ID   TWST2_HUMAN             Reviewed;         160 AA.
AC   Q8WVJ9; Q3SYL6;
DT   11-JUL-2003, integrated into UniProtKB/Swiss-Prot.
DT   01-MAR-2002, sequence version 1.
DT   24-JAN-2024, entry version 180.
DE   RecName: Full=Twist-related protein 2;
DE   AltName: Full=Class A basic helix-loop-helix protein 39;
DE            Short=bHLHa39;
DE   AltName: Full=Dermis-expressed protein 1;
DE            Short=Dermo-1;
GN   Name=TWIST2; Synonyms=BHLHA39, DERMO1;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606 {ECO:0000312|EMBL:AAH17907.1};
RN   [1] {ECO:0000305}
RP   NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION, AND TISSUE
RP   SPECIFICITY.
RC   TISSUE=Bone {ECO:0000269|PubMed:11062344};
RX   PubMed=11062344; DOI=10.1016/s8756-3282(00)00380-x;
RA   Lee M.S., Lowe G., Flanagan S., Kuchler K., Glackin C.A.;
RT   "Human Dermo-1 has attributes similar to twist in early bone development.";
RL   Bone 27:591-602(2000).
RN   [2] {ECO:0000312|EMBL:AAH17907.1}
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Brain {ECO:0000312|EMBL:AAH17907.1}, Lung
RC   {ECO:0000312|EMBL:AAH33168.1}, and Pancreas;
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 project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [3]
RP   INVOLVEMENT IN FFDD3.
RX   PubMed=20691403; DOI=10.1016/j.ajhg.2010.07.009;
RA   Tukel T., Sosic D., Al-Gazali L.I., Erazo M., Casasnovas J., Franco H.L.,
RA   Richardson J.A., Olson E.N., Cadilla C.L., Desnick R.J.;
RT   "Homozygous nonsense mutations in TWIST2 cause Setleis syndrome.";
RL   Am. J. Hum. Genet. 87:289-296(2010).
RN   [4]
RP   INVOLVEMENT IN AMS, INVOLVEMENT IN BBRSAY, VARIANT AMS LYS-75,
RP   CHARACTERIZATION OF VARIANT AMS LYS-75, VARIANTS BBRSAY ALA-75; GLN-75 AND
RP   GLN-ARG-78 INS, AND CHARACTERIZATION OF VARIANTS BBRSAY ALA-75; GLN-75 AND
RP   GLN-ARG-78 INS.
RX   PubMed=26119818; DOI=10.1016/j.ajhg.2015.05.017;
RA   Marchegiani S., Davis T., Tessadori F., van Haaften G., Brancati F.,
RA   Hoischen A., Huang H., Valkanas E., Pusey B., Schanze D., Venselaar H.,
RA   Vulto-van Silfhout A.T., Wolfe L.A., Tifft C.J., Zerfas P.M., Zambruno G.,
RA   Kariminejad A., Sabbagh-Kermani F., Lee J., Tsokos M.G., Lee C.C.,
RA   Ferraz V., da Silva E.M., Stevens C.A., Roche N., Bartsch O., Farndon P.,
RA   Bermejo-Sanchez E., Brooks B.P., Maduro V., Dallapiccola B., Ramos F.J.,
RA   Chung H.Y., Le Caignec C., Martins F., Jacyk W.K., Mazzanti L.,
RA   Brunner H.G., Bakkers J., Lin S., Malicdan M.C., Boerkoel C.F., Gahl W.A.,
RA   de Vries B.B., van Haelst M.M., Zenker M., Markello T.C.;
RT   "Recurrent Mutations in the basic domain of TWIST2 cause ablepharon
RT   macrostomia and Barber-Say syndromes.";
RL   Am. J. Hum. Genet. 97:99-110(2015).
RN   [5]
RP   VARIANT FFDD3 PRO-109.
RX   PubMed=25410422; DOI=10.1111/cge.12539;
RA   Rosti R.O., Uyguner Z.O., Nazarenko I., Bekerecioglu M., Cadilla C.L.,
RA   Ozgur H., Lee B.H., Aggarwal A.K., Pehlivan S., Desnick R.J.;
RT   "Setleis syndrome: clinical, molecular and structural studies of the first
RT   TWIST2 missense mutation.";
RL   Clin. Genet. 88:489-493(2015).
CC   -!- FUNCTION: Binds to the E-box consensus sequence 5'-CANNTG-3' as a
CC       heterodimer and inhibits transcriptional activation by MYOD1, MYOG,
CC       MEF2A and MEF2C. Also represses expression of pro-inflammatory
CC       cytokines such as TNFA and IL1B. Involved in postnatal glycogen storage
CC       and energy metabolism (By similarity). Inhibits the premature or
CC       ectopic differentiation of preosteoblast cells during osteogenesis,
CC       possibly by changing the internal signal transduction response of
CC       osteoblasts to external growth factors. {ECO:0000250,
CC       ECO:0000269|PubMed:11062344}.
CC   -!- SUBUNIT: Efficient DNA binding requires dimerization with another bHLH
CC       protein. Forms a heterodimer with TCF3/E12. Also interacts with MEF2C
CC       (By similarity). {ECO:0000250}.
CC   -!- INTERACTION:
CC       Q8WVJ9; P01023: A2M; NbExp=3; IntAct=EBI-1797313, EBI-640741;
CC       Q8WVJ9; P54253: ATXN1; NbExp=6; IntAct=EBI-1797313, EBI-930964;
CC       Q8WVJ9; Q9UBB4: ATXN10; NbExp=3; IntAct=EBI-1797313, EBI-702390;
CC       Q8WVJ9; Q9BSQ5: CCM2; NbExp=3; IntAct=EBI-1797313, EBI-1573056;
CC       Q8WVJ9; Q14203-5: DCTN1; NbExp=3; IntAct=EBI-1797313, EBI-25840379;
CC       Q8WVJ9; P15036: ETS2; NbExp=2; IntAct=EBI-1797313, EBI-1646991;
CC       Q8WVJ9; Q9BZE0: GLIS2; NbExp=3; IntAct=EBI-1797313, EBI-7251368;
CC       Q8WVJ9; P42858: HTT; NbExp=15; IntAct=EBI-1797313, EBI-466029;
CC       Q8WVJ9; D3DTS7: PMP22; NbExp=3; IntAct=EBI-1797313, EBI-25882629;
CC       Q8WVJ9; P37840: SNCA; NbExp=3; IntAct=EBI-1797313, EBI-985879;
CC       Q8WVJ9; Q99081: TCF12; NbExp=3; IntAct=EBI-1797313, EBI-722877;
CC       Q8WVJ9; Q99081-3: TCF12; NbExp=3; IntAct=EBI-1797313, EBI-11952764;
CC       Q8WVJ9; P15923-3: TCF3; NbExp=3; IntAct=EBI-1797313, EBI-12000326;
CC       Q8WVJ9; P15884: TCF4; NbExp=4; IntAct=EBI-1797313, EBI-533224;
CC   -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00981,
CC       ECO:0000269|PubMed:11062344}. Cytoplasm {ECO:0000269|PubMed:11062344}.
CC       Note=Mainly nuclear during embryonic development. Cytoplasmic in adult
CC       tissues.
CC   -!- TISSUE SPECIFICITY: In the embryo, highly expressed in chondrogenic
CC       cells. In embryonic skin, expressed in the undifferentiated mesenchymal
CC       layer beneath the epidermis which later develops into the dermis.
CC       Expressed in early myeloid cells but not in lymphoid cells in the
CC       liver. Expression also detected in the secretory ependymal epithelium
CC       of the choroid plexus primordium. In the adult, expressed in secreting
CC       glandular tissues and tubules. {ECO:0000269|PubMed:11062344}.
CC   -!- DISEASE: Focal facial dermal dysplasia 3, Setleis type (FFDD3)
CC       [MIM:227260]: A form of focal facial dermal dysplasia, a group of
CC       developmental defects characterized by bitemporal or preauricular skin
CC       lesions resembling aplasia cutis congenita. FFDD3 is characterized by
CC       distinctive bitemporal scar-like depressions resembling forceps marks,
CC       and additional facial features, including a coarse and leonine
CC       appearance, absent eyelashes on both lids or multiple rows on the upper
CC       lids, absent Meibomian glands, slanted eyebrows, chin clefting, and
CC       hypo- or hyperpigmentation of the skin. Histologically, the bitemporal
CC       lesion is an ectodermal dysplasia with near absence of subcutaneous
CC       fat, suggesting insufficient migration of neural crest cells into the
CC       frontonasal process and the first branchial arch.
CC       {ECO:0000269|PubMed:20691403, ECO:0000269|PubMed:25410422}. Note=The
CC       disease is caused by variants affecting the gene represented in this
CC       entry.
CC   -!- DISEASE: Ablepharon-macrostomia syndrome (AMS) [MIM:200110]: A
CC       congenital ectodermal dysplasia characterized by absent eyelids,
CC       macrostomia, microtia, redundant skin, sparse hair, dysmorphic nose and
CC       ears, variable abnormalities of the nipples, genitalia, fingers, and
CC       hands, largely normal intellectual and motor development, and poor
CC       growth. {ECO:0000269|PubMed:26119818}. Note=The disease is caused by
CC       variants affecting the gene represented in this entry.
CC   -!- DISEASE: Barber-Say syndrome (BBRSAY) [MIM:209885]: A rare ectodermal
CC       dysplasia characterized by ectropion, macrostomia, ear abnormalities,
CC       broad nasal bridge, bulbous nose, redundant skin, hypertrichosis,
CC       dental abnormalities, and variable other features.
CC       {ECO:0000269|PubMed:26119818}. Note=The disease is caused by variants
CC       affecting the gene represented in this entry.
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DR   EMBL; BC017907; AAH17907.1; -; mRNA.
DR   EMBL; BC033168; AAH33168.1; -; mRNA.
DR   EMBL; BC103755; AAI03756.1; -; mRNA.
DR   CCDS; CCDS46558.1; -.
DR   RefSeq; NP_001258822.1; NM_001271893.3.
DR   RefSeq; NP_476527.1; NM_057179.2.
DR   AlphaFoldDB; Q8WVJ9; -.
DR   SMR; Q8WVJ9; -.
DR   BioGRID; 125591; 17.
DR   IntAct; Q8WVJ9; 16.
DR   STRING; 9606.ENSP00000482581; -.
DR   GlyGen; Q8WVJ9; 2 sites, 1 O-linked glycan (2 sites).
DR   iPTMnet; Q8WVJ9; -.
DR   PhosphoSitePlus; Q8WVJ9; -.
DR   BioMuta; TWIST2; -.
DR   DMDM; 32699724; -.
DR   jPOST; Q8WVJ9; -.
DR   MassIVE; Q8WVJ9; -.
DR   PaxDb; 9606-ENSP00000482581; -.
DR   PeptideAtlas; Q8WVJ9; -.
DR   ProteomicsDB; 74799; -.
DR   Antibodypedia; 34502; 293 antibodies from 31 providers.
DR   DNASU; 117581; -.
DR   Ensembl; ENST00000448943.2; ENSP00000405176.2; ENSG00000233608.5.
DR   Ensembl; ENST00000612363.2; ENSP00000482581.1; ENSG00000233608.5.
DR   Ensembl; ENST00000671947.1; ENSP00000500609.1; ENSG00000288335.2.
DR   Ensembl; ENST00000673387.1; ENSP00000500440.1; ENSG00000288335.2.
DR   Ensembl; ENST00000710607.1; ENSP00000518373.1; ENSG00000233608.5.
DR   Ensembl; ENST00000710608.1; ENSP00000518374.1; ENSG00000288335.2.
DR   GeneID; 117581; -.
DR   KEGG; hsa:117581; -.
DR   MANE-Select; ENST00000612363.2; ENSP00000482581.1; NM_001271893.4; NP_001258822.1.
DR   UCSC; uc010znx.2; human.
DR   AGR; HGNC:20670; -.
DR   CTD; 117581; -.
DR   DisGeNET; 117581; -.
DR   GeneCards; TWIST2; -.
DR   HGNC; HGNC:20670; TWIST2.
DR   HPA; ENSG00000233608; Tissue enhanced (cervix).
DR   MalaCards; TWIST2; -.
DR   MIM; 200110; phenotype.
DR   MIM; 209885; phenotype.
DR   MIM; 227260; phenotype.
DR   MIM; 607556; gene.
DR   neXtProt; NX_Q8WVJ9; -.
DR   OpenTargets; ENSG00000233608; -.
DR   Orphanet; 920; Ablepharon macrostomia syndrome.
DR   Orphanet; 1231; Barber-Say syndrome.
DR   Orphanet; 1807; Focal facial dermal dysplasia type III.
DR   PharmGKB; PA134973713; -.
DR   VEuPathDB; HostDB:ENSG00000233608; -.
DR   eggNOG; KOG4447; Eukaryota.
DR   GeneTree; ENSGT00940000161996; -.
DR   HOGENOM; CLU_112073_0_1_1; -.
DR   InParanoid; Q8WVJ9; -.
DR   OMA; RAHSYEE; -.
DR   OrthoDB; 5394263at2759; -.
DR   PhylomeDB; Q8WVJ9; -.
DR   TreeFam; TF315153; -.
DR   PathwayCommons; Q8WVJ9; -.
DR   Reactome; R-HSA-8878166; Transcriptional regulation by RUNX2.
DR   SignaLink; Q8WVJ9; -.
DR   SIGNOR; Q8WVJ9; -.
DR   BioGRID-ORCS; 117581; 12 hits in 1085 CRISPR screens.
DR   GeneWiki; TWIST2; -.
DR   GenomeRNAi; 117581; -.
DR   Pharos; Q8WVJ9; Tbio.
DR   PRO; PR:Q8WVJ9; -.
DR   Proteomes; UP000005640; Chromosome 2.
DR   RNAct; Q8WVJ9; Protein.
DR   Bgee; ENSG00000233608; Expressed in stromal cell of endometrium and 92 other cell types or tissues.
DR   ExpressionAtlas; Q8WVJ9; baseline and differential.
DR   GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR   GO; GO:0005730; C:nucleolus; IDA:HPA.
DR   GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR   GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR   GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IBA:GO_Central.
DR   GO; GO:0046983; F:protein dimerization activity; IEA:InterPro.
DR   GO; GO:0000977; F:RNA polymerase II transcription regulatory region sequence-specific DNA binding; IBA:GO_Central.
DR   GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW.
DR   GO; GO:0032502; P:developmental process; IBA:GO_Central.
DR   GO; GO:0043066; P:negative regulation of apoptotic process; IEA:Ensembl.
DR   GO; GO:0045892; P:negative regulation of DNA-templated transcription; ISS:UniProtKB.
DR   GO; GO:0045668; P:negative regulation of osteoblast differentiation; IDA:UniProtKB.
DR   GO; GO:0030335; P:positive regulation of cell migration; IGI:BHF-UCL.
DR   GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR   GO; GO:0032868; P:response to insulin; IEA:Ensembl.
DR   GO; GO:0014070; P:response to organic cyclic compound; IEA:Ensembl.
DR   CDD; cd19700; bHLH_TS_TWIST2; 1.
DR   Gene3D; 4.10.280.10; Helix-loop-helix DNA-binding domain; 1.
DR   InterPro; IPR011598; bHLH_dom.
DR   InterPro; IPR036638; HLH_DNA-bd_sf.
DR   InterPro; IPR047094; Twist2_bHLH.
DR   PANTHER; PTHR23349; BASIC HELIX-LOOP-HELIX TRANSCRIPTION FACTOR, TWIST; 1.
DR   PANTHER; PTHR23349:SF70; TWIST-RELATED PROTEIN 2; 1.
DR   Pfam; PF00010; HLH; 1.
DR   SMART; SM00353; HLH; 1.
DR   SUPFAM; SSF47459; HLH, helix-loop-helix DNA-binding domain; 1.
DR   PROSITE; PS50888; BHLH; 1.
DR   Genevisible; Q8WVJ9; HS.
PE   1: Evidence at protein level;
KW   Cytoplasm; Developmental protein; Differentiation; Disease variant;
KW   DNA-binding; Ectodermal dysplasia; Nucleus; Reference proteome; Repressor;
KW   Transcription; Transcription regulation.
FT   CHAIN           1..160
FT                   /note="Twist-related protein 2"
FT                   /id="PRO_0000127489"
FT   DOMAIN          66..117
FT                   /note="bHLH"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00981"
FT   REGION          1..63
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   VARIANT         75
FT                   /note="E -> A (in BBRSAY; decreased chromatin binding; the
FT                   mutant binds to alternative chromatin binding sites
FT                   compared to wild-type; dbSNP:rs796065048)"
FT                   /evidence="ECO:0000269|PubMed:26119818"
FT                   /id="VAR_074674"
FT   VARIANT         75
FT                   /note="E -> K (in AMS; decreased chromatin binding; the
FT                   mutant binds to alternative chromatin binding sites
FT                   compared to wild-type; dbSNP:rs796065049)"
FT                   /evidence="ECO:0000269|PubMed:26119818"
FT                   /id="VAR_074675"
FT   VARIANT         75
FT                   /note="E -> Q (in BBRSAY; decreased chromatin binding; the
FT                   mutant binds to alternative chromatin binding sites
FT                   compared to wild-type; dbSNP:rs796065049)"
FT                   /evidence="ECO:0000269|PubMed:26119818"
FT                   /id="VAR_074676"
FT   VARIANT         78
FT                   /note="R -> RQR (in BBRSAY; decreased chromatin binding;
FT                   the mutant binds to alternative chromatin binding sites
FT                   compared to wild-type)"
FT                   /evidence="ECO:0000269|PubMed:26119818"
FT                   /id="VAR_074677"
FT   VARIANT         109
FT                   /note="L -> P (in FFDD3)"
FT                   /evidence="ECO:0000269|PubMed:25410422"
FT                   /id="VAR_072927"
FT   CONFLICT        31
FT                   /note="R -> L (in Ref. 1; no nucleotide entry)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        109
FT                   /note="L -> V (in Ref. 1; no nucleotide entry)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   160 AA;  18124 MW;  8F44750916940C0A CRC64;
     MEEGSSSPVS PVDSLGTSEE ELERQPKRFG RKRRYSKKSS EDGSPTPGKR GKKGSPSAQS
     FEELQSQRIL ANVRERQRTQ SLNEAFAALR KIIPTLPSDK LSKIQTLKLA ARYIDFLYQV
     LQSDEMDNKM TSCSYVAHER LSYAFSVWRM EGAWSMSASH
//