ARX_HUMAN
ID ARX_HUMAN Reviewed; 562 AA.
AC Q96QS3;
DT 27-JAN-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-2001, sequence version 1.
DT 03-AUG-2022, entry version 175.
DE RecName: Full=Homeobox protein ARX;
DE AltName: Full=Aristaless-related homeobox;
GN Name=ARX;
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 TISSUE SPECIFICITY.
RX PubMed=12359145; DOI=10.1016/s1096-7192(02)00126-9;
RA Ohira R.H., Zhang Y.H., Guo W., Dipple K., Shih S., Doerr J., Huang B.-L.,
RA Fu L., Abu-Khalil A., Geschwind D., McCabe E.;
RT "Human ARX gene: genomic characterization and expression.";
RL Mol. Genet. Metab. 77:179-188(2002).
RN [2]
RP VARIANT DEE1 ALA-ALA-ALA-ALA-ALA-ALA-ALA-ALA-155 INS.
RX PubMed=12376946; DOI=10.1002/ajmg.10714;
RA Turner G., Partington M., Kerr B., Mangelsdorf M., Gecz J.;
RT "Variable expression of mental retardation, autism, seizures, and dystonic
RT hand movements in two families with an identical ARX gene mutation.";
RL Am. J. Med. Genet. 112:405-411(2002).
RN [3]
RP VARIANTS XLID29 PRO-33 AND SER-286, AND TISSUE SPECIFICITY.
RX PubMed=11971879; DOI=10.1093/hmg/11.8.981;
RA Bienvenu T., Poirier K., Friocourt G., Bahi N., Beaumont D., Fauchereau F.,
RA Ben-Jeema L., Zemni R., Vinet M.-C., Francis F., Couvert P., Gomot M.,
RA Moraine C., van Bokhoven H., Kalscheuer V., Frints S., Gecz J., Ohzaki K.,
RA Chaabouni H., Fryns J.-P., Desportes V., Beldjord C., Chelly J.;
RT "ARX, a novel Prd-class-homeobox gene highly expressed in the
RT telencephalon, is mutated in X-linked mental retardation.";
RL Hum. Mol. Genet. 11:981-991(2002).
RN [4]
RP VARIANTS DEE1 ALA-ALA-ALA-ALA-ALA-ALA-ALA-115 INS;
RP ALA-ALA-ALA-ALA-ALA-ALA-ALA-ALA-155 INS AND LEU-353, VARIANT PRTS
RP ALA-ALA-ALA-ALA-ALA-ALA-ALA-ALA-155 INS, AND TISSUE SPECIFICITY.
RX PubMed=11889467; DOI=10.1038/ng862;
RA Stroemme P., Mangelsdorf M.E., Shaw M.A., Lower K.M., Lewis S.M.E.,
RA Bruyere H., Luetcherath V., Gedeon A.K., Wallace R.H., Scheffer I.E.,
RA Turner G., Partington M., Frints S.G.M., Fryns J.-P., Sutherland G.R.,
RA Mulley J.C., Gecz J.;
RT "Mutations in the human ortholog of aristaless cause X-linked mental
RT retardation and epilepsy.";
RL Nat. Genet. 30:441-445(2002).
RN [5]
RP VARIANTS LISX2 HIS-332 AND GLN-343.
RX PubMed=12379852; DOI=10.1038/ng1009;
RA Kitamura K., Yanazawa M., Sugiyama N., Miura H., Iizuka-Kogo A., Kusaka M.,
RA Omichi K., Suzuki R., Kato-Fukui Y., Kamiirisa K., Matsuo M., Kamijo S.,
RA Kasahara M., Yoshioka H., Ogata T., Fukuda T., Kondo I., Kato M.,
RA Dobyns W.B., Yokoyama M., Morohashi K.;
RT "Mutation of ARX causes abnormal development of forebrain and testes in
RT mice and X-linked lissencephaly with abnormal genitalia in humans.";
RL Nat. Genet. 32:359-369(2002).
RN [6]
RP VARIANTS LISX2 PRO-332; HIS-332; GLN-343; ARG-353 AND THR-521, AND VARIANT
RP ACCAG ASN-333.
RX PubMed=14722918; DOI=10.1002/humu.10310;
RA Kato M., Das S., Petras K., Kitamura K., Morohashi K., Abuelo D.N.,
RA Barr M., Bonneau D., Brady A.F., Carpenter N.J., Cipero K.L., Frisone F.,
RA Fukuda T., Guerrini R., Iida E., Itoh M., Lewanda A.F., Nanba Y., Oka A.,
RA Proud V.K., Saugier-Veber P., Schelley S.L., Selicorni A., Shaner R.,
RA Silengo M., Stewart F., Sugiyama N., Toyama J., Toutain A., Vargas A.L.,
RA Yanazawa M., Zackai E.H., Dobyns W.B.;
RT "Mutations of ARX are associated with striking pleiotropy and consistent
RT genotype-phenotype correlation.";
RL Hum. Mutat. 23:147-159(2004).
RN [7]
RP VARIANT DEE1 LEU-353.
RX PubMed=27864847; DOI=10.1002/humu.23149;
RG Clinical Study Group;
RA Parrini E., Marini C., Mei D., Galuppi A., Cellini E., Pucatti D.,
RA Chiti L., Rutigliano D., Bianchini C., Virdo S., De Vita D., Bigoni S.,
RA Barba C., Mari F., Montomoli M., Pisano T., Rosati A., Guerrini R.;
RT "Diagnostic targeted resequencing in 349 patients with drug-resistant
RT pediatric epilepsies identifies causative mutations in 30 different
RT genes.";
RL Hum. Mutat. 38:216-225(2017).
CC -!- FUNCTION: Transcription factor required for normal brain development.
CC May be important for maintenance of specific neuronal subtypes in the
CC cerebral cortex and axonal guidance in the floor plate.
CC -!- INTERACTION:
CC Q96QS3; P12814: ACTN1; NbExp=2; IntAct=EBI-11107474, EBI-351710;
CC Q96QS3; Q9UPP1: PHF8; NbExp=3; IntAct=EBI-11107474, EBI-1560800;
CC Q96QS3; Q9NRD5: PICK1; NbExp=2; IntAct=EBI-11107474, EBI-79165;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00108,
CC ECO:0000255|PROSITE-ProRule:PRU00138}.
CC -!- TISSUE SPECIFICITY: Expressed predominantly in fetal and adult brain
CC and skeletal muscle. Expression is specific to the telencephalon and
CC ventral thalamus. There is an absence of expression in the cerebellum
CC throughout development and also in adult. {ECO:0000269|PubMed:11889467,
CC ECO:0000269|PubMed:11971879, ECO:0000269|PubMed:12359145}.
CC -!- DISEASE: Lissencephaly, X-linked 2 (LISX2) [MIM:300215]: A classic type
CC lissencephaly associated with abnormal genitalia. Patients have severe
CC congenital or postnatal microcephaly, lissencephaly, agenesis of the
CC corpus callosum, neonatal-onset intractable epilepsy, poor temperature
CC regulation, chronic diarrhea, and ambiguous or underdeveloped
CC genitalia. {ECO:0000269|PubMed:12379852, ECO:0000269|PubMed:14722918}.
CC Note=The disease is caused by variants affecting the gene represented
CC in this entry.
CC -!- DISEASE: Developmental and epileptic encephalopathy 1 (DEE1)
CC [MIM:308350]: A severe form of epilepsy characterized by frequent tonic
CC seizures or spasms beginning in infancy with a specific EEG finding of
CC suppression-burst patterns, characterized by high-voltage bursts
CC alternating with almost flat suppression phases. Patients may progress
CC to West syndrome, which is characterized by tonic spasms with
CC clustering, arrest of psychomotor development, and hypsarrhythmia on
CC EEG. {ECO:0000269|PubMed:11889467, ECO:0000269|PubMed:12376946,
CC ECO:0000269|PubMed:27864847}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Partington syndrome (PRTS) [MIM:309510]: An X-linked
CC developmental disorder characterized by intellectual disability,
CC episodic dystonic hand movements, lower limb spasticity, and
CC dysarthria. {ECO:0000269|PubMed:11889467}. Note=The disease is caused
CC by variants affecting the gene represented in this entry.
CC -!- DISEASE: Intellectual developmental disorder, X-linked 29 (XLID29)
CC [MIM:300419]: A disorder characterized by significantly below average
CC general intellectual functioning associated with impairments in
CC adaptive behavior and manifested during the developmental period.
CC Intellectual deficiency is the only primary symptom of non-syndromic X-
CC linked forms, while syndromic intellectual disability presents with
CC associated physical, neurological and/or psychiatric manifestations.
CC {ECO:0000269|PubMed:11971879}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Agenesis of the corpus callosum, with abnormal genitalia
CC (ACCAG) [MIM:300004]: An X-linked syndrome with variable expression in
CC females. It is characterized by agenesis of corpus callosum,
CC intellectual disability and seizures. Manifestations in surviving males
CC include severe acquired micrencephaly, intellectual disability, limb
CC contractures, scoliosis, tapered fingers with hyperconvex nails, a
CC characteristic face with large eyes, prominent supraorbital ridges,
CC synophrys, optic atrophy, broad alveolar ridges, and seizures. Urologic
CC anomalies include renal dysplasia, cryptorchidism, and hypospadias.
CC {ECO:0000269|PubMed:14722918}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the paired homeobox family. Bicoid subfamily.
CC {ECO:0000305}.
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DR EMBL; AY038071; AAK93901.1; -; mRNA.
DR CCDS; CCDS14215.1; -.
DR RefSeq; NP_620689.1; NM_139058.2.
DR AlphaFoldDB; Q96QS3; -.
DR SMR; Q96QS3; -.
DR BioGRID; 127998; 27.
DR IntAct; Q96QS3; 28.
DR MINT; Q96QS3; -.
DR STRING; 9606.ENSP00000368332; -.
DR GlyGen; Q96QS3; 2 sites, 1 O-linked glycan (2 sites).
DR iPTMnet; Q96QS3; -.
DR PhosphoSitePlus; Q96QS3; -.
DR BioMuta; ARX; -.
DR DMDM; 27923733; -.
DR jPOST; Q96QS3; -.
DR MassIVE; Q96QS3; -.
DR PaxDb; Q96QS3; -.
DR PeptideAtlas; Q96QS3; -.
DR PRIDE; Q96QS3; -.
DR ProteomicsDB; 77895; -.
DR Antibodypedia; 24612; 400 antibodies from 32 providers.
DR DNASU; 170302; -.
DR Ensembl; ENST00000379044.5; ENSP00000368332.4; ENSG00000004848.8.
DR GeneID; 170302; -.
DR KEGG; hsa:170302; -.
DR MANE-Select; ENST00000379044.5; ENSP00000368332.4; NM_139058.3; NP_620689.1.
DR UCSC; uc004dbp.5; human.
DR CTD; 170302; -.
DR DisGeNET; 170302; -.
DR GeneCards; ARX; -.
DR HGNC; HGNC:18060; ARX.
DR HPA; ENSG00000004848; Tissue enhanced (brain, ovary, skeletal muscle).
DR MalaCards; ARX; -.
DR MIM; 300004; phenotype.
DR MIM; 300215; phenotype.
DR MIM; 300382; gene.
DR MIM; 300419; phenotype.
DR MIM; 308350; phenotype.
DR MIM; 309510; phenotype.
DR neXtProt; NX_Q96QS3; -.
DR OpenTargets; ENSG00000004848; -.
DR Orphanet; 2508; Corpus callosum agenesis-abnormal genitalia syndrome.
DR Orphanet; 1934; Early infantile epileptic encephalopathy.
DR Orphanet; 364063; Infantile epileptic-dyskinetic encephalopathy.
DR Orphanet; 3451; Infantile spasms syndrome.
DR Orphanet; 94083; Partington syndrome.
DR Orphanet; 452; X-linked lissencephaly with abnormal genitalia.
DR Orphanet; 777; X-linked non-syndromic intellectual disability.
DR Orphanet; 3175; X-linked spasticity-intellectual disability-epilepsy syndrome.
DR PharmGKB; PA25024; -.
DR VEuPathDB; HostDB:ENSG00000004848; -.
DR eggNOG; KOG0490; Eukaryota.
DR GeneTree; ENSGT00940000160633; -.
DR HOGENOM; CLU_047013_7_0_1; -.
DR InParanoid; Q96QS3; -.
DR OMA; RENAPFA; -.
DR OrthoDB; 944129at2759; -.
DR PhylomeDB; Q96QS3; -.
DR TreeFam; TF350743; -.
DR PathwayCommons; Q96QS3; -.
DR SignaLink; Q96QS3; -.
DR SIGNOR; Q96QS3; -.
DR BioGRID-ORCS; 170302; 9 hits in 715 CRISPR screens.
DR GeneWiki; Aristaless_related_homeobox; -.
DR GenomeRNAi; 170302; -.
DR Pharos; Q96QS3; Tbio.
DR PRO; PR:Q96QS3; -.
DR Proteomes; UP000005640; Chromosome X.
DR RNAct; Q96QS3; protein.
DR Bgee; ENSG00000004848; Expressed in left ovary and 122 other tissues.
DR ExpressionAtlas; Q96QS3; baseline and differential.
DR Genevisible; Q96QS3; HS.
DR GO; GO:0000785; C:chromatin; ISA:NTNU_SB.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0003682; F:chromatin binding; IEA:Ensembl.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IDA:MGI.
DR GO; GO:0001227; F:DNA-binding transcription repressor activity, RNA polymerase II-specific; IEA:Ensembl.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA 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:0007411; P:axon guidance; IEA:Ensembl.
DR GO; GO:0021846; P:cell proliferation in forebrain; IEA:Ensembl.
DR GO; GO:0021853; P:cerebral cortex GABAergic interneuron migration; IEA:Ensembl.
DR GO; GO:0021800; P:cerebral cortex tangential migration; IEA:Ensembl.
DR GO; GO:0021831; P:embryonic olfactory bulb interneuron precursor migration; IEA:Ensembl.
DR GO; GO:0048484; P:enteric nervous system development; IBA:GO_Central.
DR GO; GO:0072148; P:epithelial cell fate commitment; IEA:Ensembl.
DR GO; GO:0021759; P:globus pallidus development; IEA:Ensembl.
DR GO; GO:0044241; P:lipid digestion; IEA:Ensembl.
DR GO; GO:0035265; P:organ growth; IEA:Ensembl.
DR GO; GO:0010628; P:positive regulation of gene expression; IEA:Ensembl.
DR GO; GO:0046622; P:positive regulation of organ growth; IEA:Ensembl.
DR GO; GO:0050678; P:regulation of epithelial cell proliferation; IEA:Ensembl.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR CDD; cd00086; homeodomain; 1.
DR InterPro; IPR009057; Homeobox-like_sf.
DR InterPro; IPR017970; Homeobox_CS.
DR InterPro; IPR001356; Homeobox_dom.
DR InterPro; IPR003654; OAR_dom.
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 Developmental protein; Differentiation; Disease variant; DNA-binding;
KW Epilepsy; Homeobox; Intellectual disability; Lissencephaly; Neurogenesis;
KW Nucleus; Reference proteome; Transcription; Transcription regulation;
KW Triplet repeat expansion.
FT CHAIN 1..562
FT /note="Homeobox protein ARX"
FT /id="PRO_0000048819"
FT DNA_BIND 328..387
FT /note="Homeobox"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00108"
FT REGION 1..21
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 50..81
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 118..255
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 530..543
FT /note="OAR"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00138"
FT COMPBIAS 122..136
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 161..175
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 222..253
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT VARIANT 33
FT /note="L -> P (in XLID29; dbSNP:rs28936077)"
FT /evidence="ECO:0000269|PubMed:11971879"
FT /id="VAR_015669"
FT VARIANT 115
FT /note="A -> AAAAAAAA (in DEE1)"
FT /id="VAR_015177"
FT VARIANT 155
FT /note="A -> AAAAAAAAA (in DEE1 and PRTS; also found in non-
FT specific intellectual disability families; frequent
FT variant)"
FT /evidence="ECO:0000269|PubMed:11889467,
FT ECO:0000269|PubMed:12376946"
FT /id="VAR_015670"
FT VARIANT 286
FT /note="G -> S (in XLID29; dbSNP:rs28935479)"
FT /evidence="ECO:0000269|PubMed:11971879"
FT /id="VAR_015671"
FT VARIANT 332
FT /note="R -> H (in LISX2; dbSNP:rs111033612)"
FT /evidence="ECO:0000269|PubMed:12379852,
FT ECO:0000269|PubMed:14722918"
FT /id="VAR_015178"
FT VARIANT 332
FT /note="R -> P (in LISX2)"
FT /evidence="ECO:0000269|PubMed:14722918"
FT /id="VAR_033260"
FT VARIANT 333
FT /note="T -> N (in ACCAG; dbSNP:rs104894745)"
FT /evidence="ECO:0000269|PubMed:14722918"
FT /id="VAR_033261"
FT VARIANT 343
FT /note="L -> Q (in LISX2; dbSNP:rs104894741)"
FT /evidence="ECO:0000269|PubMed:12379852,
FT ECO:0000269|PubMed:14722918"
FT /id="VAR_015179"
FT VARIANT 353
FT /note="P -> L (in DEE1; corpus callosum hypoplasia and
FT simplified gyral pattern observed in one patient;
FT dbSNP:rs104894743)"
FT /evidence="ECO:0000269|PubMed:11889467,
FT ECO:0000269|PubMed:27864847"
FT /id="VAR_015180"
FT VARIANT 353
FT /note="P -> R (in LISX2)"
FT /evidence="ECO:0000269|PubMed:14722918"
FT /id="VAR_033262"
FT VARIANT 521
FT /note="A -> T (in LISX2; severe phenotype;
FT dbSNP:rs746120093)"
FT /evidence="ECO:0000269|PubMed:14722918"
FT /id="VAR_033263"
SQ SEQUENCE 562 AA; 58160 MW; FBDF41E387C65532 CRC64;
MSNQYQEEGC SERPECKSKS PTLLSSYCID SILGRRSPCK MRLLGAAQSL PAPLTSRADP
EKAVQGSPKS SSAPFEAELH LPPKLRRLYG PGGGRLLQGA AAAAAAAAAA AAAAATATAG
PRGEAPPPPP PTARPGERPD GAGAAAAAAA AAAAAWDTLK ISQAPQVSIS RSKSYRENGA
PFVPPPPALD ELGGPGGVTH PEERLGVAGG PGSAPAAGGG TGTEDDEEEL LEDEEDEDEE
EELLEDDEEE LLEDDARALL KEPRRCPVAA TGAVAAAAAA AVATEGGELS PKEELLLHPE
DAEGKDGEDS VCLSAGSDSE EGLLKRKQRR YRTTFTSYQL EELERAFQKT HYPDVFTREE
LAMRLDLTEA RVQVWFQNRR AKWRKREKAG AQTHPPGLPF PGPLSATHPL SPYLDASPFP
PHHPALDSAW TAAAAAAAAA FPSLPPPPGS ASLPPSGAPL GLSTFLGAAV FRHPAFISPA
FGRLFSTMAP LTSASTAAAL LRQPTPAVEG AVASGALADP ATAAADRRAS SIAALRLKAK
EHAAQLTQLN ILPGTSTGKE VC
