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   05-OCT-2010, entry version 36.
DE   RecName: Full=Protein ALEX;
DE   AltName: Full=Alternative gene product encoded by XL-exon;
GN   Name=GNAS; Synonyms=GNAS1;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC   Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC   Catarrhini; Hominidae; Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   MEDLINE=21638749; 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.,
RA   Beasley O.P., Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J.,
RA   Buck D., Burrill W.D., Butler A.P., Carder C., Carter N.P.,
RA   Chapman J.C., Clamp M., Clark G., Clark L.N., Clark S.Y., Clee C.M.,
RA   Clegg S., Cobley V.E., Collier R.E., Connor R.E., Corby N.R.,
RA   Coulson A., Coville G.J., Deadman R., Dhami P.D., Dunn M.,
RA   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.,
RA   Rice C.M., Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S.,
RA   Skuce C.D., Smith M.L., Soderlund C., Steward C.A., Sulston J.E.,
RA   Swann R.M., Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A.,
RA   Tracey A., Tromans A.C., Vaudin M., Wall M., Wallis J.M.,
RA   Whitehead S.L., Whittaker P., Willey D.L., Williams L., Williams S.A.,
RA   Wilming L., Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S.,
RA   Rogers J.;
RT   "The DNA sequence and comparative analysis of human chromosome 20.";
RL   Nature 414:865-871(2001).
RN   [2]
RP   PUTATIVE FUNCTION, AND VARIANTS GNAS HYPERFUNCTION 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]
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
RT   protein, is significantly longer than suspected, and so is its
RT   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.,
RA   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
RT   uncoupling 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.,
RA   Levine M.A.;
RT   "Discordance between genetic and epigenetic defects in
RT   pseudohypoparathyroidism type 1b revealed by inconsistent loss of
RT   maternal imprinting at GNAS1.";
RL   Am. J. Hum. Genet. 73:314-322(2003).
RN   [8]
RP   INVOLVEMENT IN AIMAH.
RX   PubMed=12727968; DOI=10.1210/jc.2002-021362;
RA   Fragoso M.C.B.V., Domenice S., Latronico A.C., Martin R.M.,
RA   Pereira M.A.A., 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.,
RA   Slyper A.H., Sugimoto T., Tsatsoulis A., Crawford J.D., Jueppner H.;
RT   "Autosomal dominant pseudohypoparathyroidism type Ib is associated
RT   with a heterozygous microdeletion that likely disrupts a putative
RT   imprinting 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
RT   type Ib redefines the boundaries of a cis-acting imprinting control
RT   element of 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
RT   of 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.,
RA   Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA   Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA   Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA   Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT   "The consensus coding sequences of human breast and colorectal
RT   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
CC       produced from the same locus in a different open reading frame.
CC   -!- SUBUNIT: Interacts with the N-terminal region of the XLas isoforms
CC       of guanine nucleotide-binding protein G(s) subunit alpha (By
CC       similarity).
CC   -!- SUBCELLULAR LOCATION: Cell membrane; Peripheral membrane protein.
CC       Cell projection, ruffle (By similarity). Note=Predominantly
CC       associated with cell membrane ruffles (By similarity).
CC   -!- DISEASE: Defects in GNAS are the cause of GNAS hyperfunction
CC       [MIM:139320]. This condition is characterized by increased trauma-
CC       related bleeding tendency, prolonged bleeding time, brachydactyly
CC       and mental retardation. Both the XLas isoforms and the ALEX
CC       protein are mutated which strongly reduces the interaction between
CC       them and this may allow unimpeded activation of the XLas isoforms.
CC   -!- DISEASE: Defects in GNAS are a cause of ACTH-independent
CC       macronodular adrenal hyperplasia (AIMAH) [MIM:219080]; also known
CC       as adrenal Cushing syndrome due to AIMAH. A rare adrenal defect
CC       characterized by multiple, bilateral, non-pigmented, benign,
CC       adrenocortical nodules. It results in excessive production of
CC       cortisol leading to ACTH-independent Cushing syndrome. Clinical
CC       manifestations of Cushing syndrome include facial and trunkal
CC       obesity, abdominal striae, muscular weakness, osteoporosis,
CC       arterial hypertension, diabetes.
CC   -!- DISEASE: Genetic variations in GNAS are the cause of
CC       pseudohypoparathyroidism type 1B (PHP1B) [MIM:603233]. PHP1B is
CC       characterized by parathyroid hormone (PTH)-resistant hypocalcemia
CC       and hyperphosphatemia. Patients affected with PHP1B have normal
CC       activity of the product of GNAS, lack developmental defects
CC       characteristic of AHO, and typically show no other endocrine
CC       abnormalities besides resistance to PTH. Most affected individuals
CC       have defects in methylation of the gene. In some cases
CC       microdeletions involving the STX16 appear to cause loss of
CC       methylation at exon A/B of GNAS, resulting in PHP1B. Paternal
CC       uniparental isodisomy have also been observed.
CC   -!- DISEASE: Defects in GNAS may be a cause of colorectal cancer (CRC)
CC       [MIM:114500].
CC   -!- MISCELLANEOUS: This protein is produced by a bicistronic gene
CC       which also produces guanine nucleotide-binding protein G(s)
CC       subunit alpha from an overlapping reading frame.
CC   -!- SIMILARITY: Belongs to the ALEX family.
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DR   EMBL; AL132655; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   IPI; IPI00790404; -.
DR   RefSeq; NP_001070958.1; -.
DR   UniGene; Hs.125898; -.
DR   UniGene; Hs.694849; -.
DR   ProteinModelPortal; P84996; -.
DR   IntAct; P84996; 3.
DR   Ensembl; ENST00000306120; ENSP00000302237; ENSG00000087460.
DR   GeneID; 2778; -.
DR   UCSC; uc002xzw.1; human.
DR   CTD; 2778; -.
DR   GeneCards; GC20P057414; -.
DR   HGNC; HGNC:4392; GNAS.
DR   HPA; CAB010337; -.
DR   MIM; 114500; phenotype.
DR   MIM; 139320; gene+phenotype.
DR   MIM; 219080; phenotype.
DR   MIM; 603233; phenotype.
DR   PharmGKB; PA175; -.
DR   NextBio; 10928; -.
DR   ArrayExpress; P84996; -.
DR   Bgee; P84996; -.
DR   CleanEx; HS_GNAS; -.
DR   Genevestigator; P84996; -.
DR   GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0001726; C:ruffle; IEA:UniProtKB-SubCell.
PE   1: Evidence at protein level;
KW   Cell membrane; Cell projection; Complete proteome; Cushing syndrome;
KW   Disease mutation; Membrane; Polymorphism.
FT   CHAIN         1    626       Protein ALEX.
FT                                /FTId=PRO_0000253964.
FT   COMPBIAS    238    476       Pro-rich.
FT   VARIANT     201    201       R -> C (in a colorectal cancer sample;
FT                                somatic mutation).
FT                                /FTId=VAR_035788.
FT   VARIANT     201    201       R -> H (in a colorectal cancer sample;
FT                                somatic mutation).
FT                                /FTId=VAR_035789.
FT   VARIANT     374    374       P -> T (in GNAS hyperfunction).
FT                                /FTId=VAR_028774.
FT   VARIANT     375    375       P -> PQPIPTPGRPLTP (in GNAS
FT                                hyperfunction).
FT                                /FTId=VAR_028775.
FT   VARIANT     397    397       L -> V (in GNAS hyperfunction).
FT                                /FTId=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
//