represent a partial loss of function of the gene.
*FIELD* RF
1. Carreira, S.; Goodall, J.; Denat, L.; Rodriguez, M.; Nuciforo,
P.; Hoek, K. S.; Testori, A.; Larue, L.; Goding, C. R.: Mitf regulation
of Dia1 controls melanoma proliferation and invasiveness. Genes Dev. 20:
3426-3439, 2006.
2. Geneste, O.; Copeland, J. W.; Treisman, R.: LIM kinase and Diaphanous
cooperate to regulate serum response factor and actin dynamics. J.
Cell Biol. 157: 831-838, 2002.
3. Lynch, E. D.; Lee, M. K.; Morrow, J. E.; Welcsh, P. L.; Leon, P.
E.; King, M.-C.: Nonsyndromic deafness DFNA1 associated with mutation
of the human homolog of the Drosophila gene diaphanous. Science 278:
1315-1318, 1997.
4. Rose, R.; Weyand, M.; Lammers, M.; Ishizaki, T.; Ahmadian, M. R.;
Wittinghofer, A.: Structural and mechanistic insights into the interaction
between Rho and mammalian Dia. (Letter) Nature 435: 513-518, 2005.
*FIELD* CN
Patricia A. Hartz - updated: 3/2/2007
Patricia A. Hartz - updated: 9/16/2005
Ada Hamosh - updated: 6/15/2005
*FIELD* CD
Victor A. McKusick: 11/13/1997
*FIELD* ED
carol: 07/08/2009
carol: 6/19/2009
terry: 12/2/2008
mgross: 3/2/2007
mgross: 9/16/2005
alopez: 6/17/2005
terry: 6/15/2005
carol: 6/3/1998
joanna: 5/15/1998
alopez: 4/7/1998
alopez: 3/11/1998
terry: 3/9/1998
mark: 11/13/1997