ALX4_HUMAN
ID ALX4_HUMAN Reviewed; 411 AA.
AC Q9H161; Q96JN7; Q9H198; Q9HAY9;
DT 27-APR-2001, integrated into UniProtKB/Swiss-Prot.
DT 28-JUL-2009, sequence version 2.
DT 03-AUG-2022, entry version 190.
DE RecName: Full=Homeobox protein aristaless-like 4;
GN Name=ALX4; Synonyms=KIAA1788;
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 [MRNA], AND POSSIBLE INVOLVEMENT IN POSHS.
RX PubMed=11017806; DOI=10.1086/321218;
RA Wu Y.-Q., Badano J.L., McCaskill C., Vogel H., Potocki L., Shaffer L.G.;
RT "Haploinsufficiency of ALX4 as a potential cause of parietal foramina in
RT the 11p11.2 contiguous gene-deletion syndrome.";
RL Am. J. Hum. Genet. 67:1327-1332(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT THR-35, AND VARIANT PFM2
RP PRO-272.
RX PubMed=11106354; DOI=10.1136/jmg.37.12.916;
RA Wuyts W., Cleiren E., Homfray T., Rasore-Quartino A., Vanhoenacker F.,
RA Van Hul W.;
RT "The ALX4 homeobox gene is mutated in patients with ossification defects of
RT the skull (foramina parietalia permagna, OMIM 168500).";
RL J. Med. Genet. 37:916-920(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], VARIANTS THR-35 AND SER-102, AND
RP VARIANT PFM2 GLN-218.
RX PubMed=11137991; DOI=10.1038/83703;
RA Mavrogiannis L.A., Antonopoulou I., Baxova A., Kutilek S., Kim C.A.,
RA Sugayama S.M., Salamanca A., Wall S.A., Morriss-Kay G.M., Wilkie A.O.M.;
RT "Haploinsufficiency of the human homeobox gene ALX4 causes skull
RT ossification defects.";
RL Nat. Genet. 27:17-18(2001).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=11347906; DOI=10.1093/dnares/8.2.85;
RA Nagase T., Nakayama M., Nakajima D., Kikuno R., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. XX. The
RT complete sequences of 100 new cDNA clones from brain which code for large
RT proteins in vitro.";
RL DNA Res. 8:85-95(2001).
RN [5]
RP POSSIBLE INVOLVEMENT IN POSHS.
RX PubMed=11903336; DOI=10.1034/j.1399-0004.2001.600506.x;
RA Hall C.R., Wu Y., Shaffer L.G., Hecht J.T.;
RT "Familial case of Potocki-Shaffer syndrome associated with microdeletion of
RT EXT2 and ALX4.";
RL Clin. Genet. 60:356-359(2001).
RN [6]
RP INVOLVEMENT IN FND2, FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=19692347; DOI=10.1093/hmg/ddp391;
RA Kayserili H., Uz E., Niessen C., Vargel I., Alanay Y., Tuncbilek G.,
RA Yigit G., Uyguner O., Candan S., Okur H., Kaygin S., Balci S., Mavili E.,
RA Alikasifoglu M., Haase I., Wollnik B., Akarsu N.A.;
RT "ALX4 dysfunction disrupts craniofacial and epidermal development.";
RL Hum. Mol. Genet. 18:4357-4366(2009).
RN [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-200, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [8]
RP VARIANTS CRS5 PHE-7 AND GLU-211, VARIANT LEU-306, CHARACTERIZATION OF
RP VARIANTS CRS5 PHE-7 AND GLU-211, AND CHARACTERIZATION OF VARIANT LEU-306.
RX PubMed=22829454; DOI=10.1002/humu.22166;
RA Yagnik G., Ghuman A., Kim S., Stevens C.G., Kimonis V., Stoler J.,
RA Sanchez-Lara P.A., Bernstein J.A., Naydenov C., Drissi H., Cunningham M.L.,
RA Kim J., Boyadjiev S.A.;
RT "ALX4 gain-of-function mutations in nonsyndromic craniosynostosis.";
RL Hum. Mutat. 33:1626-1629(2012).
CC -!- FUNCTION: Transcription factor involved in skull and limb development.
CC Plays an essential role in craniofacial development, skin and hair
CC follicle development. {ECO:0000269|PubMed:19692347}.
CC -!- SUBUNIT: Binds DNA. {ECO:0000250}.
CC -!- INTERACTION:
CC Q9H161; Q8NA54: IQUB; NbExp=3; IntAct=EBI-11317841, EBI-10220600;
CC Q9H161; Q9HBI0: PARVG; NbExp=3; IntAct=EBI-11317841, EBI-3921217;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00108,
CC ECO:0000255|PROSITE-ProRule:PRU00138, ECO:0000269|PubMed:19692347}.
CC -!- TISSUE SPECIFICITY: Expression is likely to be restricted to bone.
CC Found in parietal bone.
CC -!- DISEASE: Parietal foramina 2 (PFM2) [MIM:609597]: Autosomal dominant
CC disease characterized by oval defects of the parietal bones caused by
CC deficient ossification around the parietal notch, which is normally
CC obliterated during the fifth fetal month. PFM2 is also a clinical
CC feature of Potocki-Shaffer syndrome. {ECO:0000269|PubMed:11106354,
CC ECO:0000269|PubMed:11137991}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Frontonasal dysplasia 2 (FND2) [MIM:613451]: The term
CC frontonasal dysplasia describes an array of abnormalities affecting the
CC eyes, forehead and nose and linked to midfacial dysraphia. The clinical
CC picture is highly variable. Major findings include true ocular
CC hypertelorism; broadening of the nasal root; median facial cleft
CC affecting the nose and/or upper lip and palate; unilateral or bilateral
CC clefting of the alae nasi; lack of formation of the nasal tip; anterior
CC cranium bifidum occultum; a V-shaped or widow's peak frontal hairline.
CC {ECO:0000269|PubMed:19692347}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Potocki-Shaffer syndrome (POSHS) [MIM:601224]: A syndrome
CC characterized by foramina parietalia permagna, multiple exostoses, and
CC craniofacial dysostosis, and intellectual disability in some cases.
CC {ECO:0000305|PubMed:11017806, ECO:0000305|PubMed:11903336}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Craniosynostosis 5 (CRS5) [MIM:615529]: A primary abnormality
CC of skull growth involving premature fusion of one or more cranial
CC sutures. The growth velocity of the skull often cannot match that of
CC the developing brain resulting in an abnormal head shape and, in some
CC cases, increased intracranial pressure, which must be treated promptly
CC to avoid permanent neurodevelopmental disability.
CC {ECO:0000269|PubMed:22829454}. Note=Disease susceptibility is
CC associated with variants affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the paired homeobox family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAG23961.1; Type=Frameshift; Evidence={ECO:0000305};
CC Sequence=BAB47417.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AF294629; AAG23961.1; ALT_FRAME; mRNA.
DR EMBL; AF308822; AAK38835.1; -; Genomic_DNA.
DR EMBL; AF308823; AAK38835.1; JOINED; Genomic_DNA.
DR EMBL; AF308824; AAK38835.1; JOINED; Genomic_DNA.
DR EMBL; AF308825; AAK38835.1; JOINED; Genomic_DNA.
DR EMBL; AJ404888; CAC15060.1; -; mRNA.
DR EMBL; AJ279074; CAC15120.1; -; Genomic_DNA.
DR EMBL; AJ279075; CAC15120.1; JOINED; Genomic_DNA.
DR EMBL; AJ279076; CAC15120.1; JOINED; Genomic_DNA.
DR EMBL; AJ279077; CAC15120.1; JOINED; Genomic_DNA.
DR EMBL; AB058691; BAB47417.1; ALT_INIT; mRNA.
DR CCDS; CCDS31468.1; -.
DR RefSeq; NP_068745.2; NM_021926.3.
DR PDB; 2M0C; NMR; -; A=209-280.
DR PDBsum; 2M0C; -.
DR AlphaFoldDB; Q9H161; -.
DR BMRB; Q9H161; -.
DR SMR; Q9H161; -.
DR BioGRID; 121938; 18.
DR IntAct; Q9H161; 15.
DR MINT; Q9H161; -.
DR STRING; 9606.ENSP00000332744; -.
DR iPTMnet; Q9H161; -.
DR PhosphoSitePlus; Q9H161; -.
DR BioMuta; ALX4; -.
DR DMDM; 254763249; -.
DR MassIVE; Q9H161; -.
DR MaxQB; Q9H161; -.
DR PaxDb; Q9H161; -.
DR PeptideAtlas; Q9H161; -.
DR PRIDE; Q9H161; -.
DR ProteomicsDB; 80361; -.
DR Antibodypedia; 13210; 309 antibodies from 21 providers.
DR DNASU; 60529; -.
DR Ensembl; ENST00000652299.1; ENSP00000498217.1; ENSG00000052850.8.
DR GeneID; 60529; -.
DR KEGG; hsa:60529; -.
DR MANE-Select; ENST00000652299.1; ENSP00000498217.1; NM_021926.4; NP_068745.2.
DR UCSC; uc001myb.4; human.
DR CTD; 60529; -.
DR DisGeNET; 60529; -.
DR GeneCards; ALX4; -.
DR GeneReviews; ALX4; -.
DR HGNC; HGNC:450; ALX4.
DR HPA; ENSG00000052850; Tissue enhanced (breast, choroid plexus).
DR MalaCards; ALX4; -.
DR MIM; 601224; phenotype.
DR MIM; 605420; gene.
DR MIM; 609597; phenotype.
DR MIM; 613451; phenotype.
DR MIM; 615529; phenotype.
DR neXtProt; NX_Q9H161; -.
DR OpenTargets; ENSG00000052850; -.
DR Orphanet; 60015; Enlarged parietal foramina.
DR Orphanet; 228390; Frontonasal dysplasia-alopecia-genital anomalies syndrome.
DR Orphanet; 35093; Non-syndromic sagittal craniosynostosis.
DR Orphanet; 52022; Potocki-Shaffer syndrome.
DR PharmGKB; PA24755; -.
DR VEuPathDB; HostDB:ENSG00000052850; -.
DR eggNOG; KOG0490; Eukaryota.
DR GeneTree; ENSGT00940000159662; -.
DR HOGENOM; CLU_047013_0_0_1; -.
DR InParanoid; Q9H161; -.
DR OMA; PCYGKDN; -.
DR OrthoDB; 738339at2759; -.
DR PhylomeDB; Q9H161; -.
DR TreeFam; TF350743; -.
DR PathwayCommons; Q9H161; -.
DR SignaLink; Q9H161; -.
DR SIGNOR; Q9H161; -.
DR BioGRID-ORCS; 60529; 11 hits in 1091 CRISPR screens.
DR ChiTaRS; ALX4; human.
DR GeneWiki; ALX4; -.
DR GenomeRNAi; 60529; -.
DR Pharos; Q9H161; Tbio.
DR PRO; PR:Q9H161; -.
DR Proteomes; UP000005640; Chromosome 11.
DR RNAct; Q9H161; protein.
DR Bgee; ENSG00000052850; Expressed in olfactory segment of nasal mucosa and 56 other tissues.
DR Genevisible; Q9H161; HS.
DR GO; GO:0000785; C:chromatin; ISA:NTNU_SB.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0005667; C:transcription regulator complex; IEA:Ensembl.
DR GO; GO:0003677; F:DNA binding; NAS:UniProtKB.
DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IBA:GO_Central.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISA:NTNU_SB.
DR GO; GO:0071837; F:HMG box domain binding; IEA:Ensembl.
DR GO; GO:0000977; F:RNA polymerase II transcription regulatory region sequence-specific DNA binding; IBA:GO_Central.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; IDA:ARUK-UCL.
DR GO; GO:0009952; P:anterior/posterior pattern specification; IEA:Ensembl.
DR GO; GO:0048565; P:digestive tract development; IEA:Ensembl.
DR GO; GO:0042733; P:embryonic digit morphogenesis; IEA:Ensembl.
DR GO; GO:0035115; P:embryonic forelimb morphogenesis; IEA:Ensembl.
DR GO; GO:0035116; P:embryonic hindlimb morphogenesis; IEA:Ensembl.
DR GO; GO:0048704; P:embryonic skeletal system morphogenesis; IEA:Ensembl.
DR GO; GO:0001942; P:hair follicle development; IMP:UniProtKB.
DR GO; GO:0007517; P:muscle organ development; IEA:Ensembl.
DR GO; GO:0009791; P:post-embryonic development; IEA:Ensembl.
DR GO; GO:0042981; P:regulation of apoptotic process; IEA:Ensembl.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0060021; P:roof of mouth development; IEA:Ensembl.
DR GO; GO:0001501; P:skeletal system development; NAS:UniProtKB.
DR CDD; cd00086; homeodomain; 1.
DR InterPro; IPR033203; ALX4.
DR InterPro; IPR009057; Homeobox-like_sf.
DR InterPro; IPR017970; Homeobox_CS.
DR InterPro; IPR001356; Homeobox_dom.
DR InterPro; IPR003654; OAR_dom.
DR PANTHER; PTHR24329:SF322; PTHR24329:SF322; 2.
DR Pfam; PF00046; Homeodomain; 1.
DR Pfam; PF03826; OAR; 1.
DR SMART; SM00389; HOX; 1.
DR SUPFAM; SSF46689; SSF46689; 1.
DR PROSITE; PS00027; HOMEOBOX_1; 1.
DR PROSITE; PS50071; HOMEOBOX_2; 1.
DR PROSITE; PS50803; OAR; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Activator; Craniosynostosis; Developmental protein;
KW Disease variant; DNA-binding; Homeobox; Nucleus; Phosphoprotein;
KW Reference proteome; Transcription; Transcription regulation.
FT CHAIN 1..411
FT /note="Homeobox protein aristaless-like 4"
FT /id="PRO_0000048814"
FT DNA_BIND 214..273
FT /note="Homeobox"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00108"
FT REGION 75..145
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 184..219
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 391..404
FT /note="OAR"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00138"
FT COMPBIAS 94..119
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 200
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT VARIANT 7
FT /note="V -> F (in CRS5; low-penetrance mutation associated
FT with disease susceptibility; results in gain-of-function;
FT dbSNP:rs281865153)"
FT /evidence="ECO:0000269|PubMed:22829454"
FT /id="VAR_069279"
FT VARIANT 35
FT /note="R -> T (in dbSNP:rs3824915)"
FT /evidence="ECO:0000269|PubMed:11106354,
FT ECO:0000269|PubMed:11137991"
FT /id="VAR_010783"
FT VARIANT 102
FT /note="P -> S (in dbSNP:rs12421995)"
FT /evidence="ECO:0000269|PubMed:11137991"
FT /id="VAR_010784"
FT VARIANT 211
FT /note="K -> E (in CRS5; low-penetrance mutation associated
FT with disease susceptibility; results in gain-of-function;
FT dbSNP:rs281865154)"
FT /evidence="ECO:0000269|PubMed:22829454"
FT /id="VAR_069280"
FT VARIANT 218
FT /note="R -> Q (in PFM2; dbSNP:rs104894193)"
FT /evidence="ECO:0000269|PubMed:11137991"
FT /id="VAR_010785"
FT VARIANT 257
FT /note="R -> T (in dbSNP:rs3824915)"
FT /id="VAR_058413"
FT VARIANT 272
FT /note="R -> P (in PFM2; dbSNP:rs104894196)"
FT /evidence="ECO:0000269|PubMed:11106354"
FT /id="VAR_010897"
FT VARIANT 306
FT /note="P -> L (in dbSNP:rs149897209)"
FT /evidence="ECO:0000269|PubMed:22829454"
FT /id="VAR_069281"
FT CONFLICT 134
FT /note="D -> N (in Ref. 1; AAG23961)"
FT /evidence="ECO:0000305"
FT HELIX 223..235
FT /evidence="ECO:0007829|PDB:2M0C"
FT HELIX 241..251
FT /evidence="ECO:0007829|PDB:2M0C"
FT HELIX 255..269
FT /evidence="ECO:0007829|PDB:2M0C"
SQ SEQUENCE 411 AA; 44241 MW; D41780B230C7E55C CRC64;
MNAETCVSYC ESPAAAMDAY YSPVSQSREG SSPFRAFPGG DKFGTTFLSA AAKAQGFGDA
KSRARYGAGQ QDLATPLESG AGARGSFNKF QPQPSTPQPQ PPPQPQPQQQ QPQPQPPAQP
HLYLQRGACK TPPDGSLKLQ EGSSGHSAAL QVPCYAKESS LGEPELPPDS DTVGMDSSYL
SVKEAGVKGP QDRASSDLPS PLEKADSESN KGKKRRNRTT FTSYQLEELE KVFQKTHYPD
VYAREQLAMR TDLTEARVQV WFQNRRAKWR KRERFGQMQQ VRTHFSTAYE LPLLTRAENY
AQIQNPSWLG NNGAASPVPA CVVPCDPVPA CMSPHAHPPG SGASSVTDFL SVSGAGSHVG
QTHMGSLFGA ASLSPGLNGY ELNGEPDRKT SSIAALRMKA KEHSAAISWA T
