ALEX_HUMAN
ID ALEX_HUMAN Reviewed; 626 AA.
AC P84996; A2A2S4;
DT 17-OCT-2006, integrated into UniProtKB/Swiss-Prot.
DT 17-OCT-2006, sequence version 1.
DT 03-AUG-2022, entry version 114.
DE RecName: Full=Protein ALEX;
DE AltName: Full=Alternative gene product encoded by XL-exon;
GN Name=GNAS {ECO:0000312|HGNC:HGNC:4392};
GN Synonyms=GNAS1 {ECO:0000312|HGNC:HGNC:4392};
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] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=11780052; DOI=10.1038/414865a;
RA Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R.,
RA Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L.,
RA Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., Beasley O.P.,
RA Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J., Buck D., Burrill W.D.,
RA Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G.,
RA Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E.,
RA Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D.,
RA Dunn M., Ellington A.G., Frankland J.A., Fraser A., French L., Garner P.,
RA Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E.,
RA Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J.,
RA Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D.,
RA Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S.,
RA Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D.,
RA Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A.,
RA Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T.,
RA Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I.,
RA Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., Rice C.M.,
RA Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D.,
RA Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M.,
RA Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A.,
RA Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L.,
RA Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L.,
RA Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 20.";
RL Nature 414:865-871(2001).
RN [2] {ECO:0000305}
RP PUTATIVE FUNCTION, AND VARIANTS GNASHYP THR-374;
RP GLN-PRO-ILE-PRO-THR-PRO-GLY-ARG-PRO-LEU-THR-PRO-375 INS AND VAL-397.
RX PubMed=12719376; DOI=10.1093/hmg/ddg130;
RA Freson K., Jaeken J., Van Helvoirt M., de Zegher F., Wittevrongel C.,
RA Thys C., Hoylaerts M.F., Vermylen J., Van Geet C.;
RT "Functional polymorphisms in the paternally expressed XLalphas and its
RT cofactor ALEX decrease their mutual interaction and enhance receptor-
RT mediated cAMP formation.";
RL Hum. Mol. Genet. 12:1121-1130(2003).
RN [3] {ECO:0000305}
RP IDENTIFICATION.
RX PubMed=15148396; DOI=10.1073/pnas.0308758101;
RA Abramowitz J., Grenet D., Birnbaumer M., Torres H.N., Birnbaumer L.;
RT "XL alpha-s, the extra-long form of the alpha subunit of the Gs G protein,
RT is significantly longer than suspected, and so is its companion Alex.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:8366-8371(2004).
RN [4]
RP INVOLVEMENT IN PHP1B.
RX PubMed=11067869; DOI=10.1172/jci10431;
RA Liu J., Litman D., Rosenberg M.J., Yu S., Biesecker L.G., Weinstein L.S.;
RT "A GNAS1 imprinting defect in pseudohypoparathyroidism type IB.";
RL J. Clin. Invest. 106:1167-1174(2000).
RN [5]
RP INVOLVEMENT IN PHP1B.
RX PubMed=11294659; DOI=10.1086/320117;
RA Bastepe M., Lane A.H., Jueppner H.;
RT "Paternal uniparental isodisomy of chromosome 20q -- and the resulting
RT changes in GNAS1 methylation -- as a plausible cause of
RT pseudohypoparathyroidism.";
RL Am. J. Hum. Genet. 68:1283-1289(2001).
RN [6]
RP INVOLVEMENT IN PHP1B.
RX PubMed=11029463; DOI=10.1074/jbc.m006032200;
RA Wu W.-I., Schwindinger W.F., Aparicio L.F., Levine M.A.;
RT "Selective resistance to parathyroid hormone caused by a novel uncoupling
RT mutation in the carboxyl terminus of G alpha(s). A cause of
RT pseudohypoparathyroidism type Ib.";
RL J. Biol. Chem. 276:165-171(2001).
RN [7]
RP INVOLVEMENT IN PHP1B.
RX PubMed=12858292; DOI=10.1086/377136;
RA Jan de Beur S., Ding C., Germain-Lee E., Cho J., Maret A., Levine M.A.;
RT "Discordance between genetic and epigenetic defects in
RT pseudohypoparathyroidism type 1b revealed by inconsistent loss of maternal
RT imprinting at GNAS1.";
RL Am. J. Hum. Genet. 73:314-322(2003).
RN [8]
RP INVOLVEMENT IN AIMAH1.
RX PubMed=12727968; DOI=10.1210/jc.2002-021362;
RA Fragoso M.C.B.V., Domenice S., Latronico A.C., Martin R.M., Pereira M.A.A.,
RA Zerbini M.C.N., Lucon A.M., Mendonca B.B.;
RT "Cushing's syndrome secondary to adrenocorticotropin-independent
RT macronodular adrenocortical hyperplasia due to activating mutations of
RT GNAS1 gene.";
RL J. Clin. Endocrinol. Metab. 88:2147-2151(2003).
RN [9]
RP INVOLVEMENT IN PHP1B.
RX PubMed=14561710; DOI=10.1172/jci200319159;
RA Bastepe M., Froehlich L.F., Hendy G.N., Indridason O.S., Josse R.G.,
RA Koshiyama H., Koerkkoe J., Nakamoto J.M., Rosenbloom A.L., Slyper A.H.,
RA Sugimoto T., Tsatsoulis A., Crawford J.D., Jueppner H.;
RT "Autosomal dominant pseudohypoparathyroidism type Ib is associated with a
RT heterozygous microdeletion that likely disrupts a putative imprinting
RT control element of GNAS.";
RL J. Clin. Invest. 112:1255-1263(2003).
RN [10]
RP INVOLVEMENT IN PHP1B.
RX PubMed=15800843; DOI=10.1086/429932;
RA Linglart A., Gensure R.C., Olney R.C., Jueppner H., Bastepe M.;
RT "A novel STX16 deletion in autosomal dominant pseudohypoparathyroidism type
RT Ib redefines the boundaries of a cis-acting imprinting control element of
RT GNAS.";
RL Am. J. Hum. Genet. 76:804-814(2005).
RN [11]
RP INVOLVEMENT IN PHP1B.
RX PubMed=15592469; DOI=10.1038/ng1487;
RA Bastepe M., Froehlich L.F., Linglart A., Abu-Zahra H.S., Tojo K.,
RA Ward L.M., Jueppner H.;
RT "Deletion of the NESP55 differentially methylated region causes loss of
RT maternal GNAS imprints and pseudohypoparathyroidism type Ib.";
RL Nat. Genet. 37:25-27(2005).
RN [12]
RP VARIANTS [LARGE SCALE ANALYSIS] CYS-201 AND HIS-201.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P.,
RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: May inhibit the adenylyl cyclase-stimulating activity of
CC guanine nucleotide-binding protein G(s) subunit alpha which is produced
CC from the same locus in a different open reading frame.
CC {ECO:0000269|PubMed:12719376}.
CC -!- SUBUNIT: Interacts with the N-terminal region of the XLas isoforms of
CC guanine nucleotide-binding protein G(s) subunit alpha. {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Cell membrane; Peripheral membrane protein. Cell
CC projection, ruffle {ECO:0000250}. Note=Predominantly associated with
CC cell membrane ruffles. {ECO:0000250}.
CC -!- DISEASE: GNAS hyperfunction (GNASHYP) [MIM:139320]: This condition is
CC characterized by increased trauma-related bleeding tendency, prolonged
CC bleeding time, brachydactyly and intellectual disability. Both the XLas
CC isoforms and the ALEX protein are mutated which strongly reduces the
CC interaction between them and this may allow unimpeded activation of the
CC XLas isoforms. {ECO:0000269|PubMed:12719376}. Note=The disease is
CC caused by variants affecting the gene represented in this entry.
CC -!- DISEASE: ACTH-independent macronodular adrenal hyperplasia 1 (AIMAH1)
CC [MIM:219080]: A rare adrenal defect characterized by multiple,
CC bilateral, non-pigmented, benign, adrenocortical nodules. It results in
CC excessive production of cortisol leading to ACTH-independent Cushing
CC syndrome. Clinical manifestations of Cushing syndrome include facial
CC and truncal obesity, abdominal striae, muscular weakness, osteoporosis,
CC arterial hypertension, diabetes. {ECO:0000269|PubMed:12727968}.
CC Note=The disease is caused by variants affecting the gene represented
CC in this entry.
CC -!- DISEASE: Pseudohypoparathyroidism 1B (PHP1B) [MIM:603233]: A disorder
CC characterized by end-organ resistance to parathyroid hormone,
CC hypocalcemia and hyperphosphatemia. Patients affected with PHP1B lack
CC developmental defects characteristic of Albright hereditary
CC osteodystrophy, and typically show no other endocrine abnormalities
CC besides resistance to PTH. {ECO:0000269|PubMed:11029463,
CC ECO:0000269|PubMed:11067869, ECO:0000269|PubMed:11294659,
CC ECO:0000269|PubMed:12858292, ECO:0000269|PubMed:14561710,
CC ECO:0000269|PubMed:15592469, ECO:0000269|PubMed:15800843}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry. Most affected individuals have defects in methylation of the
CC gene. In some cases microdeletions involving the STX16 appear to cause
CC loss of methylation at exon A/B of GNAS, resulting in PHP1B. Paternal
CC uniparental isodisomy have also been observed.
CC -!- DISEASE: Colorectal cancer (CRC) [MIM:114500]: A complex disease
CC characterized by malignant lesions arising from the inner wall of the
CC large intestine (the colon) and the rectum. Genetic alterations are
CC often associated with progression from premalignant lesion (adenoma) to
CC invasive adenocarcinoma. Risk factors for cancer of the colon and
CC rectum include colon polyps, long-standing ulcerative colitis, and
CC genetic family history. Note=The disease may be caused by variants
CC affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: This protein is produced by a bicistronic gene which
CC also produces guanine nucleotide-binding protein G(s) subunit alpha
CC from an overlapping reading frame. {ECO:0000269|PubMed:15148396}.
CC -!- SIMILARITY: Belongs to the ALEX family. {ECO:0000305}.
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DR EMBL; AL132655; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR RefSeq; NP_001070958.1; NM_001077490.2.
DR RefSeq; NP_001296812.1; NM_001309883.1.
DR AlphaFoldDB; P84996; -.
DR BioGRID; 109040; 213.
DR IntAct; P84996; 8.
DR MINT; P84996; -.
DR iPTMnet; P84996; -.
DR SwissPalm; P84996; -.
DR BioMuta; GNAS; -.
DR DMDM; 116242967; -.
DR PeptideAtlas; P84996; -.
DR PRIDE; P84996; -.
DR ProteomicsDB; 57761; -.
DR Antibodypedia; 4152; 809 antibodies from 44 providers.
DR DNASU; 2778; -.
DR GeneID; 2778; -.
DR UCSC; uc061ybz.1; human.
DR CTD; 2778; -.
DR DisGeNET; 2778; -.
DR GeneCards; GNAS; -.
DR GeneReviews; GNAS; -.
DR HGNC; HGNC:4392; GNAS.
DR HPA; ENSG00000087460; Low tissue specificity.
DR MalaCards; GNAS; -.
DR MIM; 114500; phenotype.
DR MIM; 139320; gene+phenotype.
DR MIM; 219080; phenotype.
DR MIM; 603233; phenotype.
DR neXtProt; NX_P84996; -.
DR PharmGKB; PA175; -.
DR VEuPathDB; HostDB:ENSG00000087460; -.
DR HOGENOM; CLU_437395_0_0_1; -.
DR OrthoDB; 754573at2759; -.
DR PathwayCommons; P84996; -.
DR SignaLink; P84996; -.
DR SIGNOR; P84996; -.
DR BioGRID-ORCS; 2778; 28 hits in 1092 CRISPR screens.
DR ChiTaRS; GNAS; human.
DR GenomeRNAi; 2778; -.
DR Pharos; P84996; Tbio.
DR Proteomes; UP000005640; Chromosome 20.
DR Bgee; ENSG00000087460; Expressed in type B pancreatic cell and 213 other tissues.
DR ExpressionAtlas; P84996; baseline and differential.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0016020; C:membrane; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0001726; C:ruffle; IEA:UniProtKB-SubCell.
DR GO; GO:0007189; P:adenylate cyclase-activating G protein-coupled receptor signaling pathway; IMP:UniProtKB.
DR GO; GO:0060348; P:bone development; IMP:UniProtKB.
DR GO; GO:0050890; P:cognition; IMP:UniProtKB.
DR GO; GO:0048589; P:developmental growth; IMP:UniProtKB.
DR GO; GO:0060789; P:hair follicle placode formation; IMP:UniProtKB.
DR GO; GO:0070527; P:platelet aggregation; IMP:UniProtKB.
DR GO; GO:0120162; P:positive regulation of cold-induced thermogenesis; ISS:YuBioLab.
DR GO; GO:0009966; P:regulation of signal transduction; IMP:CACAO.
PE 1: Evidence at protein level;
KW Cell membrane; Cell projection; Cushing syndrome; Disease variant;
KW Membrane; Reference proteome.
FT CHAIN 1..626
FT /note="Protein ALEX"
FT /id="PRO_0000253964"
FT REGION 1..29
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 173..223
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 236..473
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 556..612
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 186..216
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 254..275
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 279..314
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 317..345
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 346..361
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 362..420
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 436..465
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 577..591
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 598..612
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT VARIANT 201
FT /note="R -> C (in a colorectal cancer sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_035788"
FT VARIANT 201
FT /note="R -> H (in a colorectal cancer sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_035789"
FT VARIANT 374
FT /note="P -> T (in GNASHYP; dbSNP:rs1376506169)"
FT /evidence="ECO:0000269|PubMed:12719376"
FT /id="VAR_028774"
FT VARIANT 375
FT /note="P -> PQPIPTPGRPLTP (in GNASHYP)"
FT /id="VAR_028775"
FT VARIANT 397
FT /note="L -> V (in GNASHYP)"
FT /evidence="ECO:0000269|PubMed:12719376"
FT /id="VAR_028776"
SQ SEQUENCE 626 AA; 67948 MW; F4CEFA7FA5917EEC CRC64;
MMARPVDPQR SPDPTFRSST RHSGKLEPME ATAHLLRKQC PSRLNSPAWE ASGLHWSSLD
SPVGSMQALR PSAQHSWSPE PSVVPDQAWE DTALHQKKLC PLSLTSLPRE AAVNFSYRSQ
TLLQEAQVLQ GSPELLPRSP KPSGLQRLAP EEATALPLRR LCHLSLMEKD LGTTAHPRGF
PELSHKSTAA ASSRQSRPRV RSASLPPRTR LPSGSQAPSA AHPKRLSDLL LTSRAAAPGW
RSPDPRSRLA APPLGSTTLP STWTAPQSRL TARPSRSPEP QIRESEQRDP QLRRKQQRWK
EPLMPRREEK YPLRGTDPLP PGQPQRIPLP GQPLQPQPIL TPGQPQKIPT PGQHQPILTP
GHSQPIPTPG QPLPPQPIPT PGRPLTPQPI PTPGRPLTPQ PIQMPGRPLR LPPPLRLLRP
GQPMSPQLRQ TQGLPLPQPL LPPGQPKSAG RPLQPLPPGP DARSISDPPA PRSRLPIRLL
RGLLARLPGG ASPRAAAAAA CTTMKGWPAA TMTPAETSPT MGPPDASAGF SIGEIAAAES
PSATYSATFS CKPSGAASVD LRVPSPKPRA LSRSRRYPWR RSADRCAKKP WRSGPRSAQR
RNAVSSSTNN SRTKRWATCV RTACCF
