BHA09_HUMAN
ID BHA09_HUMAN Reviewed; 235 AA.
AC Q7RTU4; A8MSH6;
DT 10-JUN-2008, integrated into UniProtKB/Swiss-Prot.
DT 10-JUN-2008, sequence version 2.
DT 03-AUG-2022, entry version 125.
DE RecName: Full=Class A basic helix-loop-helix protein 9;
DE Short=bHLHa9;
DE AltName: Full=Class F basic helix-loop-helix factor 42;
DE Short=bHLHf42;
GN Name=BHLHA9; Synonyms=BHLHF42;
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;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16625196; DOI=10.1038/nature04689;
RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R., Gnerre S.,
RA Goldstein S., Grafham D.V., Grocock R., Hafez N., Hagopian D.S., Hart E.,
RA Norman C.H., Humphray S., Jaffe D.B., Jones M., Kamal M., Khodiyar V.K.,
RA LaButti K., Laird G., Lehoczky J., Liu X., Lokyitsang T., Loveland J.,
RA Lui A., Macdonald P., Major J.E., Matthews L., Mauceli E., McCarroll S.A.,
RA Mihalev A.H., Mudge J., Nguyen C., Nicol R., O'Leary S.B., Osoegawa K.,
RA Schwartz D.C., Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT "DNA sequence of human chromosome 17 and analysis of rearrangement in the
RT human lineage.";
RL Nature 440:1045-1049(2006).
RN [2]
RP IDENTIFICATION.
RX PubMed=14516699; DOI=10.1016/s0925-4773(03)00130-8;
RA McLellan A.S., Langlands K., Kealey T.;
RT "Exhaustive identification of human class II basic helix-loop-helix
RT proteins by virtual library screening.";
RL Mech. Dev. 119:S285-S291(2002).
RN [3]
RP FUNCTION, AND INVOLVEMENT IN SHFLD3.
RX PubMed=22147889; DOI=10.1136/jmedgenet-2011-100409;
RA Klopocki E., Lohan S., Doelken S.C., Stricker S., Ockeloen C.W.,
RA Soares Thiele de Aguiar R., Lezirovitz K., Mingroni Netto R.C.,
RA Jamsheer A., Shah H., Kurth I., Habenicht R., Warman M., Devriendt K.,
RA Kordass U., Hempel M., Rajab A., Makitie O., Naveed M., Radhakrishna U.,
RA Antonarakis S.E., Horn D., Mundlos S.;
RT "Duplications of BHLHA9 are associated with ectrodactyly and tibia
RT hemimelia inherited in non-Mendelian fashion.";
RL J. Med. Genet. 49:119-125(2012).
RN [4]
RP SUBCELLULAR LOCATION, FUNCTION, SUBUNIT, INTERACTION WITH TCF3; TCF4 AND
RP TCF12, INVOLVEMENT IN MSDD, VARIANTS MSSD ASP-71; PRO-73 AND LEU-75, AND
RP CHARACTERIZATION OF VARIANTS MSSD ASP-71; PRO-73 AND LEU-75.
RX PubMed=25466284; DOI=10.1016/j.ajhg.2014.10.012;
RA Malik S., Percin F.E., Bornholdt D., Albrecht B., Percesepe A., Koch M.C.,
RA Landi A., Fritz B., Khan R., Mumtaz S., Akarsu N.A., Grzeschik K.H.;
RT "Mutations affecting the BHLHA9 DNA-binding domain cause MSSD, mesoaxial
RT synostotic syndactyly with phalangeal reduction, Malik-Percin type.";
RL Am. J. Hum. Genet. 95:649-659(2014).
RN [5]
RP POSSIBLE INVOLVEMENT IN CCSPD, AND VARIANT CCSPD LEU-74.
RX PubMed=27041388; DOI=10.1002/ajmg.a.37643;
RA Phadke S.R., Kar A., Bhowmik A.D., Dalal A.;
RT "Complex Camptosynpolydactyly and Mesoaxial synostotic syndactyly with
RT phalangeal reduction are allelic disorders.";
RL Am. J. Med. Genet. A 170:1622-1625(2016).
CC -!- FUNCTION: Transcription factor, which play a role in limb development.
CC Is an essential player in the regulatory network governing
CC transcription of genes implicated in limb morphogenesis.
CC {ECO:0000269|PubMed:22147889, ECO:0000269|PubMed:25466284}.
CC -!- SUBUNIT: Heterodimer (PubMed:25466284). Efficient DNA binding requires
CC dimerization with another bHLH protein. Interacts with TCF3, TCF4, and
CC TCF12 (PubMed:25466284). {ECO:0000269|PubMed:25466284}.
CC -!- INTERACTION:
CC Q7RTU4; Q92843: BCL2L2; NbExp=3; IntAct=EBI-17508719, EBI-707714;
CC Q7RTU4; A6NEM1: GOLGA6L9; NbExp=3; IntAct=EBI-17508719, EBI-5916454;
CC Q7RTU4; Q2KHM9: KIAA0753; NbExp=3; IntAct=EBI-17508719, EBI-2805604;
CC Q7RTU4; Q15323: KRT31; NbExp=3; IntAct=EBI-17508719, EBI-948001;
CC Q7RTU4; Q96EZ8: MCRS1; NbExp=3; IntAct=EBI-17508719, EBI-348259;
CC Q7RTU4; Q8N987: NECAB1; NbExp=3; IntAct=EBI-17508719, EBI-11956853;
CC Q7RTU4; P01189: POMC; NbExp=3; IntAct=EBI-17508719, EBI-12219503;
CC Q7RTU4; Q9BZL4: PPP1R12C; NbExp=3; IntAct=EBI-17508719, EBI-721802;
CC Q7RTU4; P21673: SAT1; NbExp=3; IntAct=EBI-17508719, EBI-711613;
CC Q7RTU4; O75716: STK16; NbExp=3; IntAct=EBI-17508719, EBI-749295;
CC Q7RTU4; Q9UBB9: TFIP11; NbExp=3; IntAct=EBI-17508719, EBI-1105213;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00981}.
CC Cytoplasm {ECO:0000269|PubMed:25466284}.
CC -!- DISEASE: Split-hand/foot malformation with long bone deficiency 3
CC (SHFLD3) [MIM:612576]: A disease characterized by the association of
CC split-hand/foot malformation with long bone deficiency involving the
CC tibia and fibula. Split-hand/foot malformation is a limb malformation
CC involving the central rays of the autopod. Phenotypic expression is
CC extremely variable between and within families, and even between limbs
CC of a single patient, ranging from syndactyly and oligodactyly to the
CC most severe monodactyly with only a single phalanx. Limb features
CC include median clefts of the hands and feet, and aplasia and/or
CC hypoplasia of the phalanges, metacarpals, and metatarsals.
CC {ECO:0000269|PubMed:22147889}. Note=Disease susceptibility may be
CC associated with variants affecting the gene represented in this entry.
CC A copy number variation (CNV) resulting in BHLHA9 duplications is a
CC necessary but not sufficient susceptibility factor for Split-hand/foot
CC malformation with long bone deficiency, a highly variable phenotype
CC with reduced penetrance, particularly in females (PubMed:22147889).
CC {ECO:0000269|PubMed:22147889}.
CC -!- DISEASE: Syndactyly, mesoaxial synostotic, with phalangeal reduction
CC (MSSD) [MIM:609432]: An autosomal recessive, non-syndromic digit
CC anomaly characterized by mesoaxial osseous synostosis at a metacarpal
CC level, reduction of one or more phalanges, hypoplasia of distal
CC phalanges of preaxial and postaxial digits, clinodactyly of fifth
CC fingers, and preaxial fusion of toes. {ECO:0000269|PubMed:25466284}.
CC Note=The disease is caused by variants affecting the gene represented
CC in this entry.
CC -!- DISEASE: Camptosynpolydactyly, complex (CCSPD) [MIM:607539]: An
CC autosomal recessive disorder characterized by hand and foot deformities
CC consisting of polydactyly with digits arising from the dorsum of hands,
CC syn- and camptodactyly of some fingers, soft tissue syndactyly of first
CC and second toes, and dysplastic nails. {ECO:0000269|PubMed:27041388}.
CC Note=The disease may be caused by variants affecting the gene
CC represented in this entry.
CC -!- SEQUENCE CAUTION:
CC Sequence=DAA00302.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AC032044; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BK000140; DAA00302.1; ALT_INIT; Genomic_DNA.
DR CCDS; CCDS45560.1; -.
DR RefSeq; NP_001157877.1; NM_001164405.1.
DR AlphaFoldDB; Q7RTU4; -.
DR SMR; Q7RTU4; -.
DR BioGRID; 608299; 12.
DR IntAct; Q7RTU4; 11.
DR STRING; 9606.ENSP00000375248; -.
DR iPTMnet; Q7RTU4; -.
DR PhosphoSitePlus; Q7RTU4; -.
DR BioMuta; BHLHA9; -.
DR DMDM; 190358730; -.
DR PaxDb; Q7RTU4; -.
DR PRIDE; Q7RTU4; -.
DR Antibodypedia; 60610; 69 antibodies from 14 providers.
DR DNASU; 727857; -.
DR Ensembl; ENST00000391429.2; ENSP00000375248.1; ENSG00000205899.4.
DR GeneID; 727857; -.
DR KEGG; hsa:727857; -.
DR MANE-Select; ENST00000391429.2; ENSP00000375248.1; NM_001164405.2; NP_001157877.1.
DR UCSC; uc021tnd.2; human.
DR CTD; 727857; -.
DR DisGeNET; 727857; -.
DR GeneCards; BHLHA9; -.
DR HGNC; HGNC:35126; BHLHA9.
DR HPA; ENSG00000205899; Tissue enriched (brain).
DR MalaCards; BHLHA9; -.
DR MIM; 607539; phenotype.
DR MIM; 609432; phenotype.
DR MIM; 612576; phenotype.
DR MIM; 615416; gene.
DR neXtProt; NX_Q7RTU4; -.
DR OpenTargets; ENSG00000205899; -.
DR Orphanet; 1986; Gollop-Wolfgang complex.
DR Orphanet; 157801; Mesoaxial synostotic syndactyly with phalangeal reduction.
DR Orphanet; 3329; Tibial aplasia-ectrodactyly syndrome.
DR PharmGKB; PA164716602; -.
DR VEuPathDB; HostDB:ENSG00000205899; -.
DR eggNOG; ENOG502S6SC; Eukaryota.
DR GeneTree; ENSGT00390000002453; -.
DR HOGENOM; CLU_093878_0_0_1; -.
DR InParanoid; Q7RTU4; -.
DR OMA; GHLECHS; -.
DR OrthoDB; 1267717at2759; -.
DR PhylomeDB; Q7RTU4; -.
DR TreeFam; TF337642; -.
DR PathwayCommons; Q7RTU4; -.
DR SignaLink; Q7RTU4; -.
DR BioGRID-ORCS; 727857; 14 hits in 1087 CRISPR screens.
DR GeneWiki; BHLHA9; -.
DR GenomeRNAi; 727857; -.
DR Pharos; Q7RTU4; Tbio.
DR PRO; PR:Q7RTU4; -.
DR Proteomes; UP000005640; Chromosome 17.
DR RNAct; Q7RTU4; protein.
DR Bgee; ENSG00000205899; Expressed in Brodmann (1909) area 9 and 19 other tissues.
DR GO; GO:0000785; C:chromatin; ISA:NTNU_SB.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISA:NTNU_SB.
DR GO; GO:0046982; F:protein heterodimerization activity; IDA:UniProtKB.
DR GO; GO:0000977; F:RNA polymerase II transcription regulatory region sequence-specific DNA binding; IBA:GO_Central.
DR GO; GO:0032502; P:developmental process; IBA:GO_Central.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR Gene3D; 4.10.280.10; -; 1.
DR InterPro; IPR011598; bHLH_dom.
DR InterPro; IPR036638; HLH_DNA-bd_sf.
DR Pfam; PF00010; HLH; 1.
DR SMART; SM00353; HLH; 1.
DR SUPFAM; SSF47459; SSF47459; 1.
DR PROSITE; PS50888; BHLH; 1.
PE 1: Evidence at protein level;
KW Cytoplasm; Developmental protein; Disease variant; DNA-binding; Nucleus;
KW Reference proteome; Transcription; Transcription regulation.
FT CHAIN 1..235
FT /note="Class A basic helix-loop-helix protein 9"
FT /id="PRO_0000341377"
FT DOMAIN 65..117
FT /note="bHLH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00981"
FT REGION 1..69
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 132..235
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT VARIANT 71
FT /note="N -> D (in MSSD; completely abolishes the
FT transcription activation with the dimerization partners
FT TCF3, TCF4 and TCF12; dbSNP:rs672601337)"
FT /evidence="ECO:0000269|PubMed:25466284"
FT /id="VAR_073333"
FT VARIANT 73
FT /note="R -> P (in MSSD; completely abolishes the
FT transcription activation with the dimerization partners
FT TCF3, TCF4 and TCF12; dbSNP:rs672601338)"
FT /evidence="ECO:0000269|PubMed:25466284"
FT /id="VAR_073334"
FT VARIANT 74
FT /note="E -> L (in CCSPD; unknown pathological significance;
FT requires 2 nucleotide substitutions; dbSNP:rs886037856)"
FT /evidence="ECO:0000269|PubMed:27041388"
FT /id="VAR_077086"
FT VARIANT 75
FT /note="R -> L (in MSSD; completely abolishes the
FT transcription activation with the dimerization partners
FT TCF3, TCF4 and TCF12; dbSNP:rs672601339)"
FT /evidence="ECO:0000269|PubMed:25466284"
FT /id="VAR_073335"
SQ SEQUENCE 235 AA; 24132 MW; 1A4F0FD0E12F6E33 CRC64;
MLRGAPGLGL TARKGAEDSA EDLGGPCPEP GGDSGVLGAN GASCSRGEAE EPAGRRRARP
VRSKARRMAA NVRERKRILD YNEAFNALRR ALRHDLGGKR LSKIATLRRA IHRIAALSLV
LRASPAPRGP CGHLECHGPA ARGDTGDTGA SPPPPAGPSL ARPDAARPSV PSAPRCASCP
PHAPLARPSA VAEGPGLAQA SGGSWRRCPG ASSAGPPPWP RGYLRSAPGM GHPRS
