RBCC Red Blood Cell Collection

GNAS (GNAS1, GSP) [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Guanine nucleotide-binding protein G(s) subunit alpha isoforms short (Adenylate cyclase-stimulating G alpha protein)

Comments
Isoform P63092-2 was detected.

UniProt P63092
ID GNAS2_HUMAN Reviewed; 394 AA.
AC P63092; A6NI00; E1P5G5; P04895; Q12927; Q14433; Q32P26; Q5JWD2;
read moreAC Q5JWD4; Q5JWD5; Q6NR75; Q6NXS0; Q8TBC0; Q96H70;
DT 13-AUG-1987, integrated into UniProtKB/Swiss-Prot.
DT 13-AUG-1987, sequence version 1.
DT 22-JAN-2014, entry version 112.
DE RecName: Full=Guanine nucleotide-binding protein G(s) subunit alpha isoforms short;
DE AltName: Full=Adenylate cyclase-stimulating G alpha protein;
GN Name=GNAS; Synonyms=GNAS1, GSP;
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 [MRNA] (ISOFORMS GNAS-1 AND GNAS-2).
RC TISSUE=Liver;
RX PubMed=3093273; DOI=10.1016/0014-5793(86)81336-9;
RA Mattera R., Codina J., Crozat A., Kidd V., Woo S.L.C., Birnbaumer L.;
RT "Identification by molecular cloning of two forms of the alpha-subunit
RT of the human liver stimulatory (GS) regulatory component of adenylyl
RT cyclase.";
RL FEBS Lett. 206:36-42(1986).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM GNAS-1).
RX PubMed=3131741; DOI=10.1093/nar/16.8.3585;
RA Harris B.A.;
RT "Complete cDNA sequence of a human stimulatory GTP-binding protein
RT alpha subunit.";
RL Nucleic Acids Res. 16:3585-3585(1988).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND ALTERNATIVE SPLICING (ISOFORMS
RP GNAS-1 AND GNAS-2).
RX PubMed=3127824; DOI=10.1073/pnas.85.7.2081;
RA Kozasa T., Itoh H., Tsukamoto T., Kaziro Y.;
RT "Isolation and characterization of the human Gs alpha gene.";
RL Proc. Natl. Acad. Sci. U.S.A. 85:2081-2085(1988).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS GNAS-1 AND GNAS-2).
RA Puhl H.L. III, Ikeda S.R., Aronstam R.S.;
RT "cDNA clones of human proteins involved in signal transduction
RT sequenced by the Guthrie cDNA resource center (www.cdna.org).";
RL Submitted (MAR-2002) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM GNAS-1).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (AUG-2003) to the EMBL/GenBank/DDBJ databases.
RN [6]
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.,
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 [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS GNAS-1; 3 AND 4).
RC TISSUE=Bone marrow, Brain, Muscle, and Pancreas;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [9]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 12-394 (ISOFORMS GNAS-1 AND 4).
RX PubMed=3024154; DOI=10.1073/pnas.83.23.8893;
RA Bray P., Carter A., Simons C., Guo V., Puckett C., Kamholz J.,
RA Spiegel A., Nirenberg M.;
RT "Human cDNA clones for four species of G alpha s signal transduction
RT protein.";
RL Proc. Natl. Acad. Sci. U.S.A. 83:8893-8897(1986).
RN [10]
RP PROTEIN SEQUENCE OF 187-199 AND 308-317.
RC TISSUE=Adipocyte;
RX PubMed=15242332; DOI=10.1042/BJ20040647;
RA Aboulaich N., Vainonen J.P., Stralfors P., Vener A.V.;
RT "Vectorial proteomics reveal targeting, phosphorylation and specific
RT fragmentation of polymerase I and transcript release factor (PTRF) at
RT the surface of caveolae in human adipocytes.";
RL Biochem. J. 383:237-248(2004).
RN [11]
RP FUNCTION.
RX PubMed=12391161; DOI=10.1128/MCB.22.22.7942-7952.2002;
RA Pak Y., Pham N., Rotin D.;
RT "Direct binding of the beta1 adrenergic receptor to the cyclic AMP-
RT dependent guanine nucleotide exchange factor CNrasGEF leads to Ras
RT activation.";
RL Mol. Cell. Biol. 22:7942-7952(2002).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-352, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [14]
RP PALMITOYLATION AT CYS-3.
RX PubMed=21044946; DOI=10.1194/jlr.D011106;
RA Forrester M.T., Hess D.T., Thompson J.W., Hultman R., Moseley M.A.,
RA Stamler J.S., Casey P.J.;
RT "Site-specific analysis of protein S-acylation by resin-assisted
RT capture.";
RL J. Lipid Res. 52:393-398(2011).
RN [15]
RP VARIANTS AHO PRO-99 AND CYS-165.
RX PubMed=8388883; DOI=10.1210/jc.76.6.1560;
RA Miric A., Vechio J.D., Levine M.A.;
RT "Heterogeneous mutations in the gene encoding the alpha-subunit of the
RT stimulatory G protein of adenylyl cyclase in Albright hereditary
RT osteodystrophy.";
RL J. Clin. Endocrinol. Metab. 76:1560-1568(1993).
RN [16]
RP VARIANT MAS HIS-201.
RX PubMed=1594625; DOI=10.1073/pnas.89.11.5152;
RA Schwindinger W.F., Francomano C.A., Levine M.A.;
RT "Identification of a mutation in the gene encoding the alpha subunit
RT of the stimulatory G protein of adenylyl cyclase in McCune-Albright
RT syndrome.";
RL Proc. Natl. Acad. Sci. U.S.A. 89:5152-5156(1992).
RN [17]
RP VARIANTS MAS CYS-201 AND HIS-201.
RX PubMed=1944469;
RA Weinstein L.S., Shenker A., Gejman P.V., Merino M.J., Friedman E.,
RA Spiegel A.M.;
RT "Activating mutations of the stimulatory G protein in the McCune-
RT Albright syndrome.";
RL N. Engl. J. Med. 325:1688-1695(1991).
RN [18]
RP VARIANTS SOMATOTROPHINOMA CYS-201; HIS-201 AND ARG-227.
RX PubMed=2549426; DOI=10.1038/340692a0;
RA Landis C.A., Masters S.B., Spada A., Pace A.M., Bourne H.R.,
RA Vallar L.;
RT "GTPase inhibiting mutations activate the alpha chain of Gs and
RT stimulate adenylyl cyclase in human pituitary tumours.";
RL Nature 340:692-696(1989).
RN [19]
RP VARIANT AHO HIS-385.
RX PubMed=7523385;
RA Schwindinger W.F., Miric A., Zimmerman D., Levine M.A.;
RT "A novel Gs alpha mutant in a patient with Albright hereditary
RT osteodystrophy uncouples cell surface receptors from adenylyl
RT cyclase.";
RL J. Biol. Chem. 269:25387-25391(1994).
RN [20]
RP CHARACTERIZATION OF VARIANT AHO SER-366.
RX PubMed=8072545; DOI=10.1038/371164a0;
RA Iiri T., Herzmark P., Nakamoto J.M., van Dop C., Bourne H.R.;
RT "Rapid GDP release from Gs alpha in patients with gain and loss of
RT endocrine function.";
RL Nature 371:164-168(1994).
RN [21]
RP VARIANT NON-MAS ENDOCRINE TUMORS LEU-201.
RX PubMed=7751320; DOI=10.1007/BF01366965;
RA Gorelov V.N., Dumon K., Barteneva N.S., Palm D., Roher H.-D.,
RA Goretzki P.E.;
RT "Overexpression of Gs alpha subunit in thyroid tumors bearing a
RT mutated Gs alpha gene.";
RL J. Cancer Res. Clin. Oncol. 121:219-224(1995).
RN [22]
RP VARIANT PITUITARY ADENOMA HIS-227.
RX PubMed=7737262; DOI=10.1111/j.1365-2362.1995.tb01537.x;
RA Williamson E.A., Ince P.G., Harrison D., Kendall-Taylor P.,
RA Harris P.E.;
RT "G-protein mutations in human pituitary adrenocorticotrophic hormone-
RT secreting adenomas.";
RL Eur. J. Clin. Invest. 25:128-131(1995).
RN [23]
RP VARIANT PITUITARY TUMOR SER-201.
RX PubMed=8766942;
RA Yang I., Park S., Ryu M., Woo J., Kim S., Kim J., Kim Y., Choi Y.;
RT "Characteristics of gsp-positive growth hormone-secreting pituitary
RT tumors in Korean acromegalic patients.";
RL Eur. J. Endocrinol. 134:720-726(1996).
RN [24]
RP CHARACTERIZATION OF VARIANT AHO HIS-231.
RX PubMed=8702665; DOI=10.1074/jbc.271.33.19653;
RA Farfel Z., Iiri T., Shapira H., Roitman A., Mouallem M., Bourne H.R.;
RT "Pseudohypoparathyroidism, a novel mutation in the betagamma-contact
RT region of Gsalpha impairs receptor stimulation.";
RL J. Biol. Chem. 271:19653-19655(1996).
RN [25]
RP VARIANT POLYOSTOTIC FIBROUS DYSPLASIA SER-201.
RX PubMed=9267696; DOI=10.1016/S8756-3282(97)00107-5;
RA Candeliere G.A., Roughley P.J., Glorieux F.H.;
RT "Polymerase chain reaction-based technique for the selective
RT enrichment and analysis of mosaic arg201 mutations in G alpha s from
RT patients with fibrous dysplasia of bone.";
RL Bone 21:201-206(1997).
RN [26]
RP VARIANT AHO ARG-250.
RX PubMed=9328353; DOI=10.1210/me.11.11.1718;
RA Warner D.R., Gejman P.V., Collins R.M., Weinstein L.S.;
RT "A novel mutation adjacent to the switch III domain of G(S alpha) in a
RT patient with pseudohypoparathyroidism.";
RL Mol. Endocrinol. 11:1718-1727(1997).
RN [27]
RP CHARACTERIZATION OF VARIANT AHO HIS-231.
RX PubMed=9159128; DOI=10.1073/pnas.94.11.5656;
RA Iiri T., Farfel Z., Bourne H.R.;
RT "Conditional activation defect of a human Gsalpha mutant.";
RL Proc. Natl. Acad. Sci. U.S.A. 94:5656-5661(1997).
RN [28]
RP VARIANT AHO TRP-258, MUTAGENESIS OF ARG-258, AND CHARACTERIZATION OF
RP VARIANT AHO TRP-258.
RX PubMed=9727013; DOI=10.1074/jbc.273.37.23976;
RA Warner D.R., Weng G., Yu S., Matalon R., Weinstein L.S.;
RT "A novel mutation in the switch 3 region of Gs-alpha in a patient with
RT Albright hereditary osteodystrophy impairs GDP binding and receptor
RT activation.";
RL J. Biol. Chem. 273:23976-23983(1998).
RN [29]
RP VARIANT MAS GLY-201.
RX PubMed=10571700; DOI=10.1359/jbmr.1999.14.11.1987;
RA Riminucci M., Fisher L.W., Majolagbe A., Corsi A., Lala R.,
RA De Sanctis C., Robey P.G., Bianco P.;
RT "A novel GNAS1 mutation, R201G, in McCune-albright syndrome.";
RL J. Bone Miner. Res. 14:1987-1989(1999).
RN [30]
RP MUTAGENESIS OF GLN-170 AND ARG-258.
RX PubMed=10200251; DOI=10.1073/pnas.96.8.4268;
RA Warner D.R., Weinstein L.S.;
RT "A mutation in the heterotrimeric stimulatory guanine nucleotide
RT binding protein alpha-subunit with impaired receptor-mediated
RT activation because of elevated GTPase activity.";
RL Proc. Natl. Acad. Sci. U.S.A. 96:4268-4272(1999).
RN [31]
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 [32]
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 [33]
RP INVOLVEMENT IN PHP1B, VARIANT ILE-382 DEL, AND CHARACTERIZATION OF
RP VARIANT ILE-382 DEL.
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 [34]
RP VARIANT AHO HIS-231.
RX PubMed=11450852; DOI=10.1007/s100380170062;
RA Ishikawa Y., Tajima T., Nakae J., Nagashima T., Satoh K., Okuhara K.,
RA Fujieda K.;
RT "Two mutations of the Gsalpha gene in two Japanese patients with
RT sporadic pseudohypoparathyroidism type Ia.";
RL J. Hum. Genet. 46:426-430(2001).
RN [35]
RP VARIANT AHO LEU-115.
RX PubMed=11600516; DOI=10.1210/jc.86.10.4630;
RA Ahrens W., Hiort O., Staedt P., Kirschner T., Marschke C., Kruse K.;
RT "Analysis of the GNAS1 gene in Albright's hereditary osteodystrophy.";
RL J. Clin. Endocrinol. Metab. 86:4630-4634(2001).
RN [36]
RP VARIANTS PHP1A ASN-156; MET-159 AND LYS-280.
RX PubMed=11788646; DOI=10.1210/jc.87.1.189;
RA Linglart A., Carel J.-C., Garabedian M., Le T., Mallet E.,
RA Kottler M.-L.;
RT "GNAS1 lesions in pseudohypoparathyroidism Ia and Ic: genotype
RT phenotype relationship and evidence of the maternal transmission of
RT the hormonal resistance.";
RL J. Clin. Endocrinol. Metab. 87:189-197(2002).
RN [37]
RP VARIANT PHP1A GLY-280.
RX PubMed=11926205;
RA Lim S.H., Poh L.K., Cowell C.T., Tey B.H., Loke K.Y.;
RT "Mutational analysis of the GNAS1 exons encoding the stimulatory G
RT protein in five patients with pseudohypoparathyroidism type 1a.";
RL J. Pediatr. Endocrinol. Metab. 15:259-268(2002).
RN [38]
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 [39]
RP VARIANTS AHO ILE-242; SER-246 AND VAL-259.
RX PubMed=12624854; DOI=10.1086/374566;
RA Rickard S.J., Wilson L.C.;
RT "Analysis of GNAS1 and overlapping transcripts identifies the parental
RT origin of mutations in patients with sporadic Albright hereditary
RT osteodystrophy and reveals a model system in which to observe the
RT effects of splicing mutations on translated and untranslated messenger
RT RNA.";
RL Am. J. Hum. Genet. 72:961-974(2003).
RN [40]
RP VARIANT PHP1A ASN-338.
RX PubMed=12656668; DOI=10.1530/eje.0.1480463;
RA Pohlenz J., Ahrens W., Hiort O.;
RT "A new heterozygous mutation (L338N) in the human Gsalpha (GNAS1) gene
RT as a cause for congenital hypothyroidism in Albright's hereditary
RT osteodystrophy.";
RL Eur. J. Endocrinol. 148:463-468(2003).
RN [41]
RP VARIANTS AIMAH HIS-201 AND SER-201.
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 [42]
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 [43]
RP VARIANT POH ARG-281.
RX PubMed=14723729; DOI=10.1111/j.1365-2230.2004.01439.x;
RA Chan I., Hamada T., Hardman C., McGrath J.A., Child F.J.;
RT "Progressive osseous heteroplasia resulting from a new mutation in the
RT GNAS1 gene.";
RL Clin. Exp. Dermatol. 29:77-80(2004).
RN [44]
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 [45]
RP VARIANT AHO/PHP1A SER-106.
RX PubMed=15817905; DOI=10.1530/eje.1.01879;
RA Riepe F.G., Ahrens W., Krone N., Foelster-Holst R., Brasch J.,
RA Sippell W.G., Hiort O., Partsch C.-J.;
RT "Early manifestation of calcinosis cutis in pseudohypoparathyroidism
RT type Ia associated with a novel mutation in the GNAS gene.";
RL Eur. J. Endocrinol. 152:515-519(2005).
RN [46]
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 [47]
RP VARIANTS PHP1C ARG-388 AND LYS-392, AND CHARACTERIZATION OF VARIANTS
RP PHP1C ARG-388 AND LYS-392.
RX PubMed=21488135; DOI=10.1002/humu.21489;
RA Thiele S., de Sanctis L., Werner R., Grotzinger J., Aydin C.,
RA Juppner H., Bastepe M., Hiort O.;
RT "Functional characterization of GNAS mutations found in patients with
RT pseudohypoparathyroidism type Ic defines a new subgroup of
RT pseudohypoparathyroidism affecting selectively Gsalpha-receptor
RT interaction.";
RL Hum. Mutat. 32:653-660(2011).
CC -!- FUNCTION: Guanine nucleotide-binding proteins (G proteins) are
CC involved as modulators or transducers in various transmembrane
CC signaling systems. The G(s) protein is involved in hormonal
CC regulation of adenylate cyclase: it activates the cyclase in
CC response to beta-adrenergic stimuli. Stimulates the Ras signaling
CC pathway via RAPGEF2.
CC -!- SUBUNIT: G proteins are composed of 3 units; alpha, beta and
CC gamma. The alpha chain contains the guanine nucleotide binding
CC site.
CC -!- INTERACTION:
CC P42866:Oprm1 (xeno); NbExp=2; IntAct=EBI-7607528, EBI-5282656;
CC -!- SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor (By similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=8;
CC Name=Gnas-1; Synonyms=Alpha-S2, GNASl, Alpha-S-long;
CC IsoId=P63092-1, P04895-1;
CC Sequence=Displayed;
CC Name=Gnas-2; Synonyms=Alpha-S1, GNASs, Alpha-S-short;
CC IsoId=P63092-2, P04895-2;
CC Sequence=VSP_001833, VSP_001834;
CC Name=3;
CC IsoId=P63092-3; Sequence=VSP_026616, VSP_026617;
CC Note=No experimental confirmation available;
CC Name=XLas-1;
CC IsoId=Q5JWF2-1; Sequence=External;
CC Note=Gene prediction confirmed by EST data;
CC Name=XLas-2;
CC IsoId=Q5JWF2-2; Sequence=External;
CC Note=Gene prediction confirmed by EST data;
CC Name=XLas-3;
CC IsoId=Q5JWF2-3; Sequence=External;
CC Name=Nesp55;
CC IsoId=O95467-1; Sequence=External;
CC Note=Shares no sequence similarity with other isoforms due to a
CC novel first exon containing the entire reading frame spliced to
CC shared exon 2 so that exons 2-13 make up the 3'-UTR;
CC Name=4;
CC IsoId=P63092-4; Sequence=VSP_047325;
CC Note=Gene prediction based on EST data;
CC -!- DISEASE: Albright hereditary osteodystrophy (AHO) [MIM:103580]: A
CC disorder characterized by short stature, obesity, round facies,
CC brachydactyly and subcutaneous calcification. It is often
CC associated with pseudohypoparathyoidism, hypocalcemia and elevated
CC PTH levels. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- DISEASE: Pseudohypoparathyroidism 1A (PHP1A) [MIM:103580]: A
CC disorder characterized by end-organ resistance to parathyroid
CC hormone, hypocalcemia and hyperphosphatemia. It is commonly
CC associated with Albright hereditary osteodystrophy whose features
CC are short stature, obesity, round facies, short metacarpals and
CC ectopic calcification. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: McCune-Albright syndrome (MAS) [MIM:174800]:
CC Characterized by polyostotic fibrous dysplasia, cafe-au-lait
CC lesions, and a variety of endocrine disorders, including
CC precocious puberty, hyperthyroidism, hypercortisolism, growth
CC hormone excess, and hyperprolactinemia. The mutations producing
CC MAS lead to constitutive activation of GS alpha. Note=The disease
CC is caused by mutations affecting the gene represented in this
CC entry.
CC -!- DISEASE: Growth hormone-secreting pituitary adenoma (GHSPA)
CC [MIM:102200]: Pituitary adenomas include somatotropinoma and
CC prolactinoma. Note=The disease is caused by mutations affecting
CC the gene represented in this entry.
CC -!- DISEASE: Progressive osseous heteroplasia (POH) [MIM:166350]: Rare
CC autosomal dominant disorder characterized by extensive dermal
CC ossification during childhood, followed by disabling and
CC widespread heterotopic ossification of skeletal muscle and deep
CC connective tissue. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: ACTH-independent macronodular adrenal hyperplasia (AIMAH)
CC [MIM:219080]: A rare adrenal defect characterized by multiple,
CC bilateral, non-pigmented, benign, adrenocortical nodules. It
CC results in excessive production of cortisol leading to ACTH-
CC independent Cushing syndrome. Clinical manifestations of Cushing
CC syndrome include facial and truncal obesity, abdominal striae,
CC muscular weakness, osteoporosis, arterial hypertension, diabetes.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Pseudohypoparathyroidism 1B (PHP1B) [MIM:603233]: A
CC disorder characterized by end-organ resistance to parathyroid
CC hormone, hypocalcemia and hyperphosphatemia. Patients affected
CC with PHP1B lack developmental defects characteristic of Albright
CC hereditary osteodystrophy, and typically show no other endocrine
CC abnormalities besides resistance to PTH. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC Most affected individuals have defects in methylation of the gene.
CC In some cases microdeletions involving the STX16 appear to cause
CC loss of methylation at exon A/B of GNAS, resulting in PHP1B.
CC Paternal uniparental isodisomy have also been observed.
CC -!- DISEASE: GNAS hyperfunction (GNASHYP) [MIM:139320]: This condition
CC is characterized by increased trauma-related bleeding tendency,
CC prolonged bleeding time, brachydactyly and mental retardation.
CC Both the XLas isoforms and the ALEX protein are mutated which
CC strongly reduces the interaction between them and this may allow
CC unimpeded activation of the XLas isoforms. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- DISEASE: Pseudohypoparathyroidism 1C (PHP1C) [MIM:612462]: A
CC disorder characterized by end-organ resistance to parathyroid
CC hormone, hypocalcemia and hyperphosphatemia. It is commonly
CC associated with Albright hereditary osteodystrophy whose features
CC are short stature, obesity, round facies, short metacarpals and
CC ectopic calcification. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: This protein is produced by a bicistronic gene
CC which also produces the ALEX protein from an overlapping reading
CC frame.
CC -!- MISCELLANEOUS: The GNAS locus is imprinted in a complex manner,
CC giving rise to distinct paternally, maternally and biallelically
CC expressed proteins. The XLas isoforms are paternally derived, the
CC Gnas isoforms are biallelically derived and the Nesp55 isoforms
CC are maternally derived.
CC -!- SIMILARITY: Belongs to the G-alpha family. G(s) subfamily.
CC -!- WEB RESOURCE: Name=GNAS mutation db;
CC URL="http://www.le.ac.uk/genetics/maa7/GNAS1/";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/GNAS";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
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DR EMBL; X04408; CAA27996.1; -; mRNA.
DR EMBL; X04409; CAA27997.1; -; mRNA.
DR EMBL; M21142; AAA53147.1; -; Genomic_DNA.
DR EMBL; M21139; AAA53147.1; JOINED; Genomic_DNA.
DR EMBL; M21740; AAA53147.1; JOINED; Genomic_DNA.
DR EMBL; M21140; AAA53147.1; JOINED; Genomic_DNA.
DR EMBL; M21741; AAA53147.1; JOINED; Genomic_DNA.
DR EMBL; M21141; AAA53147.1; JOINED; Genomic_DNA.
DR EMBL; M21142; AAA53146.1; -; Genomic_DNA.
DR EMBL; M21139; AAA53146.1; JOINED; Genomic_DNA.
DR EMBL; M21740; AAA53146.1; JOINED; Genomic_DNA.
DR EMBL; M21140; AAA53146.1; JOINED; Genomic_DNA.
DR EMBL; M21741; AAA53146.1; JOINED; Genomic_DNA.
DR EMBL; M21141; AAA53146.1; JOINED; Genomic_DNA.
DR EMBL; M21142; AAA53148.1; -; Genomic_DNA.
DR EMBL; M21139; AAA53148.1; JOINED; Genomic_DNA.
DR EMBL; M21141; AAA53148.1; JOINED; Genomic_DNA.
DR EMBL; M21740; AAA53148.1; JOINED; Genomic_DNA.
DR EMBL; M21741; AAA53148.1; JOINED; Genomic_DNA.
DR EMBL; M21142; AAA53149.1; -; Genomic_DNA.
DR EMBL; M21139; AAA53149.1; JOINED; Genomic_DNA.
DR EMBL; M21740; AAA53149.1; JOINED; Genomic_DNA.
DR EMBL; M21741; AAA53149.1; JOINED; Genomic_DNA.
DR EMBL; M21141; AAA53149.1; JOINED; Genomic_DNA.
DR EMBL; U12466; AAB60334.2; -; Genomic_DNA.
DR EMBL; X07036; CAA30084.1; -; mRNA.
DR EMBL; AF493897; AAM12611.1; -; mRNA.
DR EMBL; AF493898; AAM12612.1; -; mRNA.
DR EMBL; BT009905; AAP88907.1; -; mRNA.
DR EMBL; AL109840; CAI42914.1; -; Genomic_DNA.
DR EMBL; AL121917; CAI42914.1; JOINED; Genomic_DNA.
DR EMBL; AL109840; CAI42915.1; -; Genomic_DNA.
DR EMBL; AL121917; CAI42915.1; JOINED; Genomic_DNA.
DR EMBL; AL109840; CAI42916.1; -; Genomic_DNA.
DR EMBL; AL121917; CAI42916.1; JOINED; Genomic_DNA.
DR EMBL; AL109840; CAI42917.1; -; Genomic_DNA.
DR EMBL; AL121917; CAI42917.1; JOINED; Genomic_DNA.
DR EMBL; AL121917; CAI42546.1; -; Genomic_DNA.
DR EMBL; AL109840; CAI42546.1; JOINED; Genomic_DNA.
DR EMBL; AL121917; CAI42547.1; -; Genomic_DNA.
DR EMBL; AL109840; CAI42547.1; JOINED; Genomic_DNA.
DR EMBL; AL121917; CAI42548.1; -; Genomic_DNA.
DR EMBL; AL109840; CAI42548.1; JOINED; Genomic_DNA.
DR EMBL; AL121917; CAI42549.1; -; Genomic_DNA.
DR EMBL; AL109840; CAI42549.1; JOINED; Genomic_DNA.
DR EMBL; AL132655; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471077; EAW75468.1; -; Genomic_DNA.
DR EMBL; CH471077; EAW75460.1; -; Genomic_DNA.
DR EMBL; CH471077; EAW75463.1; -; Genomic_DNA.
DR EMBL; BC002722; AAH02722.1; -; mRNA.
DR EMBL; BC008855; AAH08855.1; -; mRNA.
DR EMBL; BC066923; AAH66923.1; -; mRNA.
DR EMBL; BC022875; AAH22875.1; -; mRNA.
DR EMBL; BC104928; AAI04929.1; -; mRNA.
DR EMBL; BC108315; AAI08316.2; -; mRNA.
DR EMBL; M14631; AAA52583.1; -; mRNA.
DR PIR; B31927; RGHUA2.
DR PIR; C31927; RGHUA1.
DR RefSeq; NP_000507.1; NM_000516.4.
DR RefSeq; NP_001070956.1; NM_001077488.2.
DR RefSeq; NP_001070957.1; NM_001077489.2.
DR RefSeq; NP_001070958.1; NM_001077490.1.
DR RefSeq; NP_536350.2; NM_080425.2.
DR RefSeq; NP_536351.1; NM_080426.2.
DR UniGene; Hs.125898; -.
DR ProteinModelPortal; P63092; -.
DR SMR; P63092; 9-394.
DR IntAct; P63092; 5.
DR MINT; MINT-262348; -.
DR ChEMBL; CHEMBL4377; -.
DR PhosphoSite; P63092; -.
DR DMDM; 52000961; -.
DR PRIDE; P63092; -.
DR DNASU; 2778; -.
DR Ensembl; ENST00000265620; ENSP00000265620; ENSG00000087460.
DR Ensembl; ENST00000306090; ENSP00000304472; ENSG00000087460.
DR Ensembl; ENST00000354359; ENSP00000346328; ENSG00000087460.
DR Ensembl; ENST00000371085; ENSP00000360126; ENSG00000087460.
DR Ensembl; ENST00000371095; ENSP00000360136; ENSG00000087460.
DR GeneID; 2778; -.
DR KEGG; hsa:2778; -.
DR UCSC; uc021wfo.1; human.
DR CTD; 2778; -.
DR GeneCards; GC20P057414; -.
DR HGNC; HGNC:4392; GNAS.
DR HPA; CAB010337; -.
DR MIM; 102200; phenotype.
DR MIM; 103580; phenotype.
DR MIM; 139320; gene+phenotype.
DR MIM; 166350; phenotype.
DR MIM; 174800; phenotype.
DR MIM; 219080; phenotype.
DR MIM; 603233; phenotype.
DR MIM; 612462; phenotype.
DR neXtProt; NX_P63092; -.
DR PharmGKB; PA175; -.
DR HOVERGEN; HBG063184; -.
DR KO; K04632; -.
DR OMA; YEHTKTL; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_15518; Transmembrane transport of small molecules.
DR Reactome; REACT_604; Hemostasis.
DR ChiTaRS; GNAS; human.
DR GenomeRNAi; 2778; -.
DR NextBio; 10928; -.
DR PRO; PR:P63092; -.
DR ArrayExpress; P63092; -.
DR Bgee; P63092; -.
DR CleanEx; HS_GNAS; -.
DR Genevestigator; P63092; -.
DR GO; GO:0005737; C:cytoplasm; IDA:LIFEdb.
DR GO; GO:0005834; C:heterotrimeric G-protein complex; TAS:UniProtKB.
DR GO; GO:0031224; C:intrinsic to membrane; IDA:UniProtKB.
DR GO; GO:0032588; C:trans-Golgi network membrane; IDA:UniProtKB.
DR GO; GO:0004016; F:adenylate cyclase activity; TAS:Reactome.
DR GO; GO:0005525; F:GTP binding; IEA:UniProtKB-KW.
DR GO; GO:0003924; F:GTPase activity; TAS:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004871; F:signal transducer activity; IDA:UniProtKB.
DR GO; GO:0007190; P:activation of adenylate cyclase activity; TAS:UniProtKB.
DR GO; GO:0071880; P:adenylate cyclase-activating adrenergic receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0007191; P:adenylate cyclase-activating dopamine receptor signaling pathway; ISS:BHF-UCL.
DR GO; GO:0007596; P:blood coagulation; TAS:Reactome.
DR GO; GO:0071870; P:cellular response to catecholamine stimulus; ISS:BHF-UCL.
DR GO; GO:0071377; P:cellular response to glucagon stimulus; TAS:Reactome.
DR GO; GO:0071380; P:cellular response to prostaglandin E stimulus; ISS:BHF-UCL.
DR GO; GO:0006112; P:energy reserve metabolic process; TAS:Reactome.
DR GO; GO:0046907; P:intracellular transport; NAS:UniProtKB.
DR GO; GO:0043950; P:positive regulation of cAMP-mediated signaling; IDA:UniProtKB.
DR GO; GO:0032320; P:positive regulation of Ras GTPase activity; IDA:UniProtKB.
DR GO; GO:0050796; P:regulation of insulin secretion; TAS:Reactome.
DR GO; GO:0007608; P:sensory perception of smell; TAS:UniProtKB.
DR GO; GO:0055085; P:transmembrane transport; TAS:Reactome.
DR GO; GO:0006833; P:water transport; TAS:Reactome.
DR Gene3D; 1.10.400.10; -; 1.
DR InterPro; IPR000367; Gprotein_alpha_S.
DR InterPro; IPR001019; Gprotein_alpha_su.
DR InterPro; IPR011025; GproteinA_insert.
DR InterPro; IPR027417; P-loop_NTPase.
DR PANTHER; PTHR10218; PTHR10218; 1.
DR Pfam; PF00503; G-alpha; 1.
DR PRINTS; PR00318; GPROTEINA.
DR PRINTS; PR00443; GPROTEINAS.
DR SMART; SM00275; G_alpha; 1.
DR SUPFAM; SSF47895; SSF47895; 1.
DR SUPFAM; SSF52540; SSF52540; 2.
PE 1: Evidence at protein level;
KW ADP-ribosylation; Alternative splicing; Cell membrane;
KW Complete proteome; Cushing syndrome; Direct protein sequencing;
KW Disease mutation; GTP-binding; Isopeptide bond; Lipoprotein;
KW Magnesium; Membrane; Metal-binding; Nucleotide-binding; Palmitate;
KW Phosphoprotein; Polymorphism; Proto-oncogene; Reference proteome;
KW Transducer; Ubl conjugation.
FT CHAIN 1 394 Guanine nucleotide-binding protein G(s)
FT subunit alpha isoforms short.
FT /FTId=PRO_0000203721.
FT NP_BIND 47 54 GTP (By similarity).
FT NP_BIND 198 204 GTP (By similarity).
FT NP_BIND 223 227 GTP (By similarity).
FT NP_BIND 292 295 GTP (By similarity).
FT METAL 54 54 Magnesium (By similarity).
FT METAL 204 204 Magnesium (By similarity).
FT BINDING 366 366 GTP; via amide nitrogen (By similarity).
FT MOD_RES 201 201 ADP-ribosylarginine; by cholera toxin (By
FT similarity).
FT MOD_RES 352 352 Phosphoserine.
FT LIPID 2 2 N-palmitoyl glycine (By similarity).
FT LIPID 3 3 S-palmitoyl cysteine.
FT CROSSLNK 300 300 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin).
FT VAR_SEQ 71 72 EG -> DS (in isoform Gnas-2).
FT /FTId=VSP_001833.
FT VAR_SEQ 71 71 E -> D (in isoform 3).
FT /FTId=VSP_026616.
FT VAR_SEQ 72 86 Missing (in isoform 3).
FT /FTId=VSP_026617.
FT VAR_SEQ 73 86 Missing (in isoform Gnas-2).
FT /FTId=VSP_001834.
FT VAR_SEQ 86 86 G -> GS (in isoform 4).
FT /FTId=VSP_047325.
FT VARIANT 99 99 L -> P (in AHO).
FT /FTId=VAR_003439.
FT VARIANT 106 106 I -> S (in AHO/PHP1A).
FT /FTId=VAR_031872.
FT VARIANT 115 115 P -> L (in AHO).
FT /FTId=VAR_017843.
FT VARIANT 156 156 D -> N (in PHP1A).
FT /FTId=VAR_031873.
FT VARIANT 159 159 V -> M (in PHP1A).
FT /FTId=VAR_031874.
FT VARIANT 165 165 R -> C (in AHO).
FT /FTId=VAR_003440.
FT VARIANT 201 201 R -> C (in MAS and somatotrophinoma;
FT dbSNP:rs11554273).
FT /FTId=VAR_003442.
FT VARIANT 201 201 R -> G (in MAS).
FT /FTId=VAR_017844.
FT VARIANT 201 201 R -> H (in MAS, somatotrophinoma and
FT AIMAH).
FT /FTId=VAR_003441.
FT VARIANT 201 201 R -> L (in non-MAS endocrine tumors).
FT /FTId=VAR_017845.
FT VARIANT 201 201 R -> S (in AIMAH, pituitary tumor and
FT polyostotic fibrous dysplasia).
FT /FTId=VAR_017846.
FT VARIANT 227 227 Q -> H (in pituitary adenoma; ACTH-
FT secreting adenoma; in a patient with
FT severe Cushing syndrome complicated by
FT psychosis).
FT /FTId=VAR_017847.
FT VARIANT 227 227 Q -> R (in somatotrophinoma).
FT /FTId=VAR_003443.
FT VARIANT 231 231 R -> H (in AHO; impairs the ability to
FT mediate hormonal stimulation).
FT /FTId=VAR_017848.
FT VARIANT 242 242 T -> I (in AHO).
FT /FTId=VAR_031875.
FT VARIANT 246 246 F -> S (in AHO).
FT /FTId=VAR_031876.
FT VARIANT 250 250 S -> R (in AHO; may alter guanine
FT nucleotide binding which could lead to
FT thermolability and impaired function).
FT /FTId=VAR_017849.
FT VARIANT 258 258 R -> W (in AHO; defective GDP binding
FT resulting in increased thermolability and
FT decreased activation).
FT /FTId=VAR_015388.
FT VARIANT 259 259 E -> V (in AHO).
FT /FTId=VAR_031877.
FT VARIANT 280 280 R -> G (in PHP1A).
FT /FTId=VAR_031878.
FT VARIANT 280 280 R -> K (in PHP1A).
FT /FTId=VAR_031879.
FT VARIANT 281 281 W -> R (in POH).
FT /FTId=VAR_031880.
FT VARIANT 338 338 K -> N (in PHP1A).
FT /FTId=VAR_031881.
FT VARIANT 366 366 A -> S (in AHO; paradoxical combination
FT of AHO and testotoxicosis; constitutively
FT activates adenylyl cyclase in vitro;
FT accounts for the testotoxicosis
FT phenotype; mutant form is quite stable at
FT testis temperature; rapidly degraded at
FT 37 degrees explaining the AHO phenotype
FT caused by loss of Gs activity).
FT /FTId=VAR_017850.
FT VARIANT 380 380 R -> L (in dbSNP:rs8986).
FT /FTId=VAR_049358.
FT VARIANT 382 382 Missing (unable to interact with the
FT receptor for PTH).
FT /FTId=VAR_034744.
FT VARIANT 385 385 R -> H (in AHO; uncouples receptors from
FT adenylyl cyclases).
FT /FTId=VAR_003444.
FT VARIANT 388 388 L -> R (in PHP1C; significantly reduces
FT receptor-mediated activation; displays
FT normal receptor-independent activation).
FT /FTId=VAR_066387.
FT VARIANT 392 392 E -> K (in PHP1C; significantly reduces
FT receptor-mediated activation; displays
FT normal receptor-independent activation).
FT /FTId=VAR_066388.
FT MUTAGEN 170 170 Q->A: Increases GDP release but does not
FT affect receptor-mediated activation.
FT MUTAGEN 258 258 R->A: Increases GDP release and impairs
FT receptor-mediated activation; markedly
FT elevated intrinsic GTPase rate which will
FT lead to more rapid inactivation.
FT CONFLICT 3 3 C -> Y (in Ref. 8; AAH66923).
FT CONFLICT 6 6 N -> T (in Ref. 3; CAA30084).
FT CONFLICT 72 72 Missing (in Ref. 8; AAH66923).
FT CONFLICT 167 167 N -> D (in Ref. 8; AAH22875).
FT CONFLICT 230 230 E -> Q (in Ref. 9; AAA52583).
SQ SEQUENCE 394 AA; 45665 MW; CD541181FC4412EF CRC64;
MGCLGNSKTE DQRNEEKAQR EANKKIEKQL QKDKQVYRAT HRLLLLGAGE SGKSTIVKQM
RILHVNGFNG EGGEEDPQAA RSNSDGEKAT KVQDIKNNLK EAIETIVAAM SNLVPPVELA
NPENQFRVDY ILSVMNVPDF DFPPEFYEHA KALWEDEGVR ACYERSNEYQ LIDCAQYFLD
KIDVIKQADY VPSDQDLLRC RVLTSGIFET KFQVDKVNFH MFDVGGQRDE RRKWIQCFND
VTAIIFVVAS SSYNMVIRED NQTNRLQEAL NLFKSIWNNR WLRTISVILF LNKQDLLAEK
VLAGKSKIED YFPEFARYTT PEDATPEPGE DPRVTRAKYF IRDEFLRIST ASGDGRHYCY
PHFTCAVDTE NIRRVFNDCR DIIQRMHLRQ YELL
//

MIM 102200
*RECORD*
*FIELD* NO
102200
*FIELD* TI
#102200 PITUITARY ADENOMA, GROWTH HORMONE-SECRETING
;;SOMATOTROPINOMA, FAMILIAL ISOLATED; FIS;;
read moreISOLATED FAMILIAL SOMATOTROPINOMA; IFS;;
SOMATOTROPHINOMA, FAMILIAL;;
ACROMEGALY DUE TO PITUITARY ADENOMA
PITUITARY ADENOMA PREDISPOSITION, INCLUDED; PAP, INCLUDED;;
PITUITARY ADENOMA, FAMILIAL ISOLATED, INCLUDED; FIPA, INCLUDED;;
SOMATOSTATIN ANALOG, RESISTANCE TO, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because growth
hormone-secreting pituitary adenomas, also known as somatotropinomas,
can be caused by mutation in the aryl hydrocarbon receptor-interacting
protein (AIP; 605555).

Sporadic growth hormone-secreting adenomas can be caused by somatic
activating mutations in the GNAS1 gene (139320).

DESCRIPTION

Pituitary adenomas are benign monoclonal neoplasms of the anterior
pituitary gland, accounting for approximately 15% of intracranial
tumors. Growth hormone (GH; 139250)-secreting tumors, which clinically
result in acromegaly, comprise about 20% of all pituitary tumors and are
the second most common hormone-secreting pituitary tumor after prolactin
(176760)-secreting tumors (600634), which account for 40 to 45% of
pituitary tumors. ACTH-secreting tumors, resulting in Cushing disease
(219090), and thyrotropin (TSHB; 188540)-secreting tumors are much less
common. Nonsecreting pituitary tumors, which account for about 33%, can
cause symptoms due to local compressive effects of tumor growth
(Vierimaa et al., 2006; Georgitsi et al., 2007; Horvath and Stratakis,
2008).

Acromegaly is characterized by coarse facial features, protruding jaw,
and enlarged extremities (Vierimaa et al., 2006). Familial isolated
somatotropinoma (FIS) is defined as the occurrence of at least 2 cases
of acromegaly or gigantism in a family that does not exhibit features of
other endocrine syndromes. FIS patients tend to have onset about 4 to 10
years earlier than patients with sporadic disease (Gadelha et al., 1999;
Horvath and Stratakis, 2008).

Familial isolated pituitary adenoma (FIPA) and pituitary adenoma
predisposition (PAP) are terms referring to families in which 2 or more
individuals develop pituitary tumors. Within a family, tumor types can
be heterogeneous, with members of the same family having GH-secreting,
prolactin-secreting, ACTH-secreting, or nonsecreting adenomas; in
contrast, some families are homogeneous with regard to tumor type.
Familial isolated somatotropinoma refers specifically to GH-secreting
tumors and is usually associated with an acromegaly phenotype. Thus, FIS
is a subset of FIPA or PAP (Toledo et al., 2007).

Familial acromegaly can also occur in association with multiple
endocrine neoplasia type I (MEN1; 131100), Carney complex (CNC1;
160980), and the McCune-Albright syndrome (174800).

CLINICAL FEATURES

Levin et al. (1974) reported 2 brothers with acromegaly confirmed by
elevated serum GH levels and the finding of pituitary tumors. Both also
had acanthosis nigricans.

Jones et al. (1984) reported an uncle and nephew with acromegaly. The
authors considered MEN type I to be unlikely because of the absence of
other endocrine disease at an advanced age.

Abbassioun et al. (1986) and McCarthy et al. (1990) also reported
familial acromegaly.

Pestell et al. (1989) described a family in which 5 members over 3
generations had isolated functional pituitary adenomas. Four patients
had acromegaly and 1 had galactorrhea from prolactin excess. Affected
individuals were related as uncle and nephew or uncle and niece or as
second cousins; no parent-child transmission was observed and there was
no consanguinity. Pestell et al. (1989) proposed autosomal dominant
inheritance with reduced penetrance. The authors considered the disorder
in this family to be distinct from MEN1.

Links et al. (1993) reported a father and son with acromegaly associated
with pituitary adenoma. The adenoma from the son was also found to
secrete thyrotropin (see TSHB; 188540) and prolactin. The father was
deceased at the time of the report.

Gadelha et al. (1999) reported 2 unrelated families with isolated
acromegaly/gigantism. In one family, 3 of 4 sibs were affected, with
ages at diagnosis of 19, 21, and 23 years. In the other family, 5 of 13
sibs were diagnosed as affected at 13, 15, 17, 17, and 24 years of age.
There was no history of consanguinity in either family, and the medical
histories and laboratory results excluded MEN1 and the Carney complex.

Verloes et al. (1999) reported 3 unrelated families in which 2 members
each had acromegaly not associated with other clinical features of MEN1.
Two of the 6 patients also had galactorrhea due to prolactin secretion.
Age at onset was usually in the twenties. After a review of similar
families that had been published, Verloes et al. (1999) concluded that
the disorder was a unique entity and showed autosomal dominant
inheritance with reduced penetrance.

Jorge et al. (2001) reported a Brazilian family with acromegaly due to
pituitary adenomas. The proband was a 24-year-old woman who presented
with headaches, galactorrhea, menstrual irregularities, and progressive
enlargement of hands and feet. Physical examination revealed evident
acromegalic facial and acral features. Serum GH (139250) and prolactin
were increased. The proband's brother presented at age 29 years with a
10-year history of progressive enlargement of hands, feet, and mandible.
Serum growth hormone and insulin-like growth factor-1 (IGF1; 147440)
were increased, but prolactin was normal. Other endocrine values were
normal in both patients, excluding endocrine syndromes. Their father had
acromegalic features confirmed by family pictures; he had died of an
unrelated cause at the age of 40 years without endocrine evaluation.
Molecular analysis of the sibs excluded germline mutations in the MEN1,
GNAS1, GNAI2 (139360), and GHRHR (139191) genes.

Vierimaa et al. (2006) described a very large kindred in northern
Finland in which multiple individuals had pituitary adenomas, secreting
either prolactin (176760) (5) or growth hormone (4); 2 individuals had a
mixed tumor secreting both hormones. There were 3 clear cases of
acromegaly or gigantism. Genealogy could be traced to the 1700s.
Vierimaa et al. (2006) postulated that the phenotype represented a
hereditary predisposition to pituitary adenomas (PAP) with very low
penetrance. A second family had 2 individuals in 2 generations with
somatotropinomas. Compared to patients with sporadic pituitary tumors,
those with PAP had a significantly younger age at time of diagnosis
(24.7 vs 43.6 years, P = 0.0003), but there were no differences in tumor
size or sex distribution. Six of the 15 patients diagnosed under 35
years of age (40%) in the population-based series had PAP.

OTHER FEATURES

Lopez-Velasco et al. (1997) found that hypertension was present in
approximately 43% of patients with active acromegaly and in 28% of
patients in whom acromegaly was cured. Studies of other cardiac
parameters, including functional cardiac indexes and echocardiography,
showed that hypertension was independently related to cardiac morphology
and to systolic and diastolic function. Acromegaly was related to an
increase in left ventricular mass, stroke volume, cardiac output, and
isovolumic relaxation time, which were independent of the presence of
hypertension. In the 5 patients in whom active acromegaly was
successfully treated, left ventricular mass and left ventricular
posterior wall thickness were reduced 1 year later. Lopez-Velasco et al.
(1997) concluded that asymptomatic morphologic and functional cardiac
abnormalities present in acromegalic patients are independently related
to acromegaly and hypertension, suggesting the existence of a specific
acromegalic myocardiopathy that might be aggravated by the coexistence
of hypertension.

Among 25 patients with uncomplicated acromegaly and 25 controls, Colao
et al. (2002) found similar resting blood pressure, whereas heart rate
at rest and systolic blood pressure at peak exercise were higher in the
patients. The left ventricular mass index was higher in acromegalic
patients than in controls; 7 patients had left ventricular hypertrophy.
Diastolic function was similar in the 2 groups. The ejection fraction at
rest, but not at peak exercise, was significantly increased in the
patients compared with controls; as a consequence, the exercise-induced
changes in the ejection fraction were lower in patients than controls.
At common carotid ultrasonography, young patients with acromegaly had
increased diastolic peak velocity and increased intima media thickness.
The authors concluded that short-term GH excess, despite causing
enhanced cardiac performance at rest, reduces cardiac performance on
effort and impairs vascular morphology. These deleterious effects of
early-onset acromegaly were ameliorated by suppressing GH/IGF1 levels
for 6 months.

Parkinson et al. (2001) found that women with active acromegaly had
serum IGF1 values 82 ng/ml less than males (P less than 0.02) for a
given serum GH value. In females receiving oral estrogen, mean serum
IGF1 for a given GH value was 130 ng/ml lower than in males (P = 0.01),
but only 60 ng/ml lower than in the remaining 45 females (NS; P = 0.2).
The authors concluded that there is a gender difference in the
relationship between serum GH and IGF1 in patients with active
acromegaly consistent with relative GH resistance observed in normal and
GH-deficient females, which may, in part, be mediated by estrogen.

CLINICAL MANAGEMENT

Barlier et al. (1998) found that GNAS-mutant GH-secreting pituitary
adenomas secreted significantly more growth hormone relative to tumor
size compared to adenomas without GNAS mutations. In vitro and in vivo
studies found that the mutant adenomas showed better sensitivity to
octreotide; the GH nadir was significantly lower in the mutant adenomas
compared to the nonmutant adenomas (85% of maximal inhibition vs 52%).
In 18 acromegalic patients treated with octreotide for at least 3 months
before surgery, the percent inhibition of GH hypersecretion was higher
in those with somatic GNAS-mutant adenomas compared to nonmutant
adenomas (76% vs 47%). GH hypersecretion was controlled in all patients
with GNAS-mutant adenomas during 2 years of postoperative follow-up,
even in those in whom tumor tissue remained after surgery. In contrast,
patients with GNAS-negative adenomas did not respond as well to
octreotide treatment.

Ballare et al. (2001) reported a mutation in the SSTR5 gene
(182455.0001) that abrogated the antiproliferative action of
somatostatin and activated mitogenic pathways in a patient with
acromegaly resistant to treatment with octreotide who carried an
activating GNAS mutation (R201C; 139320.0008).

MAPPING

Thakker et al. (1993) found loss of heterozygosity (LOH) for chromosome
11q13 in 4 somatotrophinomas derived from non-MEN1 patients with
acromegaly.

Gadelha et al. (1999) found loss of heterozygosity of chromosome 11q13
in all pituitary adenomas isolated from affected members of 2 unrelated
families with acromegaly. None of the patients had germline mutations in
the MEN1 gene, and a somatic mutation was not identified in tumor tissue
from 1 patient. Gadelha et al. (1999) concluded that LOH in these
affected family members was independent of MEN1 changes and due to
another tumor suppressor gene in the 11q13 region.

By linkage analysis of 2 unrelated families with familial isolated
somatotropinomas, Gadelha et al. (2000) found linkage to an 8.6-cM
region on chromosome 11q13.1-13.3 (maximum 2-point lod scores of 3.0 or
more between FGF3 (164950) and D11S1335). Stratakis and Kirschner (2000)
recalculated the lod scores for 11q using the germline alleles reported
by Gadelha et al. (2000); this analysis yielded 2-point lod scores that
were strongly positive, but not conclusive. Stratakis and Kirschner
(2000) concluded that LOH at 11q13 was likely to be a tertiary hit at
the tumor tissue level.

Using haplotyping and allelotyping techniques to evaluate 8 families
with FIS and 15 sporadic somatotropinomas, Soares et al. (2005) narrowed
the candidate locus to a 2.21-Mb region on chromosome 11q13.3. LOH at
this region was found in all families and in 40% of sporadic tumors.
Three potential candidate genes in this region were sequenced, but no
mutations were found.

By whole genome single-nucleotide polymorphism (SNP) genotyping of a
large Finnish family with pituitary adenoma predisposition, Vierimaa et
al. (2006) found linkage to chromosome 11q12-q13. The results yielded a
lod score of 7.1 when combined with a second affected family that shared
the linked haplotype. No mutations were identified in the MEN1 gene,
which maps to this region.

MOLECULAR GENETICS

- Germline Mutations in the AIP Gene

In affected individuals from a large Finnish family with pituitary
adenoma predisposition, Vierimaa et al. (2006) identified a heterozygous
germline mutation in the AIP gene (Q14X; 605555.0001). Further screening
identified this mutation in 6 of 45 patients from a population-based
cohort with acromegaly. Affected Italian sibs were found to have an
R304X mutation (605555.0003). Loss of heterozygosity at the AIP locus
was detected in all 8 pituitary tumors analyzed, including
somatotropinomas, prolactinomas, and mixed-type tumors.

In the Brazilian sibs with acromegaly and GH (139250)-secreting
pituitary adenomas reported by Jorge et al. (2001), Toledo et al. (2007)
identified a heterozygous mutation in the AIP gene (605555.0007). A
41-year-old brother with the mutation was clinically unaffected, but was
found on imaging to have a small, apparently nonsecreting pituitary
nodule. A 3-year-old boy with the mutation was also unaffected, but was
younger than the average age at symptom onset.

In 9 of 460 patients from Europe and the U.S. with pituitary adenomas,
Georgitsi et al. (2007) identified 9 different germline mutations in the
AIP gene (see, e.g., 605555.0004-605555.0006). Eight patients had
GH-secreting tumors and acromegaly, and 1 had Cushing syndrome due to an
ACTH-secreting tumor (219090). Age at diagnosis ranged from 8 to 41
years.

Daly et al. (2007) studied the frequency of AIP gene mutations in a
large cohort of patients with familial isolated pituitary adenoma from 9
different countries. Seventy-three FIPA families were identified, with
156 patients with pituitary adenomas; the FIPA cohort was evenly divided
between families with homogeneous and heterogeneous tumor expression.
Eleven FIPA families had 10 germline AIP mutations; 9 of the mutations
were novel. Tumors were significantly larger (p = 0.0005) and diagnosed
at a younger age (p = 0.0006) in AIP mutation-positive versus
mutation-negative subjects. Although somatotropinomas predominated among
FIPA families with AIP mutations, mixed GH/prolactin-secreting tumors
(600634), prolactinomas, and nonsecreting adenomas were also found.
Approximately 85% of the FIPA cohort and 50% of those with familial
somatotropinomas were negative for AIP mutations.

Barlier et al. (2007) did not identify mutations in the AIP gene in 107
European patients with sporadic pituitary adenomas, including
prolactinomas (49), somatotropinomas (26), ACTH-secreting tumors (2),
TSH-secreting tumors (1), and nonfunctioning tumors (29). One additional
patient with a somatotropinoma was found to have a germline mutation in
the AIP gene (R22X; 605555.0009). Barlier et al. (2007) concluded that
germline AIP mutations are infrequent in patients with sporadic
pituitary adenomas.

Igreja et al. (2010) analyzed the AIP gene in 38 families with FIPA, in
which at least 2 family members had pituitary adenoma without features
of MEN1 (131100) or Carney complex (see 160980), and identified
mutations in 11 of the families, including 3 with large deletions. The
authors reviewed the clinical characteristics of these 38 families and
26 previously reported families (Leontiou et al., 2008), confirming that
patients with AIP mutations had a lower mean age at diagnosis. Igreja et
al. (2010) noted that overall, AIP mutations were implicated in 20 (31%)
of the 64 families in their FIPA cohort.

- Somatic Mutations in the GNAS1 Gene

Thakker et al. (1993) found somatic mutations in the GNAS1 gene in 2
non-MEN1 somatotropinomas, one of which also demonstrated allele loss of
chromosome 11 (see, e.g., 139320.0009).

Hayward et al. (2001) noted that approximately 40% of growth
hormone-secreting pituitary adenomas harbor somatic mutations in the
GNAS1 gene. Mutations at arg201 or glu227 (see, e.g., 139320.0008 and
139320.0010, respectively) constitutively activate the alpha subunit of
GNAS1.

PATHOGENESIS

Shimon and Melmed (1997) reviewed the multiple molecular events known at
the time that result in pituitary adenomas. These events include early
chromosomal mutations (11q13, 13q14 LOH) and possibly expression of
pituitary-specific protooncogenes and/or growth factors including GNAS1,
CREB (see CREB1; 123810 and CREB2; 123811), HST (see FGF4; 164980) and
TGF-alpha (see TGFA; 190170). Subsequent permissive factors allowing
clonal expansion of the transformed cell include hypothalamic hormone
receptor signals, paracrine growth factor signals, and disordered cell
cycle regulation.

Lania et al. (1998) found that 8 GH (139250)-secreting adenomas with
activating GNAS mutations (gsp+) had similar intracellular cAMP levels
as 10 GH-secreting adenomas without GNAS mutations (gsp-). However,
pharmacologic inhibition of phosphodiesterase (PDE; see 171885) induced
a marked increase in cAMP in all but 1 mutation-positive adenomas (77 to
2900% increase) and a slight rise in only 2 mutation-negative adenomas.
PDE blockade caused a further increase in 3 of 5 mutation-positive
adenomas but not in negative tumors. By direct measurement, PDE activity
was about 7-fold higher in mutation-positive adenomas. Mutation-positive
adenomas also had significantly higher GH release compared to
mutation-negative adenomas (315 vs 82 micro g/well; P less than 0.01).
Lania et al. (1998) concluded that activating mutations of the Gs-alpha
gene in pituitary adenomas are associated with increased PDE activity
that might partially counteract the constitutive activation of the
cAMP-dependent pathway.

Ballare et al. (1998) found that activating mutations in the GNAS gene
were associated with decreased levels of the GS-alpha protein in
GH-secreting adenomas. The low Gs-alpha content in gsp+ tumors was not
due to a reduction in RNA synthesis or stability, as Gs-alpha mRNA
levels were similar in wildtype and mutant tissues. The authors
concluded that there is accelerated removal of mutant Gs-alpha, which
may represent an additional mechanism of feedback response to the
constitutive activation of cAMP signaling in pituitary tumors with
mutations in the Gs-alpha gene.

Barlier et al. (1999) found that somatotroph adenomas with GNAS
mutations (gsp+) had decreased expression of the Gs-alpha gene compared
to GNAS-negative (gsp-) tumors, suggesting the existence of a negative
feedback of the oncogenic protein upon its own mRNA. In contrast,
Gi2-alpha (GNAI2; 139360), PIT1 (POU1F1; 173110), and GH mRNAs were not
significantly different between the 2 groups. There was a positive
correlation between octreotide-induced inhibition of GH secretion and
the expression of SSTR2 (182452) mRNA, although the expression of the
SSTR2 gene did not differ between gsp+ and gsp- adenomas. SSTR2 gene
expression was significantly correlated to that of Gi2-alpha and PIT1,
and Gs-alpha mRNA expression was positively correlated with that of
Gi2-alpha and PIT1. The authors concluded there is a concerted
dysregulation of the expression of these genes, which are involved in
secretory activity, in both categories of adenomas.

Persani et al. (2001) found that normal pituitary and gsp- GH-secreting
adenomas showed similar PDE activities, whereas gsp+ tumors showed
7-fold higher PDE levels. In gsp+ tumors, the increased activity was
mainly due to isobutyl-methyl-xanthine-sensitive phosphodiesterase-4 and
to isobutyl-methyl-xanthine-insensitive isoforms. By semiquantitative
RT-PCR, all phosphodiesterase-4 transcripts were expressed in the normal
and tumoral pituitary. However, the levels of phosphodiesterase-4C
(600128) and -4D (600129) mRNAs were significantly higher in gsp+ than
in gsp- GH-secreting adenomas and normal pituitary. Expression of the
thyroid-specific isobutyl-methyl-xanthine-insensitive
phosphodiesterase-8B (603390) was absent in the normal pituitary but
detectable in almost all GH-secreting adenomas and higher in gsp+ (P
less than 0.02). The authors concluded that up-regulation of PDEs is a
mechanism to counteract the constitutive activation of cAMP production
and may have a significant impact on the phenotypic expression of gsp
mutations such as the rates of GH secretion or tumor growth.

In 6 of 14 sparsely granulated human somatotroph adenomas, Asa et al.
(2007) identified somatic mutation of codon 49 (H49L or H49R) of the
growth hormone receptor gene (GHR; 600946) within an extracellular
cysteine-rich immunoglobulin-like loop. In vitro functional studies with
mutant rabbit Ghr showed that codon 49 mutations impaired receptor
processing, activation, and binding of GH. Mutant Ghr was retained
within cytoplasmic granules in the endoplasmic reticulum, and there was
relative resistance of mutant Ghr to activation of intracellular
signaling by GH. Thus, mutant Ghr showed ineffective sensing of ambient
GH and lacked negative feedback on GH production and growth, suggesting
another pathogenetic mechanism for a subgroup of pituitary somatotroph
adenomas. Asa et al. (2007) noted that the findings were significant for
treatment, in that the disruption of GH autoregulation by a GHR mutation
in sparsely granulated adenomas renders GHR antagonism a more
appropriate therapeutic option than GH antagonism, since the former
would be less likely to be associated with treatment-induced tumor
activation.

In studies of acromegalics with abnormally high levels of GH (139250),
Boguszewski et al. (1997) evaluated the proportion of circulating
non-22-kD isoforms of GH and found the proportion was fairly constant in
different samples from the same patient, regardless of the GH level. A
wide variation of values was observed among acromegalics, both before
(14 to 51%) and after surgery (8 to 62%). The proportion of non-22-kD GH
isoforms was increased in untreated patients, compared with controls
(26.6 vs 17.4%; P less than 0.01), and the values correlated
significantly to tumor size, mean 24-hour GH concentration, serum PRL,
and extracellular water. They concluded that acromegalics have an
increased proportion of circulating non-22-kD GH isoforms. Although
values are fairly constant in different samples from an individual, a
large spectrum can be observed among patients. This variability
suggested to Boguszewski et al. (1997) that different pituitary adenomas
secrete GH isoforms in variable amounts. Their observation that a higher
proportion of non-22-kD GH isoforms is present in patients not truly
cured after surgery suggested to the authors that the evaluation of
non-22-kD GH isoforms can be useful in the follow-up of acromegalic
patients.

HISTORY

Chahal et al. (2011) identified the arg304-to-ter mutation in the AIP
gene (605555.0003) in DNA extracted from the teeth of an Irish patient
with gigantism who lived from 1761 to 1783. This patient's skeleton had
been examined by Harvey Cushing, who identified an enlarged pituitary
fossa and ascribed his gigantism to a pituitary adenoma. Chahal et al.
(2011) also identified this mutation in 4 contemporary northern Irish
families who presented with gigantism, acromegaly, or prolactinoma and
had the same haplotype. Using coalescent theory, Chahal et al. (2011)
inferred that these persons shared a common ancestor who lived about 57
to 66 generations earlier. The skeleton of the patient (Charles Byrne,
known as 'The Irish Giant'; Bergland, 1965) is exhibited in the
Hunterian Museum of the Royal College of Surgeons in London, near the
skeleton of Caroline Crachami (see 210730).

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on chromosome 11q13 in eight families with isolated familial somatotropinoma
and in 15 sporadic somatotropinomas. J. Clin. Endocr. Metab. 90:
6580-6587, 2005.

32. Stratakis, C. A.; Kirschner, L. S.: Isolated familial somatotropinomas:
does the disease map to 11q13 or to 2p16? J. Clin. Endocr. Metab. 85:
4920 only, 2000.

33. Thakker, R. V.; Pook, M. A.; Wooding, C.; Boscaro, M.; Scanarini,
M.; Clayton, R. N.: Association of somatotrophinomas with loss of
alleles on chromosome 11 and with gsp mutations. J. Clin. Invest. 91:
2815-2821, 1993.

34. Toledo, R. A.; Lourenco, D. M., Jr.; Liberman, B.; Cunha-Neto,
M. B. C.; Cavalcanti, M. G.; Moyses, C. B.; Toledo, S. P. A.; Dahia,
P. L. M.: Germline mutation in the aryl hydrocarbon receptor interacting
protein gene in familial somatotropinoma. J. Clin. Endocr. Metab. 92:
1934-1937, 2007.

35. Verloes, A.; Stevenaert, A.; Teh, B. T.; Petrossians, P.; Beckers,
A.: Familial acromegaly: case report and review of the literature. Pituitary 1:
273-277, 1999.

36. Vierimaa, O.; Georgitsi, M.; Lehtonen, R.; Vahteristo, P.; Kokko,
A.; Raitila, A.; Tuppurainen, K.; Ebeling, T. M. L.; Salmela, P. I.;
Paschke, R.; Gundogdu, S.; De Menis, E.; Makinen, M. J.; Launonen,
V.; Karhu, A.; Aaltonen, L. A.: Pituitary adenoma predisposition
caused by germline mutations in the AIP gene. Science 312: 1228-1230,
2006.

*FIELD* CS
INHERITANCE:
Autosomal dominant;
Somatic mutation

GROWTH:
[Height];
Increased height

HEAD AND NECK:
[Face];
Coarse facial features;
Mandibular enlargement

CARDIOVASCULAR:
[Heart];
Cardiomyopathy;
Left ventricular hypertrophy;
[Vascular];
Hypertension

CHEST:
[Breasts];
Galactorrhea from increased serum prolactin

SKELETAL:
[Hands];
Enlarged hands;
[Feet];
Enlarged feet

NEUROLOGIC:
[Central nervous system];
Anterior pituitary adenoma

ENDOCRINE FEATURES:
Acromegaly;
Menstrual irregularities;
Cushing disease due to increased ACTH secretion (less common)

NEOPLASIA:
Pituitary adenoma;
Somatotrophinoma;
Prolactinoma

LABORATORY ABNORMALITIES:
Increased serum growth hormone levels;
Increased serum IGF1;
Increased serum prolactin

MISCELLANEOUS:
Onset in second or third decades

MOLECULAR BASIS:
Caused by mutation in the aryl hydrocarbon receptor-interacting protein
gene (AIP, 605555.0001);
Caused by somatic mutation in the alpha-stimulatory subunit of the
guanine nucleotide-binding protein gene (GNAS1, 139320.0008)

*FIELD* CN
Cassandra L. Kniffin - revised: 02/19/2008

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
ckniffin: 02/19/2008
alopez: 7/6/2001

*FIELD* CN
Ada Hamosh - updated: 1/19/2011
Marla J. F. O'Neill - updated: 12/20/2010
Cassandra L. Kniffin - updated: 8/26/2008
Cassandra L. Kniffin - reorganized: 2/28/2008
Cassandra L. Kniffin - updated: 2/19/2008
John A. Phillips, III - updated: 2/14/2008
Cassandra L. Kniffin - updated: 3/26/2007
John A. Phillips, III - updated: 3/21/2007
Victor A. McKusick - updated: 6/11/2003
John A. Phillips, III - updated: 1/7/2003
John A. Phillips, III - updated: 8/2/2002
John A. Phillips, III - updated: 6/10/2002
John A. Phillips, III - updated: 7/27/2001
John A. Phillips, III - updated: 7/6/2001
John A. Phillips, III - updated: 2/24/2000
John A. Phillips, III - updated: 11/29/1999
John A. Phillips, III - updated: 8/5/1997
Victor A. McKusick - edited: 5/27/1997
John A. Phillips, III - updated: 4/17/1997

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
alopez: 01/25/2011
alopez: 1/25/2011
terry: 1/19/2011
alopez: 12/20/2010
terry: 12/20/2010
alopez: 5/27/2009
ckniffin: 12/5/2008
wwang: 9/10/2008
ckniffin: 8/26/2008
carol: 6/18/2008
terry: 6/6/2008
carol: 2/28/2008
ckniffin: 2/19/2008
carol: 2/14/2008
wwang: 4/12/2007
ckniffin: 3/26/2007
carol: 3/21/2007
alopez: 7/25/2006
carol: 10/14/2005
joanna: 10/13/2005
carol: 3/9/2004
carol: 7/11/2003
tkritzer: 7/9/2003
terry: 6/11/2003
alopez: 1/7/2003
cwells: 8/2/2002
alopez: 6/10/2002
mgross: 7/27/2001
alopez: 7/6/2001
mgross: 2/24/2000
carol: 2/3/2000
alopez: 11/29/1999
carol: 10/18/1999
carol: 7/22/1998
dholmes: 7/22/1998
jenny: 8/5/1997
jenny: 5/27/1997
jenny: 5/21/1997
mark: 3/13/1997
terry: 2/5/1997
mark: 12/30/1996
mark: 12/26/1996
terry: 12/16/1996
mark: 9/22/1995
mimadm: 3/11/1994
carol: 7/9/1993
supermim: 3/16/1992
carol: 8/23/1990
supermim: 3/20/1990

MIM 103580
*RECORD*
*FIELD* NO
103580
*FIELD* TI
#103580 PSEUDOHYPOPARATHYROIDISM, TYPE IA; PHP1A
;;PHP IA;;
ALBRIGHT HEREDITARY OSTEODYSTROPHY WITH MULTIPLE HORMONE RESISTANCE
read more*FIELD* TX
A number sign (#) is used with this entry because
pseudohypoparathyroidism type Ia (PHP Ia) is caused a mutation resulting
in loss of function of the Gs-alpha isoform of the GNAS gene (139320) on
the maternal allele. This results in expression of the Gs-alpha protein
only from the paternal allele.

See also pseudopseudohypoparathyroidism (PPHP; 612463), a similar
disorder caused by mutations resulting in loss of function of the
Gs-alpha isoform of the GNAS gene on the paternal allele and resultant
expression of the Gs-alpha isoform only from the maternal allele.

DESCRIPTION

Pseudohypoparathyroidism is a term applied to a heterogeneous group of
disorders whose common feature is end-organ resistance to parathyroid
hormone (PTH; 168450). In addition to PTH resistance, PHP Ia is
characterized by resistance to other hormones, including
thyroid-stimulating hormone (TSH; see TSHB, 188540) and gonadotropins.
PHP Ia is associated with a constellation of clinical features referred
to as Albright hereditary osteodystrophy (AHO), which includes short
stature, obesity, round facies, subcutaneous ossifications,
brachydactyly, and other skeletal anomalies. Some patients have mental
retardation (Mantovani and Spada, 2006).

In contrast, pseudopseudohypoparathyroidism (PPHP; 612463) is
characterized by the physical findings of AHO but without hormone
resistance (Kinard et al., 1979; Fitch, 1982; Mantovani and Spada,
2006).

PHP1A occurs only after maternal inheritance of the molecular defect,
whereas PPHP occurs only after paternal inheritance of the molecular
defect (Davies and Hughes, 1993; Wilson et al., 1994). This is an
example of imprinting, with differential gene expression depending on
the parent of origin of the allele. See INHERITANCE and PATHOGENESIS
sections.

NOMENCLATURE

The classification of pseudohypoparathyroidism is based on the phenotype
and cellular cyclic AMP (cAMP) response to exogenous PTH administration.
Cyclic AMP is produced by an intracellular G protein hormone
receptor-adenylyl cyclase (see, e.g., ADCY1, 103072) complex. The GNAS
gene encodes the alpha-stimulatory subunit (Gs) of the intracellular G
protein, which stimulates the production of cAMP under certain
physiologic conditions (Mantovani and Spada, 2006).

- Pseudohypoparathyroidism type Ia

Individuals with PHP Ia have AHO features, multiple hormone resistance,
decreased cellular cAMP response to PTH infusion, decreased erythrocyte
Gs activity, and a GNAS1 mutation in the maternally-derived allele
(Mantovani and Spada, 2006).

- Pseudopseudohypoparathyroidism

Individuals with PPHP (612463) have AHO without endocrine abnormalities,
a normal cellular cAMP response to PTH infusion, decreased erythrocyte
Gs activity, and a GNAS1 mutation in the paternally-inherited allele
(Mantovani and Spada, 2006).

- Pseudohypoparathyroidism type Ib

Individuals with PHP Ib (PHP1B; 603233) have renal PTH resistance,
decreased cAMP response to PTH infusion, normal erythrocyte Gs activity,
and imprinting/methylation defects at the GNAS locus resulting in lack
of expression of the maternal allele in renal tissue. Classically,
patients do not have features of AHO. PHP1B is not associated with
generalized hormone resistance, although resistance to
thyroid-stimulating hormone (TSH; 188540) has been reported (Mantovani
and Spada, 2006).

Mariot et al. (2008) noted that features of AHO may rarely be observed
in patients with PHP1b who have decreased expression of G-alpha-s due to
epimutations at the GNAS locus.

- Pseudohypoparathyroidism type Ic

PHP Ic (PHP1C; 612462) is characterized by PTH resistance, generalized
hormone resistance, AHO, decreased cAMP response to PTH infusion, and
normal erythrocyte Gs activity. It may be a variant form of PHP Ia
(Bastepe, 2008).

- Pseudohypoparathyroidism type II

Individuals with PHP II (PHP2; 203330) have isolated renal PTH
resistance and lack the features of AHO. They have a normal erythrocyte
Gs activity and a normal cAMP response to PTH infusion, although the
phosphaturic effect of PTH is deficient (Mantovani and Spada, 2006).

Pseudohypoparathyroidism should not be confused with polyostotic fibrous
dysplasia (174800), to which Albright's name is also attached as
'McCune-Albright syndrome.'

CLINICAL FEATURES

Albright et al. (1942) described 3 patients with short stature, round
face, short neck, obesity, subcutaneous calcifications, and shortened
metacarpals associated with hypocalcemia and hyperphosphatemia. Although
the phenotype resembled parathyroid hormone deficiency, renal function
was normal and apparently unresponsive to administration of bovine
parathyroid extract. The authors hypothesized that the clinical findings
were due to resistance to PTH rather than to PTH deficiency, and termed
the disorder 'pseudohypoparathyroidism' (PHP). The specific pattern of
observable physical features described by Albright et al. (1942)
constitutes 'Albright hereditary osteodystrophy.'

Mann et al. (1962) observed parathyroid hyperplasia in patients with
PHP, suggesting increased serum PTH, not deficiency of PTH. Chase and
Aurbach (1968) found that PTH circulated in abnormally high
concentration in pseudohypoparathyroidism, and that secretion of the
hormone responded normally to physiologic control by calcium.

In patients with PHP, Chase et al. (1969) found that urinary cAMP did
not increase in response to PTH administration, a finding that was in
contrast to controls. The authors suggested that the basic defect in PHP
may be a deficient amount or function of PTH-sensitive adenyl cyclase in
kidney and bone.

Farfel et al. (1980) found that 5 patients with PHP I and AHO had
abnormally low urinary cAMP excretion in response to PTH infusion. There
was also a 40 to 50% reduced activity of the G protein, which the
authors termed 'N,' that couples the membrane hormone receptor to
adenylate cyclase.

Farfel et al. (1981) reported 10 patients with PHP type Ia. Typical
features included short stature, brachydactyly, hypocalcemia, elevated
serum PTH, and decreased urinary excretion of cAMP following exogenous
PTH infusion. Erythrocyte Gs activity was decreased by approximately 50%
in 15 patients with PHP type I, but was normal in 19 of their clinically
normal first-degree relatives. Inheritance patterns were not consistent
with a single mode of transmission. Bourne et al. (1981) reported 5
patients with PHP type I patients who showed a 40% reduction in red cell
N protein activity.

Downs et al. (1983) reported a 16-year-old girl with PHP Ia who had
resistance to PTH, thyrotropin, and gonadotropins. She had multiple
subcutaneous calcifications, uniformly short metacarpals, hypocalcemia,
hyperphosphatemia, elevated serum PTH, no response in urinary cAMP to
PTH infusion, elevated plasma thyrotropin, low serum thyroxine, no
thyroid enlargement, oligomenorrhea, low serum estrogen, high LH and
FSH, and normal response to endogenous ACTH during a standard metyrapone
test and after insulin-induced hypoglycemia. Red cell membrane Gs
activity was 57% of control; renal membranes showed only 30% of control.

Weisman et al. (1985) observed congenital hypothyroidism as the
presenting manifestation of PHP. Levine et al. (1985) reported a brother
and sister with infantile hypothyroidism whose mother had PHP type Ia.
Both children were normocalcemic. Resistance to thyroid-stimulating
hormone was reflected in the reduced level of Gs in red cell membranes.

Hewitt and Chambers (1988) reported a patient with PHP type I in whom
subcutaneous calcification developed at the age of 3 months. 'Hard
lumps' were located on the chest wall and groin.

Izraeli et al. (1992) described a family in which 5 members of 3
successive generations had the clinical features of AHO associated with
progressive osseus heteroplasia (POH; 166350), which is caused by
activating mutations of GNAS1 inherited on the paternal allele.

Zung et al. (1996) pictured subcutaneous nodules of the left heel in a
7-year-old girl with AHO features. The mother, aged 38 years, had
multiple subcutaneous masses of the limbs and bilateral shortening of
the fourth metacarpals. A mammogram showed calcified breast nodules
which were also palpable.

Aldred et al. (2000) reported a sister and brother with PHP Ia,
including hypocalcemia, resistance to PTH, and elevated
thyroid-stimulating hormone. Both sibs also had neonatal diarrhea and
pancreatic insufficiency that corrected spontaneously after several
months.

Mantovani et al. (2003) investigated the presence of pituitary
resistance to hypothalamic hormones acting via G-coupled receptors in
patients with PHP Ia. Six of 9 patients showed an impaired growth
hormone (GH; 139250) responsiveness to GHRH (139190) plus arginine,
consistent with a complete GH deficiency; partial and normal responses
were found in 2 and 1 patient, respectively. Accordingly, IGF1 (147440)
levels were below and in the low-normal range in 7 and 2 patients,
respectively. The authors concluded that in addition to PTH and TSH
resistance, patients with PHP Ia display variable degrees of GHRH
resistance, consistent with Gs-alpha imprinting in the human pituitary.
The findings were consistent with abnormalities of secretion of thyroid
hormone (de Wijn and Steendijk, 1982) and gonadotropins (Shapiro et al.,
1980) that had been described in patients with PHP.

Brachydactyly, classically described as shortening of III, IV, and V
metacarpals and I distal phalanx, is the typical and most specific
feature of AHO. This phenotype has been reported in 70% of PHP subjects
from routine radiologic examinations. De Sanctis et al. (2004) evaluated
the metacarpophalangeal pattern profile in 14 genetically characterized
patients with PHP Ia and determined the prevalence and patterns of left
hand bone shortening. Shortening below -2 SD score was present in at
least 1 bone in each subject, with a prevalence of 100%; however, great
variability existed between subjects and between hand bone segments.
Brachymetacarpia and brachytelephalangy characterized the hands of the
subjects.

- Clinical Variability

De Nanclares et al. (2007) reported 4 unrelated patients who were
thought to have PHP1A because of PTH and TSH resistance and mild
features of Albright hereditary osteodystrophy. Two patients showed
decreased G-alpha activity in erythrocytes. However, genetic analysis
did not reveal germline point mutations in the GNAS gene in any of the
patients; instead, all were found to have GNAS methylation defects,
which are usually associated with PHP1B. Furthermore, 1 of the patients
with normal G-alpha activity was found to have a 3.0-kb STX16 deletion
(603666.0001), which is usually associated with PHP1B. The findings
suggested that there may be an overlap between the molecular and
clinical features of PHP1A and PHP1B, and that methylation defects may
manifest as mild PHP1A.

OTHER FEATURES

Allen et al. (1988) observed that hypomagnesemia can prevent the
elevation of PTH hormone concentrations in familial PHP; this finding
indicated that the parathyroid gland retains its physiologic response to
hypomagnesemia in this disorder.

Stirling et al. (1991) reported a woman with PPHP; both she and her son
had deficiency in production of growth hormone-releasing factor (GHRH;
139190). The son responded well to growth hormone treatment.

Studies in frog neuroepithelium showed that the sense of smell is
mediated by a Gs-adenylate cyclase system. Weinstock et al. (1986) found
that all Gs-deficient patients with type Ia PHP had impaired olfaction,
whereas all Gs-normal patients with PHP type Ib had normal olfaction.
This suggested that Gs-deficient patients may be resistant or impaired
in other cAMP-mediated actions in other nonendocrine systems.

Doty et al. (1997) noted that variably decreased olfactory ability had
been described in some patients with PHP Ia, suggesting that Gs-alpha
may play a role in human olfactory transduction. Tests of odor
detection, identification, and memory among patients with PHP Ia, PHP
Ib, and PPHP showed that patients with PHP Ia and PHP Ib had olfactory
dysfunction, and that patients with PPHP had normal olfactory function.
The authors concluded that the olfactory dysfunction associated with PHP
is not the result of generalized Gs-alpha protein deficiency.

Mental deficiency occurs in 47 to 75% of patients with PHP type I.
Because mutations in the adenylate cyclase-cAMP system may affect the
learning ability of Drosophila, Farfel and Friedman (1986) assessed
mental deficiency in 25 patients whose Gs protein activity had been
determined. Nine of 14 patients with type Ia and none of 11 patients
with type Ib pseudohypoparathyroidism had mental deficiency. Farfel and
Friedman (1986) concluded that Gs-protein deficiency, reduced cAMP
levels, or both are involved in the mental deficiency of these patients.

Because obesity is frequently associated with Gs deficiency and Gs is
part of the pathway transducing the lipolytic signal through
beta-adrenergic receptors, Carel et al. (1999) tested whether
epinephrine resistance was part of the spectrum of hormonal resistance
in patients with Gs deficiency. Using a nonradioactive tracer dilution
approach to measure glycerol flux, they analyzed the lipolytic response
to epinephrine in 6 patients with Gs deficiency and PHP Ia and compared
it in 6 age-matched normal controls and 9 massively obese children.
Basal glycerol production was reduced by 50%, and lipolytic response to
epinephrine was reduced by 67% in Gs-deficient children, as compared
with controls. The degree of impairment of lipolysis was similar in
Gs-deficient children who were only moderately overweight and in
morbidly obese children.

INHERITANCE

Pseudohypoparathyroidism with AHO was originally thought to be
transmitted as an X-linked dominant disorder, most likely based on
initial observations that females were affected twice as often as males.
However, Mann et al. (1962) found that whereas only 4 of 36 female cases
were of the incomplete form, 6 of 14 male cases failed to show full
expression. This finding, contrary to that in other X-linked traits,
made it possible that the disorders were in fact sex-influenced
autosomal dominant.

Chase et al. (1969) reported a family in which 2 patients with PHP were
the progeny of a mother with PPHP (612463). Another family had 3
brothers with PHP; the mother had PPHP. Weinberg and Stone (1971)
described a family in which a brother and sister had PHP1, and the son
and daughter of the brother had PPHP. All had clinical features of AHO,
which were more prominent in the patients with PHP1. The patients were
of normal intelligence but showed ectopic calcification and
ossification, rounded facies, 'absent 4th knuckles,' and short feet and
hands with particularly short 4th metacarpals.

Williams et al. (1977) described 4 females and 1 male in a family
pedigree who showed wide clinical variability encompassing both PHP and
PPHP. Farfel et al. (1981) reported a woman with PPHP whose daughter had
classic PHP type Ia. The mother had AHO with no history of hypocalcemia
or other endocrine abnormalities and normal urinary cAMP response to
PTH, but reduced erythrocyte N protein activity.

Kinard et al. (1979) and Fitch (1982) reported kindreds in which some
individuals had AHO without hormone resistance (PPHP) while others had
hormone resistance as well (PHP1A), suggesting that PHP and PPHP are
genetically related.

Cederbaum and Lippe (1973) reported 2 sibs with PHP1A transmitted in an
apparently autosomal recessive pattern. Farfel et al. (1981) restudied
this family and found that the 2 affected sibs had decreased N-protein
while the parents were clinically and biochemically normal. They
suggested that this may have been an instance of gonadal mosaicism in
one of the parents or that one of the parents was in fact carrying the
gene and was only very mildly affected.

In a review of the literature, Fitch (1982) favored autosomal dominant
inheritance with sex modification.

Van Dop et al. (1984) found renal resistance to endogenous and exogenous
PTH as well as reduced activity of the Gs protein in a man with PHP Ia.
Both of his children also had reduced Gs activity levels and short
stature. The 11-year-old daughter had evidence of partial resistance to
PTH, whereas the 7-year-old son had no apparent abnormalities in calcium
metabolism and a normal cAMP response to administered PTH, consistent
with PPHP. The occurrence of reduced erythrocyte Gs activity in the
father and son was consistent with autosomal dominant inheritance for
the primary biochemical defect (see Spiegel et al., 1985).

In 8 kindreds, Levine et al. (1988) found that the AHO phenotype and
erythrocyte alpha-Gs deficiency were transmitted together in a dominant
inheritance pattern.

Lecumberri et al. (2010) reported 2 unrelated families in which PHP1A
and PHP1B occurred coincidentally within different branches of each of
the families. In the first family, 2 sibs with PHP1A inherited a GNAS
mutation from their affected mother. A man from another branch of the
family with PHP1B was found to have paternal uniparental isodisomy of
chromosome 20q, with presumed lack of expression of the maternal allele.
The diagnosis was confusing in this patient before molecular analysis
because he had mild features of AHO and cognitive impairment, suggestive
of PHP1A. Genetic analysis confirmed that he did not have a germline
GNAS mutation. In the second family, 1 individual with PHP1A had a GNAS
mutation (139320.0011) inherited from his mother, and a second cousin
had PHP1B with an epigenetic defect at the GNAS locus. Lecumberri et al.
(2010) emphasized the importance of molecular diagnosis for proper
genetic counseling.

- Effects of Imprinting on Inheritance Pattern

Davies and Hughes (1993) pointed out that published reports of AHO
involving 2 or more generations showed a marked excess of maternal
transmission. Furthermore, full expression of the disorder (AHO plus
hormone resistance in the form of PHP) occurred in maternally
transmitted cases, whereas only partial expression (isolated AHO, or
PPHP) occurred in paternally transmitted cases. Davies and Hughes (1993)
suggested that genomic imprinting is involved in the expression of the
disorder.

Schuster et al. (1994) reported 1 family (Schuster et al., 1993) in
which the pattern of inheritance did not support the imprinting
hypothesis. One member of the family with 'normocalcemic PHP' who had an
impaired cAMP response to PTH was born from a father with PPHP. Schuster
et al. (1994) hypothesized that mechanisms other than genomic imprinting
were responsible for the full expression of hormone resistance, at least
within this family. Additional components of signal transduction (e.g.,
calmodulin, cAMP phosphodiesterase, or protein kinase A) may be
responsible for the differences between PHP Ia and PPHP.

PATHOGENESIS

PHP1A is caused by decreased Gs signaling in the hormone
receptor-adenylate cylase complex involved in intracellular signal
transduction. GNAS is a heavily imprinted locus, with different
expression of its isoforms in different tissues dependent on the
parental origin of the gene. Individuals with PHP1A and PPHP (612463)
show about a 50% decrease in Gs expression in erythrocytes, which
normally express both parental alleles. In PHP1A, physiologic responses
are impaired in tissues in which 50% residual Gs activity from the
paternal allele is not sufficient to maintain normal signaling, thus
resulting in haploinsufficiency. Moreover, renal tubule cells are unique
in that they only express the maternal allele of Gs; the paternal allele
is not expressed. Thus, renal cells of PHP1A patients have complete lack
of Gs expression resulting from an inactive maternal allele. Hormone
resistance in patients with maternal Gs-alpha mutations affects those
tissues in which expression of Gs-alpha is predominantly from the
maternal allele (i.e., renal tubule cells). The features of AHO are
believed to result from defective signaling in other cells due to Gs
haploinsufficiency (Bastepe and Juppner, 2005; Mantovani and Spada,
2006).

Chase and Aurbach (1968) demonstrated that PTH stimulated adenyl cyclase
in the renal cortex. Maguire et al. (1977) showed that the PTH
receptor-adenylate cyclase complex involved in response to PTH consists
of a hormone receptor, adenylate cyclase, and G proteins. Gs, also
termed 'Ns,' is the stimulatory G subunit that mediates the activation
of adenylate cyclase to form cAMP.

Drezner and Burch (1978) observed altered kinetic properties of
adenylate cyclase in renal cell membrane preparations from a patient
with PHP. The abnormalities were corrected by addition of
guanosine-5-prime-triphosphate to the reaction mixtures. These results
suggested an abnormal nucleotide receptor site on the G protein,
resulting in partial uncoupling of the PTH hormone receptor and
adenylate cyclase. This was predicted to render the organ refractory to
hormonal stimulation.

Decreased activity of the G protein is found in patients with PHP type I
who usually also have AHO (PHP type Ia), whereas normal G protein
activity is found in patients with PHP type I who do not have AHO (PHP
type Ib). Heinsimer et al. (1984) found that beta-adrenergic
agonist-specific binding properties of red cell membranes were 45% of
controls in 5 patients with PHP Ia and 97% of controls in 5 patients
with PHP Ib. Further studies were consistent with a single defect
causing deficient hormone receptor-nucleotide complex formation and
adenylate cyclase activity in PHP Ia, whereas the biochemical lesion(s)
appeared not to affect the complex formation in PHP Ib.

Levine et al. (1983) demonstrated that a Gs defect was responsible for
resistance to multiple hormones in some cases of PHP type I. End-organ
resistance to a variety of hormones included dysfunction of thyroid,
gonadotropin, prolactin, and glucagon action. A blunted plasma cAMP
response to the infusion of the beta-adrenergic agonist isoproterenol
was described by Carlson and Brickman (1983).

Levine et al. (1986) found that the activity of Gs was reduced in red
cells from patients with both PHP Ia and PPHP in 6 kindreds. However,
the authors noted that patients with PPHP usually do not have obvious
endocrine dysfunction, suggesting that factors other than Gs activity
must be involved in determining hormone resistance.

In a review of G protein diseases, Farfel et al. (1999) stated that the
different phenotypes between PHP1A and PPHP probably result from
tissue-specific combinations of haploinsufficiency and paternal
imprinting.

Weinstein and Yu (1999) reviewed the clinical and molecular evidence
that supports the role of genomic imprinting of Gs-alpha in the
pathogenesis of AHO features.

Gs-alpha transcripts are imprinted in pituitary somatotrophs that
secrete growth hormone (Hayward et al., 2001), leading Germain-Lee et
al. (2003) to hypothesize that maternally inherited GNAS1 mutations
would impair GH secretion through disruption of mediation of the
pituitary response to GHRH by G-alpha-s. They studied GH status in 13
subjects with PHP type Ia. GH responses to arginine/L-dopa and
arginine/GHRH were deficient in 9 subjects, all of whom were obese and
had low serum concentrations of IGF1. By contrast, none of the 4
GH-sufficient subjects were obese, and all had normal IGF1 levels. The
authors concluded that GH deficiency is common in PHP type Ia (69%) and
may contribute to the obesity and short stature typical of AHO, and
proposed that GH status be evaluated in all patients with PHP type Ia.

Using hot-stop PCR analysis on total RNA from 6 normal human thyroid
specimens, Liu et al. (2003) showed that the majority of the Gs-alpha
mRNA (72 +/- 3%) was derived from the maternal allele. This was
considered consistent with the presence of TSH resistance in patients
with maternal Gs-alpha-null mutations (PHP Ia). The authors concluded
that there is tissue-specific imprinting of Gs-alpha in the thyroid,
which may explain mild to moderate TSH resistance in PHP Ia.

Hsu et al. (2007) demonstrated that mutation of 1 GNAS gene caused
reduced Gs-alpha signaling in patients with AHO as evidenced by
decreased maximal cAMP production. The reduced Gs-alpha signaling in AHO
patients was associated with decreased activation of the downstream
target cystic fibrosis transmembrane conductance regulator (CFTR;
602421) in vivo when compared with normal controls.

CLINICAL MANAGEMENT

Drezner et al. (1976) presented evidence to suggest that the skeletal
resistance to PTH in PHP may result from a vitamin D deficiency. In 3 of
4 patients with PHP, they found low levels of the active form of vitamin
D, 1,25-dihydroxycholecalciferol. Treatment with vitamin D restored the
serum calcium and the calcemic response to PTH, without affecting the
impaired renal response. The authors suggested that hypocalcemia and
bone disease in PHP may be due to active vitamin D deficiency caused by
inability of the kidney to convert 25-hydroxycholecalciferol to
1,25-dihydroxycholecalciferol, rather than to primary bone resistance to
PTH.

Metz et al. (1977) showed normal 25-hydroxyvitamin D but extremely low
1,25-dihydroxycholecalciferol in a patient with a unique variant of PHP.
He had elevated serum PTH and normal renal response to PTH, which could
be consistent with PHP type II. Treatment with
1,25-dihydroxycholecalciferol restored bone responsiveness to PTH. The
authors suggested that homeostatic release of calcium from bone in
classic PHP was not responsive to PTH because of a renal deficiency in
the production of 1,25-vitamin D.

MAPPING

Hall (1990) noted that the GNAS1 gene maps to a region of chromosome 20
that is homologous to an area of mouse chromosome 2 involved in both
maternal and paternal imprinting. She suggested that AHO may show
imprinting by virtue of location in this area.

MOLECULAR GENETICS

Levine et al. (1988) studied 8 kindreds with 1 or more members affected
with AHO or PHP and decreased activity of the Gs protein. RNA blot
analysis showed about 50% reduced GNAS1 mRNA levels in fibroblasts of
affected members from 6 of the pedigrees, but normal levels in affected
members of the other 2 pedigrees. No abnormalities of restriction
fragments or gene dosage were identified using a cDNA hybridization
probe, leading the authors to conclude that major rearrangements or
deletions of GNAS1 were not a common cause for the disorder.

In a proband and his mother with PHP Ia, Patten et al. (1989, 1990)
identified a heterozygous mutation in the GNAS gene (139320.0001).

In a mother with PPHP (612463) and her 4 daughters with PHP Ia (Kinard
et al., 1979), Gejman et al. (1990) and Weinstein et al. (1990)
identified a heterozygous mutation in the GNAS gene (139320.0002). A son
of 1 of the affected daughters also had PHP Ia and carried the mutation.
A second heterozygous mutation (139320.0003) was identified in a second
family in which the mother had PPHP and her daughter had PHP Ia.

In an Italian patient with PHP Ia and features of AHO, Mantovani et al.
(2000) detected a heterozygous 1-bp deletion (139320.0025) in the GNAS
gene. This mutation was also found in the patient's mother, who had
PPHP.

In a brother and sister with PHP type Ia, who also had neonatal diarrhea
and pancreatic insufficiency, Aldred et al. (2000) identified
heterozygosity for a 12-bp insertion in the GNAS1 gene (139320.0035).
The mutation was not found in 2 unaffected sibs and was also not
detected in the lymphocyte DNA of either of the clinically unaffected
parents. Haplotype analysis confirmed germline mosaicism and indicated
that the mutation was maternal in origin. Makita et al. (2007) performed
biochemical and intact cell studies of the 12-bp insertion (AVDT) and
suggested that the PHP-Ia phenotype results from instability of the
Gs-alpha-AVDT mutant and that the accompanying neonatal diarrhea may
result from its enhanced constitutive activity in the intestine.

Aldred et al. (2002) reported 2 patients with Albright hereditary
osteodystrophy and deletions of chromosome 20q, including complete
deletion of the GNAS1 gene. One boy had a paternally inherited deletion
of chromosome 20q13.13-q13.32 and a normal biochemical evaluation
consistent with PPHP. The other patient had a maternally derived
deletion of chromosome 20q13.31-q13.33 and PHP type Ia.

HISTORY

Pseudohypoparathyroidism was the first endocrine syndrome in humans to
be recognized as a failure of end-organ response to a hormone. Albright
et al. (1942) was right about AHO being a hormone resistance state but
wrong about the Sebright bantam male, the name of which he misspelled in
his 1942 article and the nature of which has been shown to be excessive
conversion of testosterone to estrogen, not resistance to androgen.

Johnson (1980) suggested a form of simple inheritance that was neither
dominant nor recessive to explain the transmission of AHO, i.e., that
resulting from metabolic interference. In this situation both
homozygotes would be normal. Only the heterozygous condition would
produce an abnormal phenotype because the 2 alleles interact to have a
deleterious effect. Metabolic interference may occur when 2 allelic
genes code for different subunits of a multisubunit enzyme or structural
protein or 2 nonallelic genes may interact in other ways. Albright
hereditary osteodystrophy, manic depressive psychosis (309200), and
'X-linked' pterygium syndrome (312150) were cited as examples of
diseases compatible with X-linked dominance but not worse in males.

The possibility of an anomalous PTH in PHP type I was suggested by
observations of Loveridge et al. (1982). When exogenous parathormone was
added to plasma of normal subjects and those with hyperparathyroidism or
primary hypoparathyroidism, response was commensurate with the amount
added; 50 to 90% of the exogenous hormone was 'recovered.' When this was
done with the plasma of 10 PHP type I patients, recovery ranged from
less than 1% up to 35%. This seemed to indicate an inhibitor in PHP
plasma.

Hedeland et al. (1992) described a mother and daughter with classic
features of pseudohypoparathyroidism type Ia in association with
proximal deletion of 15q, del(15)(q11q13), similar to that seen in
Prader-Willi syndrome (176270) and Angelman syndrome (105830). Using a
series of DNA probes that often show deletion or uniparental disomy in
the latter 2 conditions, Hedeland et al. (1992) found no evidence for
either in the mother or the daughter.

ANIMAL MODEL

Yu et al. (1998) disrupted the Gnas gene by targeted mutagenesis in the
mouse and demonstrated that Gnas is imprinted in a tissue-specific
manner. Consistent with Gnas being an imprinted gene, heterozygous mice
with paternal (+/p-) and maternal (m-/+) transmission of the Gnas null
allele (GsKO) had distinct phenotypes. M-/+ but not +/p- mice were
resistant to parathyroid hormone, whereas both m-/+ and +/p- mice had a
normal maximal physiologic response to vasopressin. Studies of the
expression of the alpha subunit demonstrated that Gnas is imprinted,
with the paternal allele relatively inactive in renal cortex (the site
of PTH (168450) action) and brown and white adipose tissue. In contrast,
Gnas was not imprinted in the renal inner medulla (the site of
vasopressin action). Tissue-specific imprinting of Gnas was thought to
be the mechanism for variable and tissue-specific hormone resistance in
these mice and in Albright hereditary osteodystrophy.

*FIELD* SA
Campbell et al. (1994); Carlson et al. (1977); Elrick et al. (1950);
Farfel and Bourne (1980); Goeminne (1965); Hermans et al. (1964);
Levine et al. (1981); Levine et al. (1980); Logan and Miller (1979);
Matsuda et al. (1979); Northrup et al. (1980); Palubinskas and Davies
(1959); Spiegel et al. (1982); Van Dop and Bourne (1983); White and
Marx (1978); Winter and Hughes (1980)
*FIELD* RF
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77. Weinstock, R. S.; Wright, H. N.; Spiegel, A. M.; Levine, M. A.;
Moses, A. M.: Olfactory dysfunction in humans with deficient guanine
nucleotide-binding protein. Nature 322: 635-636, 1986.

78. Weisman, Y.; Golancer, A.; Spirer, Z.; Farfel, Z.: Pseudohypoparathyroidism
type Ia presenting as congenital hypothyroidism. J. Pediat. 107:
413-415, 1985.

79. White, B. J.; Marx, S. J.: Dermatoglyphic and radiographic findings
in a mother and daughter with pseudohypoparathyroidism. Clin. Genet. 13:
359-368, 1978.

80. Williams, A. J.; Wilkinson, J. L.; Taylor, W. H.: Pseudohypoparathyroidism:
variable manifestations within a family. Arch. Dis. Child. 52: 798-800,
1977.

81. Wilson, L. C.; Oude Luttikhuis, M. E. M.; Clayton, P. T.; Fraser,
W. D.; Trembath, R. C.: Parental origin of Gs-alpha gene mutations
in Albright's hereditary osteodystrophy. J. Med. Genet. 31: 835-839,
1994.

82. Winter, J. S. D.; Hughes, I. A.: Familial pseudohypoparathyroidism
without somatic anomalies. J. Canad. Med. Assoc. 123: 26-31, 1980.

83. Yu, S.; Yu, D.; Lee, E.; Eckhaus, M.; Lee, R.; Corria, Z.; Accili,
D.; Westphal, H.; Weinstein, L. S.: Variable and tissue-specific
hormone resistance in heterotrimeric Gs protein alpha-subunit (Gs-alpha)
knockout mice is due to tissue-specific imprinting of the Gs-alpha
gene. Proc. Nat. Acad. Sci. 95: 8715-8720, 1998.

84. Zung, A.; Herzenberg, J. E.; Chalew, S. A.: Radiological case
of the month. Arch. Pediat. Adolesc. Med. 15: 643-644, 1996.

*FIELD* CS
INHERITANCE:
Autosomal dominant

GROWTH:
[Height];
Short stature;
[Weight];
Obesity

HEAD AND NECK:
[Face];
Round face;
Full cheeks;
[Eyes];
Cataract;
Nystagmus;
[Nose];
Low nasal bridge;
[Teeth];
Delayed tooth eruption;
Enamel hypoplasia;
[Neck];
Short neck

SKELETAL:
Osteoporosis;
[Hands];
Brachydactyly;
Short metacarpals (especially 4th and 5th);
[Feet];
Brachydactyly;
Short metatarsals (especially 4th and 5th)

SKIN, NAILS, HAIR:
[Skin];
Subcutaneous ossifications

NEUROLOGIC:
[Central nervous system];
Cognitive deficits;
Mental retardation;
Hypocalcemic tetany;
Seizures;
Basal ganglion calcification;
Calcified choroid plexus;
[Peripheral nervous system];
Hypocalcemic tetany

ENDOCRINE FEATURES:
Pseudohypoparathyroidism;
Hypogonadism;
Hypothyroidism

LABORATORY ABNORMALITIES:
Hypocalcemia;
Hyperphosphatemia;
Elevated serum parathyroid hormone (PTH) level;
Low urinary cyclic AMP response to PTH administration;
Reduced erythrocyte Gs activity

MISCELLANEOUS:
Variable phenotype;
Caused by inheritance of the mutation on the maternal allele (imprinting);
See also pseudopseudohypoparathyroidism (612463);
See also pseudohypoparathyroidism type Ib (603233) and Ic (612462)

MOLECULAR BASIS:
Caused by mutation in the G-protein, alpha-stimulating 1 gene (GNAS1,
139320.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 8/25/2003
Ada Hamosh - updated: 4/14/2000
Kelly A. Przylepa - revised: 2/21/2000

*FIELD* ED
joanna: 07/23/2013
joanna: 12/24/2008
ckniffin: 12/15/2008
joanna: 12/5/2008
ckniffin: 8/25/2003
joanna: 4/14/2000
kayiaros: 2/25/2000
kayiaros: 2/21/2000

*FIELD* CN
Cassandra L. Kniffin - updated: 5/28/2010
Cassandra L. Kniffin - updated: 2/5/2009
Cassandra L. Kniffin - updated: 12/15/2008
Marla J. F. O'Neill - updated: 10/8/2008
John A. Phillips, III - updated: 8/2/2005
John A. Phillips, III - updated: 7/8/2005
Cassandra L. Kniffin - reorganized: 8/27/2003
Cassandra L. Kniffin - updated: 8/25/2003
Deborah L. Stone - updated: 6/16/2003
Wilson H. Y. Lo - updated: 10/18/1999
Victor A. McKusick - updated: 8/11/1998

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 12/05/2012
wwang: 6/2/2010
ckniffin: 5/28/2010
ckniffin: 5/18/2009
alopez: 4/24/2009
wwang: 2/10/2009
ckniffin: 2/5/2009
mgross: 1/12/2009
carol: 12/19/2008
ckniffin: 12/15/2008
ckniffin: 12/8/2008
wwang: 10/15/2008
terry: 10/8/2008
carol: 3/26/2008
ckniffin: 2/19/2008
alopez: 8/2/2005
alopez: 7/8/2005
ckniffin: 9/3/2003
ckniffin: 8/27/2003
carol: 8/27/2003
ckniffin: 8/25/2003
carol: 6/16/2003
carol: 5/13/2003
carol: 10/18/1999
mgross: 5/10/1999
carol: 8/14/1998
terry: 8/11/1998
terry: 7/31/1998
terry: 11/10/1997
alopez: 6/4/1997
mark: 11/27/1996
terry: 11/12/1996
terry: 11/4/1996
carol: 7/26/1996
carol: 3/2/1995
davew: 8/18/1994
terry: 7/18/1994
mimadm: 4/12/1994
warfield: 4/7/1994
pfoster: 3/25/1994

MIM 139320
*RECORD*
*FIELD* NO
139320
*FIELD* TI
*139320 GNAS COMPLEX LOCUS; GNAS
;;GNAS1 GENE, FORMERLY; GNAS1, FORMERLY
GUANINE NUCLEOTIDE-BINDING PROTEIN, ALPHA-STIMULATING ACTIVITY POLYPEPTIDE
read more1, INCLUDED; GNAS1, INCLUDED;;
Gs, ALPHA SUBUNIT, INCLUDED;;
STIMULATORY G PROTEIN, INCLUDED;;
ADENYLATE CYCLASE STIMULATORY PROTEIN, ALPHA SUBUNIT, INCLUDED;;
SECRETOGRANIN VI, INCLUDED;;
NEUROENDOCRINE SECRETORY PROTEIN 55, INCLUDED; NESP55, INCLUDED;;
XL-ALPHA-S, INCLUDED; XLAS, INCLUDED;;
A/B TRANSCRIPT, INCLUDED;;
ALTERNATIVE GENE PRODUCT ENCODED BY THE XL EXON, INCLUDED; ALEX, INCLUDED
*FIELD* TX

DESCRIPTION

GNAS is a complex imprinted locus that produces multiple transcripts
through the use of alternative promoters and alternative splicing. The
most well-characterized transcript derived from GNAS, Gs-alpha, encodes
the alpha subunit of the stimulatory guanine nucleotide-binding protein
(G protein). Gs-alpha is expressed biallelically in nearly all tissues
and plays essential roles in a multitude of physiologic processes. Other
transcripts produced by GNAS are expressed exclusively from either the
paternal or the maternal GNAS allele (Bastepe and Juppner, 2005).

CLONING

- Overview of Transcripts Produced by GNAS

The GNAS locus is imprinted and encodes 4 main transcripts, Gs-alpha,
XLAS, NESP55, and the A/B transcript, as well as an antisense GNAS
transcript (GNASAS; 610540). The 4 main transcripts are produced through
the use of alternative promoters and splicing of 4 unique first exons
onto the shared exons 2 through 13. Gs-alpha is ubiquitously expressed
and encodes a protein that stimulates adenylyl cyclase when activated by
an agonist-occupied G protein-coupled receptor, thereby generating the
second messenger cAMP. Gs-alpha is biallelically expressed except in a
small number of tissues, including renal proximal tubules, thyroid,
gonads, and pituitary, where it is predominantly expressed from the
maternal GNAS allele. XLAS is a large variant of Gs-alpha that is
expressed exclusively from the paternal GNAS allele, primarily in
neuroendocrine tissues and the nervous system. The XLAS and Gs-alpha
proteins are identical over their C-terminal portions, but they have
distinct N termini. NESP55 is exclusively expressed from the maternal
GNAS allele and encodes a chromogranin (see 118910)-like neuroendocrine
secretory protein that, due to a stop codon in its unique first exon,
shares no amino acid sequence with Gs-alpha. The A/B transcript, which
uses the alternative first exon A/B (also referred to as exon 1A or
1-prime), and the antisense GNAS transcript, which consists of exons
that do not overlap with any other GNAS exons, are ubiquitously
expressed noncoding transcripts that are derived exclusively from the
paternal GNAS allele. Consistent with their parent-specific expression,
the promoters of the XLAS, NESP55, A/B, and antisense transcripts are
within differentially methylated regions (DMRs), and in each case the
nonmethylated promoter drives expression. In contrast, the promoter for
Gs-alpha lacks methylation and is biallelically active in most tissues
(Bastepe and Juppner, 2005).

- Gs-Alpha Transcript

Using oligonucleotide probes for recombinants that code for alpha
subunits of G signal transduction proteins, Bray et al. (1986) screened
human brain cDNA libraries and identified 11 clones corresponding to 4
species of Gs-alpha cDNA. One of the clones was predicted to encode a
384-amino acid protein with homology to the bovine and rat Gs-alpha
proteins. The 4 clones differed in nucleotide sequence in the region
that codes for amino acid residues 71 to 88. Two forms corresponded to
proteins with molecular masses of 52 and 45 kD. The authors suggested
alternative splicing of a single precursor mRNA.

- A/B Transcript

Ishikawa et al. (1990) reported a Gs-alpha mRNA that uses a different
promoter and exon, which they termed exon 1-prime (later termed exon 1A
or A/B) that is located 2.5 kb upstream of GNAS exon 1. Exon 1-prime
does not contribute an in-frame ATG, and thus its mRNA may encode a
truncated form of Gs-alpha.

- XLAS Transcript

By restriction landmark genomic scanning, Hayward et al. (1998)
identified a differentially methylated locus containing a previously
undescribed GNAS1 exon. This exon was included within transcripts
homologous to an mRNA encoding the large G protein XL-alpha (s) in the
rat (Kehlenbach et al., 1994). Two restriction sites flanking this exon
were methylated on a maternal allele and unmethylated on a paternal
allele. RT-PCR of human fetal tissues showed that in contrast to
Gs-encoding transcripts, which were biallelic, mRNAs encoding XLAS were
derived exclusively from the paternal allele. The paternally active
alternative promoter was located 35 kb upstream of exon 1.

In rat, the paternally expressed XLAS gene is a splice variant of GNAS,
consisting of exon 1 of XL and exons 2 to 13 of GNAS. A second open
reading frame in XL exon 1, which completely overlaps the XL domain ORF,
encodes ALEX (alternative gene product encoded by the XL exon), which is
translated from the XLAS mRNA and binds the XL domain of XLAS (Klemke et
al., 2001).

- NESP55 Transcript

Hayward et al. (1998) identified a second promoter upstream of the
Gs-alpha site in addition to that for XLAS. Both upstream promoters were
associated with a large coding exon and showed opposite patterns of
allele-specific methylation and monoallelic transcription. The more
5-prime of these exons encoded the neuroendocrine secretory protein-55
(NESP55), which was expressed exclusively from the maternal allele. The
NESP55 exon is 11 kb 5-prime to the paternally expressed XLAS exon. The
transcripts from these 2 promoters both splice onto GNAS1 exon 2, yet
share no coding sequences. Despite their structural unrelatedness, the
encoded proteins, of opposite allelic origin, have both been implicated
in regulated secretion in neuroendocrine tissues. Hayward et al. (1998)
concluded that maternally (NESP55), paternally (XLAS), and biallelically
(Gs-alpha)-derived proteins are produced by different patterns of
promoter use and alternative splicing of GNAS1, a gene showing
simultaneous imprinting in both the paternal and maternal directions.

By sequencing clones obtained from human pheochromocytoma and rat
pituitary cDNA libraries, Weiss et al. (2000) identified 2 main splice
variants that included NESP55 sequences. In the 2,400-bp variant, NESP55
exons were spliced onto GNAS exons 2 to 13, and in the shorter 1800-bp
variant, NESP55 exons were spliced onto GNAS exons 2, 3, and N1. Several
cDNA clones contained inverted repeats on either the 5-prime or 3-prime
terminus, and heterogeneity in the GNAS region, such as deletion of exon
3 or insertion of a CAG trinucleotide after exon 3, was also found. The
2,400-bp variant contains an open reading frame (ORF) encoding the
NESP55 protein and an ORF encoding a truncated form of GNAS lacking exon
1. The sequence TAATG encodes the stop codon (TAA) of the NESP55 ORF as
well as the initiating methionine (ATG) of the truncated GNAS. The human
NESP55 ORF encodes a protein of about 28 kD, which has high homology
with rat Nesp55, particularly in the first 70 amino acids. Northern blot
analysis and RT-PCR detected the longer transcript in rat adrenal
medulla, pituitary, and locus ceruleus, and the shorter transcript only
in pituitary. Biochemical analysis indicated that rat Nesp55 is a
keratan sulfate proteoglycan, and like other chromogranins, Nesp55 was
proteolytically processed into smaller peptides in several rat tissues,
including a predominant GPIPIRRH peptide that is also found in human
NESP55.

- GNAS Antisense Transcript

Hayward and Bonthron (2000) described a spliced polyadenylated antisense
transcript (GNASAS; 610540) arising from the maternally methylated
region upstream of the XL-alpha-s exon, which spans the upstream NESP55
region. The antisense transcript is imprinted, and expressed only from
the paternal allele, suggesting to the authors that it may have a
specific role in suppressing in cis the activity of the paternal NESP55
allele. For further information on the GNAS antisense transcript, see
610540,

GENE STRUCTURE

Rickard and Wilson (2003) provided a schematic representation of the
GNAS locus. Exons 1 through 13 of GNAS produce the Gs-alpha transcript.
Imprinted first exons specifically used for the NESP55, XLAS, and exon
1A transcripts are located approximately 35, 14, and 2.5 kb upstream of
GNAS exon 1, respectively. These exons are spliced to GNAS exons 2
through 13. The GNAS antisense transcript originates upstream of the
XLAS exon. An alternative 3-prime exon, located within GNAS intron 3,
includes an alternative stop codon and polyadenylation site.

Bastepe and Juppner (2005) noted that the promoter regions associated
with the imprinted NESP55, XLAS, exon A/B, and antisense transcripts are
located within differentially methylated regions. In each case, the
nonmethylated promoter drives expression of the transcript. In contrast,
the Gs-alpha promoter lacks methylation and is biallelically active in
most tissues.

MAPPING

Using a cDNA probe in connection with a mouse/human somatic cell hybrid
panel, Sparkes et al. (1987) mapped the gene encoding the
alpha-stimulating polypeptide of G protein to chromosome 20. (See also
Blatt et al. (1988).) Ashley et al. (1987) mapped the corresponding gene
in the mouse to chromosome 2 which, by the argument of homology of
synteny, supports the assignment of the human stimulatory G protein gene
to chromosome 20.

Gejman et al. (1991) mapped the GNAS1 gene to the distal long arm of
chromosome 20 by linkage studies using a polymorphism detected by
denaturing gradient gel electrophoresis (DGGE). A maximum lod score of
9.31 was obtained at a theta of 0.042 with the locus D20S15, previously
reported to be on the long arm of chromosome 20 (Donis-Keller et al.,
1987).

By in situ hybridization, Gopal Rao et al. (1991) assigned the GNAS1
gene to chromosome 20q12-q13.2. Using the same method, Levine et al.
(1991) mapped the GNAS1 gene to chromosome 20q13.2-q13.3.

GENE FAMILY

- G Protein Family

G proteins transduce extracellular signals received by transmembrane
receptors to effector proteins. The activity of hormone-sensitive
adenylate cyclase is regulated by at least 2 G proteins, 1 stimulatory
(Gs) and 1 inhibitory (Gi; see 139310). A third G protein, Go (139311),
is abundant in brain. Each G protein is a heterotrimer composed of an
alpha, beta, and gamma subunit. The GNAS locus encodes Gs-alpha, the
alpha subunit of the G stimulatory protein. Each of the 3 G protein
subunits is encoded by a member of 1 of 3 corresponding gene families.
Hurowitz et al. (2000) counted 16 different members of the alpha subunit
family, 5 different members of the beta subunit family, and 11 different
members of the gamma subunit family, as described in mammals. Using
BACs, they determined the gene structure and chromosome location of each
gene. The G protein family includes transducin (189970).

BIOCHEMICAL FEATURES

- Crystal Structure

Rasmussen et al. (2011) presented the crystal structure of the active
state ternary complex composed of agonist-occupied monomeric
beta-2-adrenergic receptor (AR) (ADRB2; 109690) and nucleotide-free Gs
heterotrimer. The principal interactions between the beta-2-AR and Gs
involve the amino- and carboxy-terminal alpha-helices of Gs, with
conformational changes propagating to the nucleotide-binding pocket. The
largest conformational changes in the beta-2-AR include a 14-angstrom
outward movement at the cytoplasmic end of transmembrane segment 6 and
an alpha-helical extension of the cytoplasmic end of transmembrane
segment 5. The most surprising observation is a major displacement of
the alpha-helical domain of G-alpha-s relative to the Ras-like GTPase
domain.

Chung et al. (2011) applied peptide amide hydrogen-deuterium exchange
mass spectrometry to probe changes in the structure of the
heterotrimeric bovine G protein, Gs, on formation of a complex with
agonist-bound human beta-2-AR, and reported structural links between the
receptor-binding surface and the nucleotide-binding pocket of Gs that
undergo higher levels of hydrogen-deuterium exchange than would be
predicted from the crystal structure of the beta-2-AR-Gs complex.
Together with x-ray crystallographic and electron microscopic data of
the beta-2-AR-Gs complex, Chung et al. (2011) provided a rationale for a
mechanism of nucleotide exchange, whereby the receptor perturbs the
structure of the amino-terminal region of the alpha-subunit of Gs and
consequently alters the 'P-loop' that binds the beta-phosphate in GDP.

GENE FUNCTION

- Function of Gs-Alpha Protein

Mehlmann et al. (2002) demonstrated that meiotic arrest of the oocyte
can be released in mice by microinjecting the oocyte within the follicle
with an antibody that inhibits Gs. This indicates that Gs activity in
the oocyte is required to maintain meiotic arrest within the ovarian
follicle and suggests that the follicle may keep the cell cycle arrested
by activating Gs.

Harrison et al. (2003) demonstrated that signaling via the erythrocyte
ADRB2 and heterotrimeric G-alpha-s regulated the entry of the human
malaria parasite Plasmodium falciparum. Agonists that stimulate cAMP
production led to an increase in malarial infection that could be
blocked by specific receptor antagonists. Moreover, peptides designed to
inhibit G-alpha-s protein function reduced parasitemia in P. falciparum
cultures in vitro, and beta-antagonists reduced parasitemia of P.
berghei infections in an in vivo mouse model. Harrison et al. (2003)
suggested that signaling via erythrocyte ADRB2 and G-alpha-s may
regulate malarial infection across parasite species.

Adams et al. (2009) demonstrated that hematopoietic stem and progenitor
cell (HSPC) engraftment of bone marrow in fetal development is dependent
on G-alpha-S. The authors observed that HSPCs from adult mice deficient
in G-alpha-S differentiated and underwent chemotaxis, but did not home
to or engraft in the bone marrow in adult mice, and demonstrated a
marked inability to engage the marrow microvasculature. Deletion of
G-alpha-S after engraftment did not lead to lack of retention in the
marrow; rather, cytokine-induced mobilization into the blood was
impaired. In tests of the effect of G-alpha-S activation on HSPCs,
pharmacologic activators enhanced homing and engraftment in vivo. Adams
et al. (2009) concluded that G-alpha-S governs specific aspects of HSPC
localization under physiologic conditions in vivo and may be
pharmacologically targeted to improve transplantation efficiency.

- Imprinting of GNAS

Hall (1990) noted that the region of chromosome 20 occupied by the
Gs-alpha gene is homologous to an area of mouse chromosome 2 involved in
both maternal and paternal imprinting.

Campbell et al. (1994) presented evidence suggesting that GNAS1 is
biallelically expressed in a wide range of human fetal tissues. Of 75
fetuses genotyped, 13 heterozygous for a FokI polymorphism in GNAS1 were
identified whose mothers were homozygous for one or another allele.
Analysis of GNAS1 RNA from each fetus showed expression from both
parental alleles. No tissue-specific pattern of expression was
discerned. Campbell et al. (1994) concluded that if genomic imprinting
regulates the expression of the GNAS1 gene, the effect must either be
subtle and quantitative or be confined to a small subset of specialized
hormone-responsive cells within the target tissues.

Hayward et al. (2001) investigated GNAS1 imprinting in the normal adult
pituitary and found that Gs-alpha was monoallelically expressed from the
maternal allele in this tissue. They found that this monoallelic
expression of Gs-alpha was frequently relaxed in somatotroph tumors
regardless of GNAS1 mutation status. These findings implied a possible
role for loss of Gs-alpha imprinting during pituitary somatotroph
tumorigenesis and also suggested that Gs-alpha imprinting is regulated
separately from that of the other GNAS1 products, NESP55 and XL-alpha-s,
which retain maternal and paternal imprinting, respectively, in these
tumors.

To establish if the GNAS1 gene is imprinted in human endocrine tissues,
Mantovani et al. (2002) selected 14 thyroid, 10 granulosa cell, 13
pituitary (3 normal glands, 7 GH-secreting adenomas, and 3
nonfunctioning adenomas), 3 adrenal, and 11 lymphocyte samples shown to
be heterozygous for a known polymorphism in exon 5. RNA from these
tissues was analyzed by RT-PCR, and expression from both parental
alleles was evaluated by enzymatic digestion and subsequent
quantification of the resulting fragments. Most thyroid, ovarian, and
pituitary samples showed an almost exclusive or significantly
predominant expression of the maternal allele over the paternal one,
whereas in lymphocyte and adrenal samples both alleles were equally
expressed. The authors concluded that their results provided evidence
for a predominant maternal origin of GNAS1 transcripts in different
human adult endocrine tissues, particularly thyroid, ovary, and
pituitary.

Using hot-stop PCR analysis on total RNA from 6 normal human thyroid
specimens, Liu et al. (2003) showed that the majority of the Gs-alpha
mRNA (72 +/- 3%) was derived from the maternal allele. This was
considered consistent with the presence of TSH (see 188540) resistance
in patients with maternal Gs-alpha-null mutations (PHP 1a; 103580) and
the absence of TSH resistance in patients with paternal Gs-alpha
mutations (pseudopseudohypoparathyroidism). Patients with PTH (168450)
resistance in the absence of Albright hereditary osteodystrophy (PHP1B;
603233) have an imprinting defect of the Gs-alpha gene resulting in both
alleles having a paternal epigenotype, which would lead to a more
moderate level of thyroid-specific Gs-alpha deficiency. The authors
found evidence of borderline TSH resistance in 10 of 22 PHP Ib patients.
The authors concluded that their study provided further evidence for
tissue-specific imprinting of Gs-alpha in humans and provided a
potential mechanism for mild to moderate TSH resistance in PHP Ia and
borderline resistance in some patients with PHP Ib.

Liu et al. (2000) showed that the human GNAS exon 1A promoter region
(2.5 kb upstream from exon 1) is imprinted in a manner similar to that
in the mouse: the region is normally methylated on the maternal allele
and unmethylated on the paternal allele. In 13 patients with
pseudohypoparathyroidism Ib, the exon 1A region was unmethylated on both
alleles, and was thus biallelically expressed. Liu et al. (2000)
proposed that the exon 1A differentially methylated region (DMR) is
important for establishing or maintaining tissue-specific GNAS
imprinting and that loss of exon 1A imprinting is the cause of PHP Ib.
(See also Bastepe et al. (2001, 2001).)

Freson et al. (2002) described a PHP Ib patient with lack of methylation
of the exon XL and 1A promoters, and biallelic methylation of the NESP55
promoter. Platelets of this patient showed a functional Gs defect,
decreased cAMP formation upon Gs-receptor stimulation, and normal
Gs-alpha sequence, but reduced Gs-alpha protein levels. The authors
hypothesized that transcriptional deregulation between the biallelically
active promoters of both exon 1A and exon 1 of Gs-alpha could explain
the decreased Gs-alpha expression in platelets and presumably in the
proximal renal tubules. Platelets demonstrated decreased NESP55 and
increased XL-alpha-s protein levels, in agreement with the methylation
status of their corresponding first exons. In a megakaryocytic cell line
MEG-01, exon 1A is methylated on both alleles, in contrast to the
normally maternally methylated exon 1A in leukocytes. Experimental
demethylation of exon 1A in MEG-01 cells led to reduced Gs-alpha
expression, in agreement with the observations in the patient. The
authors proposed that platelet studies may allow more facile evaluation
of disturbances of the GNAS1 cluster in PHP Ib patients.

Genomic imprinting, by which maternal and paternal alleles of some genes
have different levels of activity, has profound effects on growth and
development of the mammalian fetus. Plagge et al. (2004) disrupted a
paternally expressed transcript at the Gnas locus, Gnasxl, which encodes
the unusual Gs-alpha isoform XL-alpha-s. Mice with mutations in Gnasxl
had poor postnatal growth and survival and a spectrum of phenotypic
effects indicating that XL-alpha-s controls a number of key postnatal
physiologic adaptations, including suckling, blood glucose, and energy
homeostasis. Increased cAMP levels in brown adipose tissue of Gnasxl
mutants and phenotypic comparison with Gnas mutants suggested that
XL-alpha-s can antagonize Gs-alpha-dependent signaling pathways. The
opposing effects of maternally and paternally expressed products of the
Gnas locus provided tangible molecular support for the parental conflict
hypothesis of imprinting.

Two candidate imprinting control regions (ICRs) have been identified at
the compact imprinted Gnas cluster on distal mouse chromosome 2: one at
exon 1A upstream of Gnas itself and one covering the promoters of Gnasxl
and the antisense Gnas transcript, also called Nespas (Coombes et al.,
2003). Gnas itself is mainly biallelically expressed but is weakly
paternally repressed in specific tissues. Williamson et al. (2004)
showed that a paternally-derived targeted deletion of the germline
differentially methylated region at exon 1A abolished tissue-specific
imprinting of Gnas, which rescued the abnormal phenotype of mice with a
maternally-derived Gnas mutation. Imprinting of alternative transcripts,
Nesp, Gnasxl, and Nespas in the cluster was unaffected. The results
established that the differentially methylated region in exon 1A
contains an imprinting control element that specifically regulates Gnas
and comprises a characterized ICR for a gene that is only weakly
imprinted in a minority of tissues. Williamson et al. (2004) concluded
that there must be a second ICR regulating the alternative transcripts.

Williamson et al. (2006) identified a second ICR at the mouse Gnas
cluster. They showed that a paternally-derived targeted deletion of the
germline DMR associated with the antisense Nespas transcript
unexpectedly affected both the expression of all transcripts in the
cluster and methylation of 2 DMRs. The results established that the
Nespas DMR is the principal ICR at the Gnas cluster and functions
bidirectionally as a switch for modulating expression of the
antagonistically acting genes Gnasxl and Gnas. Uniquely, the Nespas DMR
acts on the downstream ICR at exon 1A to regulate tissue-specific
imprinting of the Gnas gene.

Mantovani et al. (2004) investigated the presence of a parent
specificity of Gs-alpha mutations in 10 patients affected with
McCune-Albright syndrome (MAS; 174800) and 12 isolated tumors (10
GH-secreting adenomas, 1 toxic thyroid adenoma, and 1 hyperfunctioning
adrenal adenoma). The parental origin of Gs-alpha mutations was assessed
by evaluating NESP55 and exon 1A transcripts, which are monoallelically
expressed from the maternal and paternal alleles, respectively. By this
approach, Mantovani et al. (2004) demonstrated that in isolated
GH-secreting adenomas, as well as in MAS patients with acromegaly,
Gs-alpha mutations were on the maternal allele. By contrast, the
involvement of other endocrine organs in MAS patients was not associated
with a particular parent specificity, as precocious puberty and
hyperthyroidism were present in patients with mutations on either the
maternal or the paternal allele. Moreover, isolated hyperfunctioning
thyroid and adrenal adenomas displayed the mutation on the maternal and
paternal alleles, respectively. Mantovani et al. (2004) concluded that
their data confirmed the importance of Gs-alpha imprinting in the
pituitary gland and demonstrated the high degree of tissue specificity
of this phenomenon.

To establish whether Gs-alpha is imprinted also in tissues that are site
of alteration both in PHP Ia and PPHP, Mantovani et al. (2004) selected
20 bone and 10 adipose tissue samples that were heterozygous for a known
polymorphism in exon 5. Expression from both parental alleles was
evaluated by RT-PCR and enzymatic digestion of the resulting fragments.
By this approach, the great majority of the samples analyzed showed an
equal expression of the 2 alleles. The authors concluded that their
results provided evidence for the absence of Gs-alpha imprinting in
human bone and fat and suggested that the clinical finding of
osteodystrophy and obesity in PHP Ia and PPHP patients despite the
presence of a normal Gs-alpha allele is likely due to Gs-alpha
haploinsufficiency in these tissues.

By analyzing 30 polymorphic sites across the Gnas1 gene region in
C57BL/6J x Mus spretus F1 mice, Li et al. (2004) identified 2 allelic
switch regions (ASRs) that marked boundaries of epigenetic information.
Activating signals consisting of histone acetylation and methylation of
H3 lys4 (see 602810) and silencing signals consisting of histone
methylation of H3 lys9 and DNA methylation segregated independently
across the ASRs. The authors suggested that these ASRs may allow the
transcriptional elongation to proceed through the silenced domain of
nearby imprinted promoters.

Sakamoto et al. (2004) examined the chromatin state of each parental
allele within the exon 1A-Gs-alpha promoter region by chromatin
immunoprecipitation of samples derived from mice with heterozygous
deletions within the region using antibodies to covalently modified
histones. The exon 1A DMR had allele-specific differences in histone
acetylation and methylation, with histone acetylation and H3 lysine-4
(H3K4) methylation of the paternal allele, and H3 lysine-9 (H3K9)
methylation of the maternal allele. Both parental alleles had similar
levels of histone acetylation and H3K4 methylation within the Gs-alpha
promoter and first exon, with no H3K9 methylation. In liver, where
Gs-alpha is biallelically expressed, both parental alleles had similar
levels of tri- and dimethylated H3K4 within the Gs-alpha first exon. In
contrast, in renal proximal tubules there was a greater ratio of tri- to
dimethylated H3K4 of Gs-alpha exon 1 in the more transcriptionally
active maternal as compared with the paternal allele. The authors
concluded that allele-specific differences in Gs-alpha expression
correlate in a tissue-specific manner with allele-specific differences
in the extent of H3K4 methylation, and chronic transcriptional
activation in mammals is correlated with trimethylation of H3K4.

Morison et al. (2005) reported a census of known imprinted genes in
humans and mice. They listed 83 transcriptional units, of which 29 are
imprinted in both species. They noted that there is a high level of
discordance of imprinting status between the mouse and human and that a
high proportion of imprinted genes are noncoding RNAs or genes derived
by retrotransposition.

MOLECULAR GENETICS

- Inactivating Mutations in the GNAS Gene

Inactivating loss-of-function mutations in the GNAS1 gene result in
pseudohypoparathyroidism Ia (PHP1A; 103580),
pseudopseudohypoparathyroidism (PPHP; 612463), and progressive osseous
heteroplasia (POH; 166350) (Aldred and Trembath, 2000).

In a patient with PHP Ia and his affected mother, Patten et al. (1989,
1990) identified a heterozygous mutation in the GNAS gene (139320.0001).

Ahmed et al. (1998) performed mutation analysis in 13 unrelated
families, 8 with PHP Ia and PPHP patients, and 5 with PPHP patients
only. GNAS1 mutations were detected in 4 of the 8 families with PHP Ia:
2 novel de novo missense mutations and an identical frameshift deletion
in 2 unrelated families (139320.0011). GNAS1 mutations were not detected
in any of the families with PPHP only.

Aldred and Trembath (2000) found that a recurring 4-bp deletion in exon
7 of the GNAS1 gene (139320.0011) was common among patients with PHP1A.
The authors noted that inactivating mutations are scattered throughout
the GNAS gene with some evidence of clustering.

In 4 unrelated Italian families with PHP Ia, Mantovani et al. (2000)
identified heterozygous mutations in GNAS: 2 families had 2 previously
reported deletions in exons 5 and 7, whereas the other 2 families had 2
novel frameshift deletions (139320.0025 and 139320.0026). No mutations
were detected in the families in which PPHP was the only clinical
manifestation.

Ahrens et al. (2001) investigated 29 unrelated patients with Albright
hereditary osteodystrophy and PHP Ia or pseudopseudohypoparathyroidism
and their affected family members. All patients showed a reduced GNAS1
protein activity (mean 59% compared with healthy controls). In 21 of 29
patients (72%), 15 different mutations in GNAS1, including 11 novel
mutations, were detected. There were 8 instances in which a mother had
PPHP and her offspring had PHP Ia with AHO due to the same mutation
(see, e.g., 139320.0028). They also reported 5 unrelated patients with a
previously described 4-bp deletion in exon 7 (139320.0011), confirming
the presence of a hotspot for loss-of-function mutations in GNAS1. In 8
patients, no molecular abnormality was found in the GNAS1 gene despite a
functional defect of Gs-alpha.

Shore et al. (2002) identified heterozygous inactivating GNAS1 mutations
in 13 of 18 probands with progressive osseous heteroplasia. The
defective allele in POH was inherited exclusively from fathers, a result
consistent with a model of imprinting for GNAS1. Direct evidence that
the same mutation can cause either POH or PPHP was observed in a single
family; in this family 5 sisters had POH due to a frameshift deletion of
4 nucleotides (139320.0011) inherited from the father in whom the
mutation was nonpenetrant. Three offspring of these sisters had PPHP,
including traces of subcutaneous ossification. Shore et al. (2002)
described a second family in which the unaffected father was
heterozygous for the same GNAS1 mutation associated with POH in his 3
affected daughters. Shore et al. (2002) noted that hormone resistance,
such as that in PHP Ia, is strongly correlated with GNAS1 mutations in
the maternally derived allele, indicating that the maternal allele is
critical in some tissues for cellular functions required for signal
transduction. In contrast, severe, progressive heterotopic ossification,
such as that found in POH, correlates with paternal inheritance of the
GNAS1 mutation, suggesting that the paternal allele specifically
influences progressive osteoblastic differentiation, proliferation of
cells in soft connective tissues, or both.

Linglart et al. (2002) conducted clinical and biologic studies including
screening for mutations in the GNAS1 gene in 30 patients from 21
families with PHP: 19 with PHP associated with decreased erythrocyte Gs
activity (PHP Ia); 10 with AHO associated with decreased erythrocyte Gs
activity (isolated AHO); and 1 with PHP, hormonal resistance, and AHO
but normal erythrocyte Gs activity (PHP Ic). A heterozygous GNAS1 gene
lesion was found in 14 of 17 (82%) of the PHP Ia index cases, including
11 new mutations and a mutation hotspot involving codons 189-190 (21%).
These lesions led to a truncated protein in all but 3 cases with
missense mutations. In the patient diagnosed with PHP Ic, Gs-alpha
protein was shortened by just 4 amino acids, a finding consistent with
the conservation of Gs activity in erythrocytes and the loss of receptor
contact. No GNAS1 lesions were found in the 5 individuals with isolated
AHO who were not related to the PHP Ia patients. Intrafamilial
segregation analyses of the mutated GNAS1 allele in 9 PHP Ia patients
established that the mutation had occurred de novo on the maternal
allele in 4 and had been transmitted by a mother with a mild phenotype
in the other 5. They concluded that imprinting of GNAS1 plays a role in
the clinical phenotype of loss-of-function mutations and that a
functional maternal GNAS1 allele has a predominant role in preventing
the hormonal resistance of PHP Ia.

Aldred et al. (2002) reported 2 patients with Albright hereditary
osteodystrophy and deletions of chromosome 20q, including complete
deletion of the GNAS1 gene. One boy had a paternally inherited deletion
of chromosome 20q13.13-q13.32 and a normal biochemical evaluation
consistent with pseudopseudohypoparathyroidism. The other patient had a
maternally derived deletion of chromosome 20q13.31-q13.33 and
pseudohypoparathyroidism type Ia. Neither patient showed evidence of
soft tissue ossification.

In patients with AHO, Rickard and Wilson (2003) searched the 3
overlapping upstream exons, NESP55, XL-alpha-s, and exon 1A. Analysis of
the NESP55 transcripts revealed the creation of a novel splice site in 1
patient and an unusual intronic mutation that caused retention of the
intron in another patient, neither of which could be detected by
analysis of the cDNA of GNAS1.

In a brother and sister with a PHP-Ia phenotype, who also had neonatal
diarrhea and pancreatic insufficiency, Aldred et al. (2000) identified
heterozygosity for a 12-bp in-frame insertion in the GNAS1 gene
(139320.0035). The mutation was inherited from the unaffected mother,
who was found to have germline mosaicism. Makita et al. (2007) performed
biochemical and intact cell studies of the 12-bp insertion (AVDT) and
suggested that the PHP-Ia phenotype results from the instability of the
Gs-alpha-AVDT mutant and that the accompanying neonatal diarrhea may
result from its enhanced constitutive activity in the intestine.

Adegbite et al. (2008) reviewed the charts of 111 individuals with
cutaneous and subcutaneous ossification. While most individuals with
superficial or progressive ossification had inactivating mutations in
GNAS, there were no specific genotype-phenotype correlations that
distinguished the more progressive forms such as POH from the
nonprogressive forms such as PPHP and PHP Ia/c.

- Pseudohypoparathyroidism Type Ib

In 3 brothers with a clinical diagnosis of PHP Ib (603233), Wu et al.
(2001) identified heterozygosity for a 3-bp deletion in the GNAS gene
(139320.0033). The boys had decreased cAMP response to PTH infusion, but
normal erythrocyte Gs activity. When expressed in vitro, the mutant
Gs-alpha was unable to interact with PTHR1 (168468) but showed normal
coupling to other coexpressed heptahelical receptors. Wu et al. (2001)
noted that the absence of PTH resistance in the mother and maternal
grandfather who carried the same mutation was consistent with models of
paternal imprinting of the GNAS gene.

In affected members and obligate carriers of 12 unrelated families with
PHP Ib, Bastepe et al. (2003) identified a 3-kb heterozygous
microdeletion located approximately 220 kb centromeric of exon 1A, which
they called exon A/B, of the GNAS gene. Four of 16 apparently sporadic
PHP Ib patients also had the deletion. Affected individuals with the
microdeletion showed loss of exon 1A methylation, but no other
epigenetic abnormalities. In all examined cases, the deletion was
inherited from the mother, consistent with the observation of PHP Ib
developing only in offspring of female obligate carriers. The deletion
also removed 3 of 8 exons encoding syntaxin-16 (STX16; 603666.0001), but
Bastepe et al. (2003) considered the involvement of STX16 in the
molecular pathogenesis of PHP Ib unlikely. They postulated that the
microdeletion disrupts a putative cis-acting element required for
methylation at exon 1A and that this epigenetic defect underlies the
pathogenesis of PHP Ib.

In all affected individuals and obligate carriers in a large kindred
with PHP Ib, Linglart et al. (2005) identified a 4.4-kb microdeletion
overlapping with a region of the 3-kb deletion identified by Bastepe et
al. (2003). Affected individuals exhibited loss of methylation only at
GNAS exon A/B. Linglart et al. (2005) concluded that PHP Ib comprises at
least 2 distinct conditions sharing the same clinical phenotype: one
associated with the loss of exon A/B methylation alone and, in most
cases, with a heterozygous microdeletion in the STX16 region, and the
other associated with methylation abnormalities at all GNAS DMRs,
including the DMR at exon A/B.

In affected members of 2 unrelated kindreds with PHP Ib, Bastepe et al.
(2005) identified a 4.7-kb deletion (139320.0031) removing the entire
NESP55 DMR and exons 3 and 4 of the antisense transcript of the GNAS
gene (GNASAS; 610540.0001) . Maternal inheritance of the deletion caused
loss of imprinting in cis at the entire GNAS locus.

Liu et al. (2005) found that all of 20 PHP Ib probands studied had loss
of GNAS exon 1A imprinting (a paternal epigenotype on both alleles). All
5 probands with familial disease had a deletion mutation within the
closely linked STX16 gene and a GNAS imprinting defect involving only
the exon 1A region. In contrast, the STX16 mutation was absent in all
sporadic cases. The majority of these patients had abnormal imprinting
of the more upstream regions in addition to the exon 1A imprinting
defect, with 8 of 15 having a paternal epigenotype on both alleles
throughout the GNAS locus. In virtually all cases, the imprinting status
of the paternally methylated NESP55 and maternally methylated
NESPAS/XL-alpha-s promoters was concordant, suggesting that their
imprinting may be coregulated, whereas the imprinting of the
NESPAS/XL-alpha-s promoter region and XL-alpha-s first exon was not
always concordant, even though they are closely linked and lie within
the same DMR. The authors concluded that familial and sporadic forms of
PHP Ib have distinct GNAS imprinting patterns that occur through
different defects in the imprinting mechanism.

- Activating Mutations in the GNAS Gene

Activating gain-of-function mutations in the GNAS1 gene result in the
McCune-Albright syndrome (MAS; 174800), polyostotic fibrous dysplasia
(POFD; see 174800), and various endocrine tumors. These activating
mutations are present in the mosaic state, resulting from a postzygotic
somatic mutation appearing early in the course of development which
yields a monoclonal population of mutated cells within variously
affected tissues. The nonmosaic state for activating mutations is
presumably lethal to the embryo (Aldred and Trembath, 2000; Lumbroso et
al., 2004).

Weinstein et al. (1991) analyzed DNA from tissues of 4 patients with the
McCune-Albright syndrome for the presence of activating mutations in the
GNAS1 gene and identified 1 of 2 activating mutations, R201C
(139320.0008) and R201H (139320.0009) in tissues from all 4 patients.

Among 113 patients with McCune-Albright syndrome, including 98 girls and
15 boys, Lumbroso et al. (2004) found that 43% had a GNAS1 mutation
involving arg201, with a net preponderance of the R201H (n = 34)
compared to R201C (n = 15). No difference in severity or manifestations
of the disease was noted between the two mutations. In patients who had
several tissue samples analyzed, the same mutation was always found,
supporting the hypothesis of an early postzygotic somatic mutation.

Bianco et al. (2000) analyzed a series of 8 consecutive cases of
polyostotic fibrous dysplasia without other features of McCune-Albright
syndrome and identified arg201 mutations (see, e.g., 139320.0013) in the
GNAS1 gene in all of them.

In a review, Aldred and Trembath (2000) noted that mutations leading to
constitutive activation of the GNAS1 gene occur in 2 specific codons,
201 and 227.

Fragoso et al. (2003) identified somatic heterozygous mutations in the
GNAS1 gene (139320.0009; 139320.0013) in adrenal tissue from 3 unrelated
patients with ACTH-independent macronodular adrenal hyperplasia (AIMAH;
219080). The mutations resulted in constitutive activation of the G
protein. The mutations were not present in peripheral blood, and none of
the patients had signs of McCune-Albright syndrome. Fragoso et al.
(2003) discussed whether the patients could be considered part of the
spectrum of McCune-Albright syndrome or whether they represent isolated
cases of AIMAH associated with somatic mutations.

- Somatic Mutations in Pituitary Adenomas

Growth hormone-releasing hormone (GHRH; 139190) uses cAMP as a second
messenger to stimulate growth hormone (GH; 139250) secretion and
proliferation of normal pituitary somatotrophs (Billestrup et al.,
1986). Vallar et al. (1987) identified constitutive activation of Gs in
tissue from a subset of GH-secreting pituitary tumors (102200).

In a series of 32 corticotroph adenomas of the pituitary (219090),
Williamson et al. (1995) found 2 with somatic mutations in the GNAS1
gene at codon 227 (139320.0010; 139320.0012).

Hayward et al. (2001) noted that approximately 40% of growth
hormone-secreting pituitary adenomas contain somatic mutations in the
GNAS1 gene. These mutations, which occur at arg201 or glu227 (see, e.g.,
139320.0008 and 139320.0010, respectively), constitutively activate the
alpha subunit of GNAS1. Although transcripts encoding Gs-alpha are
biallelically derived in most human tissues, Hayward et al. (2001)
showed that the mutation had occurred on the maternal allele in 21 of 22
GNAS1-positive somatotroph adenomas. They also showed that Gs-alpha is
monoallelically expressed from the maternal allele in normal adult
pituitary tissue. This monoallelic expression of Gs-alpha was frequently
relaxed in somatotroph tumors regardless of GNAS1 mutation status. These
findings implied a possible role for loss of Gs-alpha imprinting during
pituitary somatotroph tumorigenesis.

- Other Disease Associations

Jia et al. (1999) identified a common silent polymorphism in the GNAS1
gene involving a change of codon 131 from ATT (ile) to ATC (ile). The
authors found a significant difference in the frequency of the alleles
between 268 white patients with essential hypertension (145500) (51% +)
and a matched group of 231 control subjects (58% +) (P = 0.02).

Genevieve et al. (2005) reported 2 unrelated girls who presented with
severe pre- and postnatal growth retardation and had de novo
interstitial deletions of chromosome 20q13.2-q13.3. Molecular studies
showed that the deletions were of paternal origin in both girls and were
approximately 4.5 Mb in size, encompassing the GNAS imprinted locus,
including paternally imprinted Gnasxl, and the TFAP2C gene (601602).
Both patients had intractable feeding difficulties, microcephaly, facial
dysmorphism with high forehead, broad nasal bridge, small chin and
malformed ears, mild psychomotor retardation, and hypotonia. Genevieve
et al. (2005) noted that a mouse model with disruption of the Gnasxl
gene had poor postnatal growth and survival (Plagge et al., 2004), and
that a patient reported by Aldred et al. (2002) with a paternal deletion
of the GNAS complex also showed pre- and postnatal growth retardation
and feeding difficulties. Moreover, disruption of the Tfap2c gene in
mice had been shown to affect embryonic development (Werling and
Schorle, 2002).

Using metaanalysis combining data from case control and family studies
in Gambia, Kenya, and Malawi and a case control study from Ghana, Auburn
et al. (2008) detected associations between intronic or conservative
SNPs of GNAS and severe malaria. SNPs with significant associations
clustered in the 5-prime end of GNAS. Auburn et al. (2008) proposed that
the impact of GNAS on malaria parasite invasion efficacy may alter
susceptibility to disease.

ANIMAL MODEL

Yu et al. (1998) generated mice with a mutation in exon 2 of the Gnas
gene, resulting in a null allele. Homozygous Gs deficiency was
embryonically lethal. Heterozygotes with maternal (m-/+) and paternal
(+/p-) inheritance of the Gnas null allele had distinct phenotypes,
suggesting that Gnas is an imprinted gene. Parathyroid hormone (PTH)
resistance is present in m-/+ but not +/p- mice. Expression of the alpha
subunit in the renal cortex (the site of PTH action) was markedly
reduced in m-/+ but not in +/p- mice, demonstrating that the Gnas
paternal allele is imprinted in this tissue. Gnas was also imprinted in
brown and white adipose tissue. The maximal physiologic response to
vasopressin (urinary concentrating ability) was normal in both m-/+ and
+/p- mice and Gnas was not imprinted in the renal inner medulla, the
site of vasopressin action. Tissue-specific imprinting of Gnas was
likely the mechanism for variable and tissue-specific hormone resistance
in the knockout mice and a similar mechanism might explain the variable
phenotype in AHO.

Exon 2 m-/+ mice are obese and hypometabolic, whereas exon 2 +/p- mice
are lean and hypermetabolic. To study the effect of Gs-alpha deficiency
without disrupting other Gnas gene products, Chen et al. (2005)
disrupted exon 1 of the Gnas gene in mice. They found that exon 1 +/p-
mice lacked the exon 2 +/p- phenotype and developed obesity and insulin
resistance. Exon 2 and exon 1 m-/+ mice both had subcutaneous edema at
birth, presumably due to loss of maternal Gs-alpha expression; however,
they differed in other respects, raising the possibility for the
presence of other maternal-specific gene products. Exon 1 m-/+ mice had
more severe obesity and insulin resistance and a lower metabolic rate
relative to exon 1 +/p- mice. Chen et al. (2005) concluded that the
lean, hypermetabolic, and insulin-sensitive exon 2 +/p- phenotype
appeared to result from XL-alpha-s deficiency, whereas loss of
paternal-specific Gs-alpha expression in exon 1 +/p- mice led to an
opposite metabolic phenotype. Thus, alternative GNAS gene products have
opposing effects on glucose and lipid metabolism. The differences
between exon 1 m-/+ and +/p- mice presumably resulted from differential
effects on Gs-alpha expression in tissues where Gs-alpha is normally
imprinted.

A suspicion of the existence of one or more imprinted genes on distal
mouse chromosome 2 had been raised by Cattanach and Kirk (1985) and
Peters et al. (1994): paternal uniparental disomy (UPD)/maternal
deletion and maternal UPD/paternal deletion of a region between
breakpoints T2Wa and T28H on distal mouse chromosome 2 resulted in
distinct phenotypes and early lethality. Neuronatin (NNAT; 603106) is an
imprinted gene on distal mouse chromosome 2 that maps outside the
T2Wa-T28H imprinted region (Kikyo et al., 1997). Given the large
distance and the presence of multiple nonimprinted genes between Gnas
and Nnat, it is likely that they lie within distinct imprinting domains.
The tissue-specific imprinting of Gnas observed by Yu et al. (1998) had
been demonstrated for other imprinted genes; e.g., DeChiara et al.
(1991) had demonstrated tissue-specific parental imprinting in the case
of the insulin-like growth factor II gene (147280) by study of targeted
disruption of the gene in mice.

Bastepe et al. (2004) studied chimeric mice containing wildtype
chondrocytes and chondrocytes with either homozygous or heterozygous
disruption of Gnas exon 2. Haploinsufficiency of Gnas signaling resulted
in chondrocytes that differentiated prematurely. The phenotype was
similar to that observed in Pthr1 (168468)-deficient mice. Bastepe et
al. (2004) determined that expression of Gnas in chondrocytes occurs
from both parental alleles. They concluded that GNAS is the primary
mediator of PTHR1 in chondrocytes and that haploinsufficiency of GNAS
signaling contributes to the skeletal phenotypes of AHO.

*FIELD* AV
.0001
PSEUDOHYPOPARATHYROIDISM, TYPE IA
GNAS, MET1VAL

In a mother and son with pseudohypoparathyroidism type Ia (103580),
Patten et al. (1989, 1990) identified a heterozygous A-to-G transition
in exon 1 of the GNAS1 gene, resulting in a met1-to-val (M1V)
substitution at the initiator codon. Initiation at the next AUG was
in-frame and predicted to result in deletion of 59 N-terminal amino
acids. Laboratory studies showed that the GNAS protein was reactive with
a C-terminal Gs-alpha antiserum, but not with 2 Gs-alpha peptide
antisera to amino acid residues 28-42 or 47-61. This was the first
molecular delineation of a mutation in a human G protein and a
conclusive demonstration that mutation at the GNAS1 locus results in
AHO.

.0002
PSEUDOHYPOPARATHYROIDISM, TYPE IA
PSEUDOPSEUDOHYPOPARATHYROIDISM, INCLUDED
GNAS, IVS10DS, G-C, +1

In 4 sisters with PHP Ia (103580), Weinstein et al. (1990) identified a
heterozygous G-to-C transversion in intron 10 of the GNAS1 gene,
resulting in a splice site mutation. The authors used PCR to amplify
genomic fragments with an attached high-melting G+C-rich region ('GC
clamp') and DGGE to analyze the fragments. All 4 daughters had decreased
Gs-alpha mRNA and functional Gs-alpha deficiency. The mother, who had
PPHP (612463), also carried the heterozygous mutation. She had minor
stigmata of Albright hereditary osteodystrophy, such as unilateral
brachyphalangy I, x-ray evidence of subcutaneous calcifications, and
short stature relative to other members of her family, but no hormonal
abnormalities. The kindred had previously been reported by Kinard et al.
(1979)l.

.0003
PSEUDOHYPOPARATHYROIDISM, TYPE IA
PSEUDOPSEUDOHYPOPARATHYROIDISM, INCLUDED;;
OSSEOUS HETEROPLASIA, PROGRESSIVE, INCLUDED
GNAS, 1-BP DEL, 725C

In a mother with PPHP (612463) and her daughter with PHP1A (103580),
Weinstein et al. (1990) identified a heterozygous 1-bp deletion (G) in
exon 10 of the GNAS gene, resulting in a frameshift.

Adegbite et al. (2008) identified the same deletion (725delC) in an
unaffected carrier father and in 3 of his 5 children with progressive
osseous heteroplasia (POH; 166350). The 3 children exhibited varying
degrees of severity based on the extent of the heterotropic ossification
lesions and resultant functional impairment.

.0004
REMOVED FROM DATABASE
.0005
PSEUDOHYPOPARATHYROIDISM, TYPE IA
GNAS, IVS3AS, A-G, -12

Levine and Deily (1990) identified a family in which members affected
with PHP1A (103580) had an A-to-G transition 12 bases from the 3-prime
terminus of intron 3 of the GNAS gene. The mutation was predicted to
result in a frameshift and a premature stop codon.

.0006
PSEUDOHYPOPARATHYROIDISM, TYPE IA
GNAS, LEU99PRO

In affected members of a family with PHP Ia (103580), Levine and Deily
(1990) identified a heterozygous T-to-C transition in the GNAS gene,
resulting in a leu99-to-pro (L99P) substitution.

.0007
PSEUDOHYPOPARATHYROIDISM, TYPE IA
GNAS, CYS165ARG

In affected members of a family with PHP1A (103580), Levine and Vechio
(1990) identified a heterozygous C-to-T transition in exon 6 of the GNAS
gene, resulting in a cys165-to-arg (C165R) substitution.

.0008
MCCUNE-ALBRIGHT SYNDROME, SOMATIC, MOSAIC
PITUITARY TUMOR, GROWTH HORMONE-SECRETING, SOMATIC, INCLUDED;;
SEX CORD STROMAL TUMOR, SOMATIC, INCLUDED
GNAS, ARG201CYS

In various tissues from 4 patients with McCune-Albright syndrome
(174800), Weinstein et al. (1991) found 1 of 2 activating mutations
within codon 201 in exon 8 of the GNAS gene. Two patients carried an
arg201-to-cys substitution (R201C); the other 2 carried an R201H
substitution (139320.0009). Tissues analyzed included affected endocrine
organs, such as gonads, adrenal glands, thyroid, and pituitary, as well
as tissues not classically involved in the McCune-Albright syndrome. In
each patient the proportion of cells affected varied from tissue to
tissue. In 2 endocrine organs, the highest proportion of mutant alleles
was found in regions of abnormal cell proliferation. Weinstein et al.
(1991) concluded that somatic mutation of the GNAS gene early in
embryogenesis resulted in the mosaic population of normal and
mutant-bearing tissues that underlie the clinical manifestations of
McCune-Albright syndrome.

Candeliere et al. (1995) found the R201C mutation in a 14-year-old boy
who had previously been reported as a case of panostotic fibrous
dysplasia (see 174800).

Landis et al. (1989) identified somatic gain-of-function mutations in
the GNAS1 gene in 4 of 8 growth hormone (GH; 139250)-secreting pituitary
tumors (102200) surgically removed from patients with acromegaly. Two
tumors contained a C-to-T transition resulting in an R201C substitution.
The other 2 tumors had an R201H substitution (139320.0009) and a Q227R
substitution (139320.0010), respectively. All the mutations resulted in
constitutive activation of Gs by inhibiting its GTPase activity and
behaved like dominantly acting oncogenes.

Yang et al. (1996) identified somatic mutations at GNAS codon 201 in 9
of 21 pituitary adenomas derived from Korean patients with acromegaly.
Eight tumors had the R201C mutation and 1 had an R201S substitution
(139320.0013). Clinically, patients with the GNAS mutations were older
and responded better to octreotide-induced growth hormone suppression
than those without mutations.

Collins et al. (2003) identified an R201C mutation in thyroid carcinoma
derived from a patient with McCune-Albright syndrome.

Fragoso et al. (1998) identified a somatic R201C mutation in 4 (66.6%)
of 14 human sex cord stromal tumors, including ovarian and testicular
Leydig cell tumors. In contrast, no GIP2 (139360) mutations were found
in any of the sex cord stromal tumors studied.

Kalfa et al. (2006) detected the R201C mutation in 8 of 30 cases of
juvenile ovarian granulosa cell tumor, the most common sex cord stromal
tumor. Laser microdissection confirmed that the mutation was exclusively
localized in the tumoral granulosa cells and was absent in the ovarian
stroma. Patients with a hyperactivated G-alpha-s exhibited a
significantly more advanced tumor (p less than 0.05) because 7 of them
(77.7%) were staged as Ic or had had a recurrence.

.0009
MCCUNE-ALBRIGHT SYNDROME, SOMATIC, MOSAIC
PITUITARY TUMOR, GROWTH HORMONE-SECRETING, SOMATIC, INCLUDED;;
ACTH-INDEPENDENT MACRONODULAR ADRENAL HYPERPLASIA, SOMATIC, INCLUDED;;
SEX CORD STROMAL TUMOR, SOMATIC, INCLUDED
GNAS, ARG201HIS

In 2 patients with McCune-Albright syndrome (174800), Weinstein et al.
(1991) identified an arg201-to-his (R201H) mutation in exon 8 of the
GNAS gene in endocrine organs affected in this disorder, such as gonads,
adrenal glands, thyroid, and pituitary, as well as tissues not
classically involved. In 2 endocrine organs, ovary and adrenal, the
highest proportion of mutant alleles was found in regions of abnormal
cell proliferation. Weinstein et al. (1991) concluded that somatic
mutation of the GNAS gene early in embryogenesis resulted in the mosaic
population of normal and mutant-bearing tissues that underlie the
clinical manifestations of McCune-Albright syndrome. It remained an open
question whether GNAS1 mutations were causally related to the
nonendocrine abnormalities in 3 of the patients: chronic liver disease
in 1, thymic hyperplasia in 2, gastrointestinal adenomatous polyps in 1,
cardiopulmonary disease in 1, and sudden death in 2.

Schwindinger et al. (1992) found a G-to-A transition resulting in the
R201H substitution in a patient with McCune-Albright syndrome who had
severe bony involvement, characteristic skin lesions, and a history of
hyperthyroidism. The mutation was found in a higher proportion of skin
cells from affected areas than from unaffected areas. The findings
confirmed the Happle (1986) hypothesis that this disorder is due to
mosaicism for a postzygotic GNAS1 mutation. The authors noted that
arg201 is also the site of ADP-ribosylation by the cholera toxin.

Collins et al. (2003) identified the R201H mutation in thyroid carcinoma
from a patient with McCune-Albright syndrome.

In 2 growth hormone (GH; 139250)-secreting pituitary tumors (102200)
surgically removed from patients with acromegaly, Landis et al. (1989)
identified a somatic mutation in the GNAS1 gene, resulting in an R201H
substitution. The mutation resulted in constitutive activation of Gs by
inhibiting its GTPase activity and behaved like a dominantly acting
oncogene.

Fragoso et al. (2003) identified a heterozygous R201H mutation in
adrenal tissue from 2 unrelated patients with ACTH-independent
macronodular adrenal hyperplasia (219080).

In 1 of 30 cases of juvenile ovarian granulosa cell tumor, the most
common sex cord stromal tumor, Kalfa et al. (2006) detected the R201H
mutation of the GNAS gene. Laser microdissection confirmed that the
mutation was exclusively localized in the tumoral granulosa cells and
was absent in the ovarian stroma.

.0010
PITUITARY TUMOR, GROWTH HORMONE-SECRETING, SOMATIC
PITUITARY ADENOMA, ACTH-SECRETING, SOMATIC, INCLUDED
GNAS, GLN227ARG

In a growth hormone (GH; 139250)-secreting pituitary tumor (102200)
surgically removed from a patient with acromegaly, Landis et al. (1989)
identified a somatic mutation in the GNAS1 gene, resulting in a
gln227-to-arg (Q227R) substitution. The mutation resulted in
constitutive activation of Gs by inhibiting its GTPase activity and
behaved like a dominantly acting oncogene.

In a series of 32 corticotroph adenomas of the pituitary (219090),
Williamson et al. (1995) found 2 with somatic mutations in the GNAS1
gene at codon 227. One had the Q227R mutation and the second had a Q227H
mutation (139320.0012).

.0011
PSEUDOHYPOPARATHYROIDISM, TYPE IA
OSSEOUS HETEROPLASIA, PROGRESSIVE, INCLUDED;;
PSEUDOPSEUDOHYPOPARATHYROIDISM, INCLUDED
GNAS, 4-BP DEL, 565CTGA

In a patient with PHP1A (103580), Weinstein et al. (1992) identified a
heterozygous 4-bp deletion (565delCTGA) in exon 7 of the GNAS1 gene,
resulting in a frameshift and premature stop codon. Analysis of
lymphocyte RNA by reverse transcription-PCR and direct sequencing showed
that the GNAS1 allele bearing the mutation was not expressed as mRNA.
Consistent with this, Northern blot analysis revealed an approximately
50% deficiency in steady state levels of GNAS1 mRNA.

Ahmed et al. (1998) identified this deletion mutation in 2 unrelated
families with PHP Ia.

Shore et al. (2002) provided direct evidence that the 4-bp deletion can
cause either progressive osseous heteroplasia (POH; 166350) or Albright
hereditary osteodystrophy without hormone resistance (PPHP; 612463) in
the same family. Five sisters with POH had inherited this mutation from
the father in whom the mutation was nonpenetrant. Three offspring of
these sisters had AHO, including traces of subcutaneous ossification.
Shore et al. (2002) suggested that POH requires paternal inheritance of
a GNAS1 mutation, whereas hormone resistance is more likely to occur
when the genetic defect is maternally inherited.

Ahmed et al. (2002) cautioned against a premature conclusion that POH
may require paternal inheritance. In a family reported by Ahmed et al.
(1998), the 4-bp deletion was found in a brother and sister and in their
mother but not in their father. Aside from brachymetacarpia and short
stature, the mother did not have features of AHO. The daughter had
typical features of AHO and hormone resistant PHP1A; in contrast, her
brother presented in the first year of life with ossification of
subcutaneous tissue that was followed by progressive, generalized
heterotopic ossification of skeletal muscle, without any clear evidence
of hormone resistance. These cases exemplified the wide phenotypic
heterogeneity in persons with mutations in GNAS1, even within 1 family.

Bastepe and Juppner (2002) suggested that, like some patients who have
either PHP type Ia or PHP type Ib, the son described by Ahmed et al.
(1998) may have developed resistance to parathyroid hormone later in
life or not at all. Given that the patient's sister and mother had PHP
type Ia and PPHP, respectively, POH resulting from maternally inherited
GNAS1 mutations may actually represent an incomplete form of PHP type
Ia. Bastepe and Juppner (2002) suggested that the underlying mechanism
for this form of POH may be distinct from that described by Shore et al.
(2002), which appears to result only from paternally inherited GNAS1
mutations.

Adegbite et al. (2008) identified heterozygosity for the 565delCTGA
mutation in the GNAS gene in 13 POH cases (10 familial cases among 3
different families, and 3 individual spontaneous cases). The mutation
resulted in variable severity and pleiotropy, both in family members and
in unrelated sporadic cases.

.0012
PITUITARY ADENOMA, ACTH-SECRETING, SOMATIC
GNAS, GLN227HIS

In a series of 32 corticotroph adenomas of the pituitary (219090),
Williamson et al. (1995) found 2 with somatic mutations in the GNAS1
gene at codon 227. One had a Q227R (139320.0010) substitution, and the
other had a mutation resulting in a gln227-to-his (Q227H) substitution.
The latter patient was a 35-year-old male who presented with severe
Cushing syndrome complicated by psychosis.

.0013
PITUITARY TUMOR, GROWTH HORMONE-SECRETING, SOMATIC
POLYOSTOTIC FIBROUS DYSPLASIA, SOMATIC, MOSAIC, INCLUDED;;
ACTH-INDEPENDENT MACRONODULAR ADRENAL HYPERPLASIA, SOMATIC, INCLUDED
GNAS, ARG201SER

In a series of growth hormone-secreting pituitary tumors (102200)
derived from 21 Korean acromegalic patients, Yang et al. (1996) found
that 1 tumor had a somatic C-to-A transversion in the GNAS1 gene,
resulting in an arg201-to-ser (R201S) substitution.

Candeliere et al. (1997) reported a patient with polyostotic fibrous
dysplasia (see 174800) in whom the R201S mutation was identified in the
somatic mosaic state.

Fragoso et al. (2003) identified a heterozygous somatic R201S mutation
in adrenal tissue from a patient with ACTH-independent macronodular
adrenal hyperplasia (219080).

.0014
PSEUDOHYPOPARATHYROIDISM, TYPE IA
GNAS, SER250ARG

In a patient with PHP Ia (103580), Warner et al. (1997) identified a
ser250-to-arg (S250R) mutation in the GNAS1 gene. Both GNAS1 activity
and expression were decreased by approximately 50% in erythrocyte
membranes from the affected patient. In vitro functional expression
studies suggested that substitution or deletion of residue 250 may alter
guanine nucleotide binding, which could lead to thermolability and
impaired function.

.0015
PSEUDOPSEUDOHYPOPARATHYROIDISM
PSEUDOHYPOPARATHYROIDISM, TYPE IA, INCLUDED
GNAS, 38-BP DEL, EX1/IVS1 BOUNDARY

In affected members of a large kindred in which 2 mothers had
pseudopseudohypoparathyroidism (PPHP; 612463) and their 6 offspring had
PHP Ia (103580), Fischer et al. (1998) identified a 38-bp deletion at
the exon 1/intron 1 boundary of the GNAS gene. The deletion was
predicted to eliminate the splice donor site of exon 1. Some of the
patients had increased basal serum levels of thyroid-stimulating hormone
(TSH; see 188540) and/or excessive TSH responses to
thyrotropin-releasing hormone (TRH; 613879). The pseudo-PHP patients had
decreased Gs activity, but normal urinary cAMP responses to PTH, normal
TSH levels and responses to TRH, and normal serum levels of calcium and
PTH.

.0016
PSEUDOPSEUDOHYPOPARATHYROIDISM
GNAS, ARG258TRP

In a 24-year-old man with PPHP (612463), Warner et al. (1998) identified
a de novo arg258-to-trp (R258W) mutation in the GNAS1 gene. Arg258 is a
nonconserved residue adjacent to a highly conserved glutamic acid
residue, glu259, that is important for contact between switch 2 and 3 in
the activated state. Warner et al. (1998) presented evidence that
substitution of arg258 led to defective GDP binding, resulting in
increased thermolability and decreased activation. Developmental delay,
brachycephaly, and decreased muscle tone were noted by age 10 months.
Throughout childhood he was small for his age and stocky in appearance.
By 6 years, he developed learning disabilities as well as impulsive and
aggressive behavior. Brachydactyly involved the distal phalanx of the
thumb and the fourth metacarpals bilaterally. He also had intracranial
calcifications in the globus pallidus. There was no evidence of
resistance to parathyroid hormone or thyrotropin.

.0017
PSEUDOPSEUDOHYPOPARATHYROIDISM
GNAS, ARG258ALA

Warner et al. (1998) identified a heterozygous arg258-to-ala (R258A)
substitution in the GNAS gene as a cause of PPHP (612463). The
substitution led to increased GDP release and impaired receptor-mediated
activation. Based on the crystal structure of GNAS1, arg258 interacts
with residue gln170 within the helical domain. Loss of this interaction
was predicted to open the cleft between the GTPase and helical domain,
resulting in more rapid GDP release, as observed in the arg258 variants.
Warner et al. (1998) suggested that interactions between arg258 and the
helical domain are important for receptor-mediated activation. This same
codon was affected in another patient with AHO (R258W; 139320.0016).

Warner and Weinstein (1999) showed that a gln170-to-ala substitution
(Q170A; 139320.0018) also leads to increased GDP release but does not
affect receptor-mediated activation. Therefore, interactions between
arg258 and gln170 are important for maintaining guanine nucleotide
binding but are not important for activation by receptor. Warner and
Weinstein (1999) also showed that the R258A mutation, but not Q170A, was
associated with a markedly elevated intrinsic GTPase rate, resulting in
more rapid inactivation. Arg258, through mutual interactions with glu50,
may constrain arg201, a residue critical for catalyzing GTP hydrolysis.
Disruption of the interaction between arg258 and glu50 may relieve this
constraint and allow arg201 to interact more efficiently with the
gamma-phosphate of GTP in the transition state. This is an example of a
mutation in a heterotrimeric G protein that increases the intrinsic
GTPase activity and provides another mechanism by which receptor
signaling can be impaired by G protein mutations.

.0018
PSEUDOPSEUDOHYPOPARATHYROIDISM
GNAS, GLN170ALA

See 139320.0017 and Warner and Weinstein (1999).

.0019
PSEUDOHYPOPARATHYROIDISM, TYPE IA, WITH TESTOTOXICOSIS
GNAS, ALA366SER

Iiri et al. (1994) studied 2 unrelated boys who had a paradoxical
combination of PHP Ia (103580) and testotoxicosis (176410). Both boys
were found to have an ala366-to-ser (A366S) mutation in the GNAS1 gene.
PHP Ia is marked by resistance to hormones acting through cyclic AMP
(parathyroid hormone and thyroid-stimulating hormone) as well as a 50%
decrease in erythrocyte Gs activity in this heterozygous disorder. In
contrast, testotoxicosis is a form of precocious puberty in which the
Leydig cells secrete testosterone in the absence of luteinizing hormone,
often due to constitutive activation of the luteinizing hormone receptor
and (indirectly) of Gs. Iiri et al. (1994) demonstrated that this A366S
mutation constitutively activated adenylyl cyclase in vitro, causing
hormone-independent cAMP accumulation when expressed in cultured cells,
and accounting for the testotoxicosis phenotype. Although the mutant
form was quite stable at testis temperature, it was rapidly degraded at
37 degrees centigrade, explaining the PHP Ia phenotype caused by loss of
Gs activity. In vitro experiments indicated that accelerated release of
GDP caused both the constitutive activity and the thermolability of the
A366S mutant form.

.0020
PSEUDOHYPOPARATHYROIDISM, TYPE IA
GNAS, ARG231HIS

In patients with pseudohypoparathyroidism type Ia (103580), Farfel et
al. (1996) identified an arg231-to-his (R231H) mutation in the GNAS1
gene which impaired the ability of the mutant protein to mediate
hormonal stimulation of cAMP accumulation in transiently transfected
cells.

Iiri et al. (1997) reported biochemical analyses showing that an
activation defect caused by the R231H mutation was paradoxically
intensified by hormonal and other stimuli. By substituting histidine for
a conserved arginine residue, the mutation removed an internal salt
bridge (to a conserved glutamate) that normally acts as an
intramolecular hasp to maintain tight binding of the gamma-phosphate of
GTP. The activation defect became prominent only under conditions that
destabilized binding of guanine nucleotide (receptor stimulation) or
impaired the ability of alpha-s to bind the gamma-phosphate of GTP
(e.g., cholera toxin). Although GDP release is usually the rate-limiting
step in nucleotide exchange, the biochemical phenotype of this mutant
GNAS indicated that efficient G protein activation by receptors and
other stimuli depends on the ability of the protein to clasp tightly the
GTP molecule that enters the binding site. The 3 affected patients in
the family carrying the R231H mutation of the GNAS1 gene showed classic
clinical features of PHP Ia, including Albright hereditary
osteodystrophy, but Gs activities in their erythrocytes were nearly
normal (ranging between 60% and 90% of normal). Erythrocyte membranes of
most PHP I patients contain only 50% of the normal complement of Gs
activity and these patients are classified as PHP Ia, indicating that
the affected patients carry inactivating mutations in the GNAS1 gene. In
contrast, the PHP Ib phenotype is found in a smaller number of PHP I
patients whose erythrocytes contain normal (or nearly normal) Gs
activity. The R231H patients showed that results of the erythrocyte Gs
assay can lead to an incorrect inference with respect to the genetic
basis of the disease. PHP I patients with apparently normal or nearly
normal erythrocyte Gs activities merit careful investigation, especially
when they display the classic clinical phenotype, including Albright
hereditary osteodystrophy. Although such patients may inherit mutations
in genes other than GNAS1, their GNAS1 gene may encode mutant proteins
with instructive qualitative defects, including impairment of
conformational change, subcellular localization, or interaction with
other proteins, including receptors, effectors, and regulators of G
protein signaling proteins.

Ishikawa et al. (2001) found the R231H mutation in exon 9 of the GNAS1
gene in a Japanese patient with pseudohypoparathyroidism type Ia.

.0021
MCCUNE-ALBRIGHT SYNDROME, SOMATIC, MOSAIC
GNAS, ARG201GLY

Riminucci et al. (1999) studied a patient who had been diagnosed with
McCune-Albright syndrome (174800) at the age of 8 years. In an affected
parietal bone sample, the authors identified a heterozygous C-to-G
transversion in the GNAS1 gene, resulting in an arg201-to-gly (R201G)
amino acid substitution. The boy presented with precocious puberty,
facial deformities, and typical cafe-au-lait spots with a 'coast of
Maine' profile. Extensive involvement of the cranial vault was apparent
on x-ray. At the age of 13, acromegalic bone changes and growth hormone
oversecretion were detected. With the exception of a single case of
polyostotic fibrous dysplasia in which an R201S mutation was found
(139320.0013), R201C (139320.0008) and R201H (139320.0009) had been the
mutations consistently found in McCune-Albright syndrome patients and in
non-MAS cases of fibrous dysplasia of bone. Thus, of the predicted
missense mutations of codon 201, only R201P and R201L remained
undetected (although R201L had been observed by Gorelov et al. (1995) in
isolated, non-MAS endocrine tumors).

.0022
PSEUDOHYPOPARATHYROIDISM, TYPE IA
PSEUDOPSEUDOHYPOPARATHYROIDISM, INCLUDED
GNAS, 2-BP DEL, GA, EXON 8

In affected members of a kindred with either PHP1A (103580) or PPHP
(612463), Yu et al. (1999) identified a 2-bp deletion in exon 8 of the
GNAS gene, resulting in premature termination of the protein. Serial
measurements of thyroid function in members of kindred 1 indicated that
thyroid-stimulating hormone (TSH; see 188540) resistance progressed with
age and became more evident after the first year of life in those with
PHP1A.

.0023
PSEUDOHYPOPARATHYROIDISM, TYPE IA
PSEUDOPSEUDOHYPOPARATHYROIDISM, INCLUDED
GNAS, 2-BP DEL, CT, EXON 4

In affected members of a kindred with either PHP1A (103580) or PPHP
(612463), Yu et al. (1999) identified a heterozygous 2-bp deletion (CT)
in exon 4 of the GNAS gene, resulting in a frameshift and premature
termination codon.

.0024
OSSEOUS HETEROPLASIA, PROGRESSIVE
PSEUDOHYPOPARATHYROIDISM, TYPE IA, INCLUDED
GNAS, 1-BP DEL, 348C

In 2 patients with progressive osseous heteroplasia (166350) from
different families, Shore et al. (2002) identified a 1-bp deletion
(348delC) in exon 5 of the GNAS1 gene.

Shapira et al. (1995) had described the same mutation in a patient with
pseudohypoparathyroidism type Ia (103580).

.0025
PSEUDOHYPOPARATHYROIDISM, TYPE IA
PSEUDOPSEUDOHYPOPARATHYROIDISM, INCLUDED
GNAS, 1-BP DEL, C, EXON 1

In an Italian patient with pseudohypoparathyroidism type Ia (103580),
Mantovani et al. (2000) detected a heterozygous 1-bp deletion (C) within
codon 38 in exon 1 of the GNAS1 gene, resulting in a premature stop
codon at position 57. This mutation was also found in the patient's
mother, who had pseudopseudohypoparathyroidism (612463).

.0026
PSEUDOHYPOPARATHYROIDISM, TYPE IA
GNAS, 2-BP DEL, TG, EXON 11

In an Italian patient with pseudohypoparathyroidism type Ia (103580),
Mantovani et al. (2000) detected a heterozygous 2-bp deletion (TG)
within codon 287 in exon 11 of the GNAS1 gene, resulting in a premature
stop codon at position 298. The mutation was also found in the patient's
mother, who presented the same clinical and biologic features.

.0027
OSSEOUS HETEROPLASIA, PROGRESSIVE
GNAS, 2-BP DEL, 860TG

In an unusual case of progressive osseous heteroplasia (166350)
involving the face in an 8-year-old Albanian girl, Faust et al. (2003)
identified a heterozygous 2-bp deletion in the GNAS1 gene, 860-861delTG,
resulting in a frameshift of 11 amino acids followed by a premature stop
codon.

.0029
PSEUDOPSEUDOHYPOPARATHYROIDISM
PSEUDOHYPOPARATHYROIDISM, TYPE IA, INCLUDED
GNAS1, PRO115LEU

In a woman with PPHP (612463), Ahrens et al. (2001) identified a C-to-T
transition in exon 5 of the GNAS gene, resulting in a pro115-to-leu
(P115L) substitution. Her son, who had the same mutation, had PHP Ia
(103580).

.0030
REMOVED FROM DATABASE
.0031
PSEUDOHYPOPARATHYROIDISM, TYPE IB
GNAS, 4.7-KB DEL

In 2 unrelated kindreds with pseudohypoparathyroidism type Ib (603233),
Bastepe et al. (2005) identified a 4.7-kb deletion in the GNAS locus
that removed the differentially methylated region (DMR) of the GNAS gene
encompassing the NESP55 region and exons 3 and 4 of the GNAS antisense
transcript (GNASAS; 610540.0001). When inherited from a female, the
deletion abolished all maternal GNAS imprints and derepressed maternally
silenced transcripts, suggesting that the deleted region contains a
cis-acting element that controls imprinting of the maternal GNAS allele.

.0032
RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE
GNAS, 36-BP DUP, ALA138ASP, PRO161ARG

This variant, formerly titled PROLONGED BLEEDING TIME, BRACHYDACTYLY,
AND MENTAL RETARDATION, has been reclassified because delineation of the
phenotype and the contribution of the variant to the phenotype are
unclear.

In 3 patients from 2 families with markedly prolonged bleeding time
accompanied by neurologic problems, brachydactyly, and a variable degree
of mental retardation, Freson et al. (2001) identified a paternally
inherited functional polymorphism in XL exon 1, consisting of a 36-bp
duplication and 2 nucleotide substitutions, resulting in changes of
codon 138 from alanine to aspartic acid (A138D) and of codon 161 from
proline to arginine (P161R), that was associated with Gs hyperfunction
in platelets, leading to an increased trauma-related bleeding tendency.

Freson et al. (2003) described 8 additional patients who inherited the
same XLAS polymorphism paternally and who showed Gs hyperfunction in
their platelets and fibroblasts. The clinical features were variable: 3
patients resembled those reported by Freson et al. (2001) and had
psychomotor retardation, disturbed behavior, facial dysmorphism, feeding
or gastrointestinal motility problems, and abnormal bleeding following
trauma, whereas 5 patients had growth deficiency and no clinical
bleeding abnormalities. All carriers also had an elongated ALEX protein
as a consequence of the paternally inherited insertion. The paternally
inherited double XLAS/ALEX functional polymorphism was also associated
with elevated platelet membrane Gs-alpha protein levels. The in vitro
interaction between the 2 elongated XLAS and ALEX proteins was markedly
reduced. Freson et al. (2003) suggested that in contrast to the strong
interaction between the 2 wildtype proteins, the defective association
may result in unimpeded receptor-stimulated activation of XLAS.

.0033
PSEUDOHYPOPARATHYROIDISM, TYPE IB
GNAS, 3-BP DEL, CAT, EXON 13

In 3 brothers with a clinical diagnosis of pseudohypoparathyroidism type
Ib (603233) and their clinically unaffected mother and maternal
grandfather, Wu et al. (2001) identified heterozygosity for a 3-bp
deletion (CAT) in exon 13 of the GNAS gene, resulting in the deletion of
ile382. Biochemical studies showed normal erythrocyte Gs activity, but
decreased cAMP response to PTH infusion. When expressed in vitro, mutant
Gs-alpha was unable to interact with PTHR1 (168468) but showed normal
coupling to other coexpressed heptahelical receptors. The mutation was
not found in the unaffected father and sister or in 30 unrelated
controls. Wu et al. (2001) noted that the absence of PTH resistance in
the mother and maternal grandfather who carried the same mutation was
consistent with models of paternal imprinting of the GNAS gene.

.0034
PSEUDOHYPOPARATHYROIDISM, TYPE IA
GNAS, 1-BP INS, A, EXON 3

In a 10-year-old girl with brachymetacarpia, mental retardation,
normocalcemic pseudohypoparathyroidism, and hypothyroidism (103580),
Thiele et al. (2007) identified a heterozygous insertion of an adenosine
in exon 3 of the GNAS gene, altering codon 85 and leading to a
frameshift and a stop at codon 87 in exon 4. Molecular studies of cDNA
from blood RNA demonstrated normal, biallelic expression of Gs-alpha-S
transcripts, whereas expression of Gs-alpha-L transcripts from the
maternal allele was reduced. Both the reduced activity and the mutation
were also found in the mother and the affected younger brother. Thiele
et al. (2007) noted that this was the first reported pathogenic mutation
in exon 3 of the GNAS gene. The mutation is associated with
pseudohypoparathyroidism type Ia due to selective deficiency of
Gs-alpha-L and a partial reduction of Gs-alpha activity.

.0035
PSEUDOHYPOPARATHYROIDISM, TYPE IA
GNAS, 12-BP INS, NT1107

In a brother and sister with a PHP Ia phenotype (103580), who also had
neonatal diarrhea and pancreatic insufficiency, Aldred et al. (2000)
identified heterozygosity for a 12-bp insertion in exon 13 of the GNAS1
gene, resulting in an in-frame ala-val-asp-thr (AVDT) repeat at codon
366 within the beta-6/alpha-5 loop. The mutation was not found in 2
unaffected sibs and was also not detected in the lymphocyte DNA of
either of the clinically unaffected parents. Haplotype analysis
confirmed germline mosaicism and indicated that the mutation was
maternal in origin.

By biochemical and intact cell analysis of the mutant Gs-alpha
containing the AVDT repeat within its GDP/GTP binding site, Makita et
al. (2007) demonstrated that the mutant protein was unstable but
constitutively active as a result of rapid GDP release and reduced GTP
hydrolysis, suggesting that instability and paradoxical inactivation by
receptor stimulation results in a loss of function. Gs-alpha-AVDT was
located primarily in the cytosol except in rat and mouse small intestine
epithelial cells, where it was found predominantly in the membrane, with
adenylyl cyclase present and constitutive increases in cAMP accumulation
occurring in parallel. Makita et al. (2007) suggested that the PHP Ia
phenotype results from the instability of the Gs-alpha-AVDT mutant and
that the accompanying neonatal diarrhea may result from its enhanced
constitutive activity in the intestine.

.0036
PSEUDOHYPOPARATHYROIDISM, TYPE IC
GNAS, TYR391TER

In a girl with PHP type Ic (612462), Linglart et al. (2002) identified a
heterozygous mutation in exon 13 of the GNAS gene, resulting in a
tyr319-to-ter (Y391X) substitution only 4 amino acids before the
wildtype stop codon. She had hormone resistance with features of
Albright hereditary osteodystrophy and decreased cAMP response to PTH
infusion, but normal erythrocyte Gs activity. The findings suggested
that the mutation interfered somehow with receptor-mediated activation.
Linglart et al. (2002) noted that the C terminus is required for
receptor coupling, and postulated that the Y391X mutation in this
patient interrupted receptor coupling, leading to hormone resistance.
The findings showed the limits of the erythrocyte Gs bioassay used in
the study.

.0037
PSEUDOHYPOPARATHYROIDISM, TYPE IB
GNAS, METHYLATION CHANGES, PATERNAL EPIGENOTYPE

Mariot et al. (2008) studied a girl with obvious Albright osteodystrophy
features, PTH resistance, and normal G-alpha-s bioactivity in red blood
cells (PHP Ib, 603233), yet no loss-of-function mutation in the GNAS
coding sequence. Methylation analysis of the 4 GNAS differentially
methylated regions, i.e., NESP, AS, XL, and A/B, revealed broad
methylation changes at all of these regions, leading to a paternal
epigenotype on both alleles. There was a dramatic decrease of
methylation at exon A/B, XL, and AS promoter regions and therefore
likely biallelic expression of A/B, XL, and AS transcripts. The NESP
region appeared fully methylated in the patient, which was predicted to
result in a dramatic decrease in NESP-specific transcripts. The cause of
the imprinting defect was unknown. Mariot et al. (2008) concluded that:
(1) the decreased expression of G-alpha-s due to GNAS epimutations is
not restricted to the renal tubule but may affect nonimprinted tissues
like bone; and (2) PHP-1b is a heterogeneous disorder that should lead
to the study of GNAS epigenotype in patients with PHP and no mutation in
GNAS exons 1 through 13, regardless of their physical features. They
suggested that Albright osteodystrophy, or at least brachymetacarpia and
obesity, are not specific symptoms of PHP-1a (103580).

.0038
PSEUDOHYPOPARATHYROIDISM, TYPE IC
GNAS, LEU388ARG

In a 12-year-old boy with PHP IC (612462), Thiele et al. (2011)
identified a heterozygous 1163T-G transversion in exon 13 of the GNAS
gene, resulting in a leu388-to-arg (L388R) substitution in a conserved
residue in the alpha-5-helix in the C-terminal part of the protein
directly involved in the contact of Gs-alpha to the G protein-coupled
receptor. The patient had characteristic features of AHO, including
round face, brachymetacarpia, short stature, obesity, and mental
retardation. Serum PTH and TSH were increased and calcium was low. His
mother, who also carried the mutation, had short stature and
brachymetacarpia, but no evidence of hormone resistance. In vitro
functional expression studies showed that the L388R mutant protein
caused complete absence of receptor-mediated cAMP production, with
normal receptor-independent cAMP production. The findings indicated
normal Gs-alpha activity, but a selective defect in Gs-alpha-receptor
coupling functions.

.0039
PSEUDOHYPOPARATHYROIDISM, TYPE IC
GNAS, GLU392TER

In 13-year-old dizygotic twins and an unrelated 5-year-old girl with PHP
IC (612462), Thiele et al. (2011) identified a heterozygous 1174G-T
transversion in exon 13 of the GNAS gene, resulting in a glu392-to-ter
(E392X) substitution in the alpha-5-helix in the C terminus. The
patients had characteristic features of AHO, including round face,
brachymetacarpia, short stature, and obesity. Serum PTH and TSH were
increased and calcium was low. Both mothers, who also carried the
mutation, had short stature, round face, and/or brachymetacarpia, but no
evidence of hormone resistance. In vitro functional expression studies
showed that the mutant protein caused complete absence of
receptor-mediated cAMP production, with normal receptor-independent cAMP
production. The findings indicated normal Gs-alpha activity, but a
selective defect in Gs-alpha-receptor coupling functions.

.0040
PSEUDOHYPOPARATHYROIDISM, TYPE IC
GNAS, GLU392LYS

In an 11-month-old girl with PHP IC (612462), Thiele et al. (2011)
identified a heterozygous 1174G-A transition in exon 13 of the GNAS
gene, resulting in a glu392-to-lys (E392K) substitution in the
alpha-5-helix in the C terminus. The patient had characteristic features
of AHO, including round face, brachymetacarpia, and short stature. Serum
PTH and TSH were increased, but calcium was normal. Her mother, who also
carried the mutation, had short stature and brachymetacarpia, but no
evidence of hormone resistance. In vitro functional expression studies
showed that the mutant protein caused a decrease in receptor-mediated
cAMP production, with normal receptor-independent cAMP production. The
findings indicated normal Gs-alpha activity, but a selective defect in
Gs-alpha-receptor coupling functions.

*FIELD* SA
Carter et al. (1987); Harris et al. (1985); Kozasa et al. (1988);
Lin et al. (1992); Mattera et al. (1989); Shenker et al. (1995); Shenker
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104. Warner, D. R.; Gejman, P. V.; Collins, R. M.; Weinstein, L. S.
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105. Warner, D. R.; Weinstein, L. S.: A mutation in the heterotrimeric
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106. Warner, D. R.; Weng, G.; Yu, S.; Matalon, R.; Weinstein, L. S.
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107. Weinstein, L. S.; Gejman, P. V.; de Mazancourt, P.; American,
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108. Weinstein, L. S.; Gejman, P. V.; Friedman, E.; Kadowaki, T.;
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8287-8290, 1990.

109. Weinstein, L. S.; Shenker, A.; Gejman, P. V.; Merino, M. J.;
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1688-1695, 1991.

110. Weiss, U.; Ischia, R.; Eder, S.; Lovisetti-Scamihorn, P.; Bauer,
R.; Fischer-Colbrie, R.: Neuroendocrine secretory protein 55 (NESP55):
alternative splicing onto transcripts of the GNAS gene and posttranslational
processing of a maternally expressed protein. Neuroendocrinology 71:
177-186, 2000.

111. Werling, U.; Schorle, H.: Transcription factor gene AP-2-gamma
essential for early murine development. Molec. Cell. Biol. 22: 3149-3156,
2002.

112. Williamson, C. M.; Ball, S. T.; Nottingham, W. T.; Skinner, J.
A.; Plagge, A.; Turner, M. D.; Powles, N.; Hough, T.; Papworth, D.;
Fraser, W. D.; Maconochie, M.; Peters, J.: A cis-acting control region
is required exclusively for the tissue-specific imprinting of Gnas. Nature
Genet. 36: 894-899, 2004.

113. Williamson, C. M.; Turner, M. D.; Ball, S. T.; Nottingham, W.
T.; Glenister, P.; Fray, M.; Tymowska-Lalanne, Z.; Plagge, A.; Powles-Glover,
N.; Kelsey, G.; Maconochie, M.; Peters, J.: Identification of an
imprinting control region affecting the expression of all transcripts
in the Gnas cluster. Nature Genet. 38: 350-355, 2006.

114. Williamson, E. A.; Ince, P. G.; Harrison, D.; Kendall-Taylor,
P.; Harris, P. E.: G-protein mutations in human pituitary adrenocorticotrophic
hormone-secreting adenomas. Europ. J. Clin. Invest. 25: 128-131,
1995.

115. Wu, W.-I.; Schwindinger, W. F.; Aparicio, L. F.; Levine, M. A.
: Selective resistance to parathyroid hormone caused by a novel uncoupling
mutation in the carboxyl terminus of G-alpha(s). J. Biol. Chem. 276:
165-171, 2001.

116. Yang, I.; Park, S.; Ryu, M.; Woo, J.; Kim, S.; Kim, J.; Kim,
Y.; Choi, Y.: Characteristics of gsp-positive growth hormone-secreting
pituitary tumors in Korean acromegalic patients. Europ. J. Endocr. 134:
720-726, 1996.

117. Yu, D.; Yu, S.; Schuster, V.; Kruse, K.; Clericuzio, C. L.; Weinstein,
L. S.: Identification of two novel deletion mutations within the
Gs-alpha gene (GNAS1) in Albright hereditary osteodystrophy. J. Clin.
Endocr. Metab. 84: 3254-3259, 1999.

118. Yu, S.; Yu, D.; Lee, E.; Eckhaus, M.; Lee, R.; Corria, Z.; Accili,
D.; Westphal, H.; Weinstein, L. S.: Variable and tissue-specific
hormone resistance in heterotrimeric Gs protein alpha-subunit (Gs-alpha)
knockout mice is due to tissue-specific imprinting of the Gs-alpha
gene. Proc. Nat. Acad. Sci. 95: 8715-8720, 1998.

*FIELD* CN
Cassandra L. Kniffin - updated: 9/25/2013
Ada Hamosh - updated: 3/7/2012
Cassandra L. Kniffin - updated: 11/30/2011
Nara Sobreira - updated: 6/17/2009
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John A. Phillips, III - updated: 5/6/2008
John A. Phillips, III - updated: 3/26/2008
Cassandra L. Kniffin - updated: 2/19/2008
George E. Tiller - updated: 10/31/2007
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Patricia A. Hartz - updated: 12/4/2006
Marla J. F. O'Neill - updated: 11/8/2006
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George E. Tiller - updated: 10/6/2006
George E. Tiller - updated: 10/5/2006
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Victor A. McKusick - updated: 3/6/2006
John A. Phillips, III - updated: 10/27/2005
Cassandra L. Kniffin - updated: 9/20/2005
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George E. Tiller - updated: 2/13/2004
Cassandra L. Kniffin - updated: 11/10/2003
Ada Hamosh - updated: 9/26/2003
Cassandra L. Kniffin - reorganized: 8/27/2003
Victor A. McKusick - updated: 8/11/2003
Victor A. McKusick - updated: 6/11/2003
Victor A. McKusick - updated: 5/9/2003
Victor A. McKusick - updated: 4/16/2003
Victor A. McKusick - updated: 4/10/2003
John A. Phillips, III - updated: 4/8/2003
Ada Hamosh - updated: 10/18/2002
John A. Phillips, III - updated: 10/10/2002
John A. Phillips, III - updated: 8/9/2002
Victor A. McKusick - updated: 6/12/2002
John A. Phillips, III - updated: 3/26/2002
John A. Phillips, III - updated: 3/20/2002
Victor A. McKusick - updated: 1/15/2002
George E. Tiller - updated: 11/19/2001
Victor A. McKusick - updated: 8/10/2001
John A. Phillips, III - updated: 7/20/2001
Victor A. McKusick - updated: 6/15/2001
John A. Phillips, III - updated: 11/8/2000
Victor A. McKusick - updated: 9/22/2000
John A. Phillips, III - updated: 8/9/2000
Victor A. McKusick - updated: 6/7/2000
George E. Tiller - updated: 5/16/2000
Victor A. McKusick - updated: 4/20/2000
Victor A. McKusick - updated: 3/15/2000
Victor A. McKusick - updated: 1/14/2000
John A. Phillips, III - updated: 11/29/1999
Victor A. McKusick - updated: 10/11/1999
Victor A. McKusick - updated: 9/15/1999
Victor A. McKusick - updated: 8/16/1999
Victor A. McKusick - updated: 5/4/1999
Ada Hamosh - updated: 3/26/1999
Victor A. McKusick - updated: 3/1/1999
Victor A. McKusick - updated: 2/3/1999
Victor A. McKusick - updated: 10/19/1998
Victor A. McKusick - updated: 10/13/1998
John A. Phillips, III - updated: 10/1/1998
Victor A. McKusick - updated: 9/30/1998
Victor A. McKusick - updated: 9/8/1998
Victor A. McKusick - updated: 8/11/1998
Victor A. McKusick - updated: 7/17/1998
Victor A. McKusick - updated: 7/13/1998
John A. Phillips, III - updated: 6/24/1998
John A. Phillips, III - updated: 11/8/1997

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
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MIM 166350
*RECORD*
*FIELD* NO
166350
*FIELD* TI
#166350 OSSEOUS HETEROPLASIA, PROGRESSIVE; POH
;;ECTOPIC OSSIFICATION, FAMILIAL;;
OSTEOMA CUTIS
read more*FIELD* TX
A number sign (#) is used with this entry because progressive osseous
heteroplasia (POH) is caused by a mutation resulting in loss of function
of the Gs-alpha isoform of the GNAS gene (139320) on the paternal
allele.

See also pseudopseudohypoparathyroidism (PPHP; 612463), a similar
disorder that is also caused by loss-of-function mutations in the GNAS
gene on the paternal allele.

DESCRIPTION

Progressive osseous heteroplasia is a rare autosomal dominant disorder
characterized by dermal ossification beginning in infancy, followed by
increasing and extensive bone formation in deep muscle and fascia
(Kaplan et al., 1994).

The molecular defect causing POH is the same as that causing PPHP: an
inactivating GNAS mutation caused only by paternal inheritance of the
mutant allele. However, patients with PPHP have a constellation of
physical findings referred to as Albright hereditary osteodystrophy
(AHO; see 103580) that is often not seen in patients with POH. Bastepe
and Juppner (2005) suggested that POH may be an extreme end of the
spectrum of the AHO features seen in PPHP.

CLINICAL FEATURES

Fawcett and Marsden (1983) reported osteoma cutis in 3 generations of a
family. The 3-year-old proposita developed hard nodules in the skin at
age 6 months. Skin biopsies showed multiple spicules of bone in the
skin, which showed normal membranous bone structures. The surrounding
dermis showed no scarring or inflammatory changes. She was diagnosed
with celiac disease at age 3 years. Her 6-year-old sister had skin
lesions of the legs and trunk starting about the same age but at age 2
years she had a painful, swollen right ankle. Soft tissue calcifications
were visualized in both the hands and feet. The father of the girls had
several cutaneous osteomas on the arms. His father, deceased, was known
to have had similar lesions on his shoulders for many years. Fawcett and
Marsden (1983) noted that Peterson and Mandel (1963) had described an
affected mother and son. The mother also had multiple pigmented nevi;
the son died at 15 months of alveolar sarcoma of the cerebellum.
Although Brook and Valman (1971) noted that early cases may have
represented AHO, Fawcett and Marsden (1983) thought that AHO was
unlikely in their family.

Gardner et al. (1988) described a family in which members in 2
generations and 3 sibships had ectopic ossification. Inheritance was
autosomal dominant. Most members had childhood onset of multifocal
subcutaneous ossifications, or primary osteoma cutis, which were of
trivial clinical significance. One family member had extensive ectopic
ossification involving the right leg, first noted at the age of 3 weeks
and severely interfering with growth of the limb by age 8 years.

McKusick (1989) observed osteoma cutis in a 38-year-old man who also had
unerupted teeth, severe bilateral carpal tunnel syndrome, and unusual
changes in the bones of the forearms and legs that were quite different
from those of pseudohypoparathyroidism.

Izraeli et al. (1992) described congenital osteoma cutis in members of 3
generations with convincing clinical and laboratory evidence of Albright
hereditary osteodystrophy and with one instance of male-to-male
transmission. In the propositus, small, flat, and hard subcutaneous
plaques were noted on the back at birth, and biopsy at the age of 3 days
confirmed the diagnosis of osteoma cutis. In a sister similar nodules
were noted in the first month of life, and the mother had had a hard
subcutaneous nodule on the hand from birth. No deficiency of Gs activity
was detected by the assay used.

Kaplan et al. (1994) reported 2 new cases and follow-up on 3 previously
reported cases, 1 of which was that reported by Gardner et al. (1988).
At follow-up examination of this family, the proband was 31 years old,
was married, and had a daughter who was clinically normal. This
patient's family was the only one in which relatives were affected;
individuals in 4 sibships in 2 generations showed minor cutaneous
ossification only. A maculopapular eruption was observed in the early
stages of the disorder and all of the children had ossification of the
skin in infancy. None of the children developed preosseous tumor-like
swellings, a nearly universal finding in fibrodysplasia ossificans
progressiva (FOP; 135100). All developed progression of heterotopic
ossification into deep connective tissues, including fascia and skeletal
muscle, in a process of ossification that was primarily intramembranous
rather than endochondral. The radiologic pattern of heterotopic
ossification in POH was a cocoon-like web of heterotopic bone entangling
the soft connective tissues from the dermis down through skeletal muscle
without regard to tissue planes.

Athanasou et al. (1994) reported a typical case in an 18-year-old girl.

Schmidt et al. (1994) reported a 9-year-old Hispanic girl who had
progressive ossification of the soft tissues on the right side of the
face and body. Histologic analysis of biopsy material showed
intramembranous, subcutaneous ossification.

Rosenfeld and Kaplan (1995) found reports of 8 classic cases, all in
female patients, and documented typical features of progressive osseous
heteroplasia in 2 boys, 1 of whom showed left-sided hemimelic
heterotopic ossification.

Urtizberea et al. (1998) described male patients.

Stoll et al. (2000) reported the clinical and radiologic features of a
patient with POH who was 20 years old at presentation. In addition to
abnormal ossifications, she had short metacarpals at the fourth and
fifth rays and short metatarsals at the second rays. Her parents were
unaffected. At the time of the patient's birth, her father and mother
were 48 and 36 years old, respectively.

Kaplan (2000) noted that patients with POH do not have the
characteristic malformation of the great toe seen in fibrodysplasia
ossificans progressiva and that patients with FOP do not have
ossification of the skin in infancy. POH is also distinct from tumoral
calcinosis (211900).

Eddy et al. (2000) reported 2 unrelated girls with typical clinical,
radiographic, and histologic features of POH who also had findings of
Albright hereditary osteodystrophy. One child had mild brachydactyly but
no endocrinopathy, whereas the other manifested brachydactyly, obesity,
and target tissue resistance to thyrotropin and parathyroid hormone.
Erythrocyte membranes from both girls showed decreased levels of the
Gs-alpha, suggesting that the 2 conditions share a similar molecular
basis and pathogenesis.

Faust et al. (2003) described an 8-year-old Albanian girl with POH of
the face. Biopsy showed osteoma cutis superficially with ectopic bone
formation in the deeper tissues, including skeletal muscle.

Adegbite et al. (2008) reviewed the charts of 111 individuals with
cutaneous and subcutaneous ossification. All patients were assessed for
8 characteristics: age of onset of heterotopic ossification (HO),
presence and location of HO, depth of HO, progression of HO, features of
Albright hereditary osteodystrophy, parathyroid hormone resistance, and
GNAS mutation analysis. Based on clinical criteria, they concluded that
POH and progressive HO syndromes are at the severe end of a phenotypic
spectrum of GNAS-inactivating conditions associated with extraskeletal
ossification and that they can be distinguished from other GNAS-based
disorders by a single clinical parameter, i.e., the extension of HO from
superficial to deep tissue.

INHERITANCE

Urtizberea et al. (1998) noted that POH has been observed in sporadic
cases and in an autosomal dominant pedigree pattern with widely variable
expression.

MOLECULAR GENETICS

Shore et al. (2002) identified heterozygous inactivating mutations in
the GNAS1 gene (e.g., 139320.0024) in 13 of 18 probands with POH. The
defective allele in POH was inherited exclusively from fathers, a result
consistent with a model of imprinting for GNAS1. Direct evidence that
the same mutation can cause either POH or AHO features was observed in a
single family, in which the phenotype correlated with the parental
origin of the mutant allele.

In an Albanian girl with POH of the face, Faust et al. (2003) identified
a heterozygous germline mutation in the GNAS1 gene (139320.0027).

GENOTYPE/PHENOTYPE CORRELATIONS

Adegbite et al. (2008) reviewed the charts of 111 individuals with
cutaneous and subcutaneous ossification. While most individuals with
superficial or progressive ossification had mutations in GNAS, there
were no specific genotype-phenotype correlations that distinguished the
more progressive forms, such as POH, from the nonprogressive forms, such
as PPHP and pseudohypoparathyroidism types Ia (103580) and Ic (612462).

HISTORY

Maclean et al. (1966) described a mother and daughter with multifocal
connective tissue ossification. The daughter was a 7-year-old mentally
retarded girl of normal stature. These cases may have represented
pseudopseudohypoparathyroidism (PPHP; 612463).

*FIELD* RF
1. Adegbite, N. S.; Xu, M.; Kaplan, F. S.; Shore, E. M.; Pignolo,
R. J.: Diagnostic and mutational spectrum of progressive osseous
heteroplasia (POH) and other forms of GNAS-based heterotopic ossification. Am.
J. Med. Genet. 146A: 1788-1796, 2008.

2. Athanasou, N. A.; Benson, M. K. D'A.; Brenton, D. P.; Smith, R.
: Progressive osseous heteroplasia: a case report. Bone 15: 471-475,
1994.

3. Bastepe, M.; Juppner, H.: GNAS locus and pseudohypoparathyroidism. Horm.
Res. 63: 65-74, 2005.

4. Brook, C. G. D.; Valman, H. B.: Osteoma cutis and Albright's hereditary
osteodystrophy. Brit. J. Derm. 85: 471-475, 1971.

5. Eddy, M. C.; Jan de Beur, S. M.; Yandow, S. M.; McAlister, W. H.;
Shore, E. M.; Kaplan, F. S.; Whyte, M. P.; Levine, M. A.: Deficiency
of the alpha-subunit of the stimulatory G protein and severe extraskeletal
ossification. J. Bone Miner. Res. 15: 2074-2083, 2000.

6. Faust, R. A.; Shore, E. M.; Stevens, C. E.; Xu, M.; Shah, S.; Phillips,
C. D.; Kaplan, F. S.: Progressive osseous heteroplasia in the face
of a child. Am. J. Med. Genet. 118A: 71-75, 2003.

7. Fawcett, H. A.; Marsden, R. A.: Hereditary osteoma cutis. J.
Roy. Soc. Med. 76: 697-699, 1983.

8. Gardner, R. J. M.; Yun, K.; Craw, S. M.: Familial ectopic ossification. J.
Med. Genet. 25: 113-117, 1988.

9. Izraeli, S.; Metzker, A.; Horev, G.; Karmi, D.; Merlob, P.; Farfel,
Z.: Albright hereditary osteodystrophy with hypothyroidism, normocalcemia,
and normal Gs protein activity: a family presenting with congenital
osteoma cutis. Am. J. Med. Genet. 43: 764-767, 1992.

10. Kaplan, F. S.: Personal Communication. Philadelphia, Pa. 10/30/2000.

11. Kaplan, F. S.; Craver, R.; MacEwen, G. D.; Gannon, F. H.; Finkel,
G.; Hahn, G.; Tabas, J.; Gardner, R. J. M.; Zasloff, M. A.: Progressive
osseous heteroplasia: a distinct developmental disorder of heterotopic
ossification: two new case reports and follow-up of three previously
reported cases. J. Bone Joint Surg. Am. 76: 425-436, 1994.

12. Maclean, G. D.; Main, R. A.; Anderson, T. E.; Best, P. V.: Connective
tissue ossification presenting in the skin. Arch. Derm. 94: 168-174,
1966.

13. McKusick, V. A.: Personal Communication. Baltimore, Md. 1989.

14. Peterson, W. C., Jr.; Mandel, S. L.: Primary osteomas of skin. Arch.
Derm. 87: 626-632, 1963.

15. Rosenfeld, S. R.; Kaplan, F. S.: Progressive osseous heteroplasia
in male patients: two new case reports. Clin. Orthop. Rel. Res. 317:
243-245, 1995.

16. Schmidt, A. H.; Vincent, K. A.; Aiona, M. D.: Hemimelic progressive
osseous heteroplasia: a case report. J. Bone Joint Surg. Am. 76:
907-912, 1994.

17. Shore, E. M.; Ahn, J.; Jan de Beur, S.; Li, M.; Xu, M.; Gardiner,
R. J. M.; Zasloff, M. A.; Whyte, M. P.; Levine, M. A.; Kaplan, F.
S.: Paternally inherited inactivating mutations of the GNAS1 gene
in progressive osseous heteroplasia. New Eng. J. Med. 346: 99-106,
2002. Note: Erratum: New Eng. J. Med. 346: 1678 only, 2002.

18. Stoll, C.; Javier, M.-R.; Bellocq, J.-P.: Progressive osseous
heteroplasia: an uncommon cause of ossification of soft tissues. Ann.
Genet. 43: 75-80, 2000.

19. Urtizberea, J. A.; Testart, H.; Cartault, F.; Boccon-Gibod, L.;
Le Merrer, M.; Kaplan, F. S.: Progressive osseous heteroplasia: report
of a family. J. Bone Joint Surg. Br. 80: 768-771, 1998.

*FIELD* CS
INHERITANCE:
Autosomal dominant

SKELETAL:
Heterotopic bone formation in dermis and subcutaneous fat;
Joint ankylosis;
[Limbs];
Growth retardation of affected limbs due to heterotopic bone formation

SKIN, NAILS, HAIR:
[Skin];
Dermal ossification (osteoma cutis);
Subcutaneous papules in infancy

MUSCLE, SOFT TISSUE:
Heterotopic bone formation in subcutaneous fat

MISCELLANEOUS:
Onset in infancy or childhood;
Progressive disorder;
Variable severity and progression;
Caused by paternally-inherited inactivating GNAS1 mutations

MOLECULAR BASIS:
Caused by mutation in the alpha-stimulatory subunit of the guanine
nucleotide-binding protein gene (GNAS1, 139320.0011)

*FIELD* CN
Cassandra L. Kniffin - revised: 2/19/2008

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 03/14/2008
ckniffin: 2/19/2008

*FIELD* CN
Nara Sobreira - updated: 6/17/2009
Cassandra L. Kniffin - updated: 12/15/2008
Cassandra L. Kniffin - reorganized: 2/28/2008
Victor A. McKusick - updated: 4/16/2003
Victor A. McKusick - updated: 1/15/2002
Victor A. McKusick - updated: 2/13/2001
Victor A. McKusick - updated: 10/30/2000

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
carol: 10/01/2013
terry: 4/4/2013
terry: 1/13/2011
carol: 6/18/2009
terry: 6/17/2009
carol: 12/19/2008
ckniffin: 12/15/2008
carol: 3/26/2008
carol: 2/28/2008
ckniffin: 2/19/2008
ckniffin: 8/27/2003
tkritzer: 4/25/2003
terry: 4/16/2003
carol: 2/27/2003
terry: 4/4/2002
carol: 1/31/2002
mcapotos: 1/17/2002
terry: 1/15/2002
carol: 2/15/2001
cwells: 2/15/2001
cwells: 2/14/2001
terry: 2/13/2001
carol: 10/30/2000
terry: 10/24/1995
mimadm: 1/14/1995
davew: 7/1/1994
jason: 6/15/1994
carol: 7/16/1992
supermim: 3/16/1992

MIM 174800
*RECORD*
*FIELD* NO
174800
*FIELD* TI
#174800 MCCUNE-ALBRIGHT SYNDROME; MAS
;;ALBRIGHT SYNDROME
POLYOSTOTIC FIBROUS DYSPLASIA, INCLUDED; PFD, INCLUDED; POFD, INCLUDED
read more*FIELD* TX
A number sign (#) is used with this entry because this phenotype is
associated with early embryonic postzygotic somatic activating mutations
in the GNAS1 gene (139320).

DESCRIPTION

Activating or gain-of-function GNAS1 mutations in patients with the
McCune-Albright syndrome are present in the mosaic state, resulting from
a postzygotic somatic mutation appearing early in the course of
development which yields a monoclonal population of mutated cells within
variously affected tissues. The nonmosaic state for most activating
mutations is presumably lethal to the embryo. The disorder is
characterized clinically by the classic triad of polyostotic fibrous
dysplasia (POFD), cafe-au-lait skin pigmentation, and peripheral
precocious puberty. However, the disorder is clinically heterogeneous
and can include various other endocrinologic anomalies such as
thyrotoxicosis, pituitary gigantism, and Cushing syndrome (219080)
(Lumbroso et al., 2004).

CLINICAL FEATURES

This disorder is called McCune-Albright syndrome or simply Albright
syndrome, but should not be confused with pseudohypoparathyroidism
(103580), which includes a constellation of features termed Albright
hereditary osteodystrophy (AHO). The predominant features of MAS occur
in 3 areas: the bony skeleton, the skin, and the endocrine system. In
all 3 systems, the extent of the abnormality and, in the case of the
endocrine system, the nature of the abnormality, are highly variable
from case to case, depending on the specific tissues involved in the
mosaicism and the extent of involvement.

- Skeletal

No bone is spared. There is a strong tendency to asymmetry. Involvement
of the skull and facial bones can be striking, and in the case of these
bones also, asymmetry is the rule. Pathologic fracture or bone deformity
may be presenting manifestations and pseudarthrosis occurs frequently.
Deafness and blindness can result from impingement of the bony process
on the cranial foramina. Shepherd's crook deformity of the proximal
femur is particularly characteristic of the bony involvement. (The bone
lesions of neurofibromatosis are usually less extensive than are those
in polyostotic fibrous dysplasia, but may be difficult to distinguish on
radiologic grounds alone.)

Hypophosphatemic osteomalacia ('rickets') has been observed in some
cases of polyostotic fibrous dysplasia. Dent and Gertner (1976)
suggested that this may represent a situation comparable to 'tumor
rickets' which is associated with mesenchymal tumors and regresses when
the tumor is removed. McArthur et al. (1979) described 4 patients with
Albright syndrome, hypophosphatemia, and inappropriately low renal
tubular reabsorption of phosphate. Three of the patients had radiologic
evidence of rickets. They postulated that a substance elaborated by the
dysplastic bone interfered with phosphate reabsorption in the renal
tubule.

Kaplan et al. (1988) reported the case of a 31-year-old woman with this
disorder in whom bone lesions progressed rapidly during pregnancy. A
study of these lesions showed the presence of estrogen and progesterone
receptors in osteogenic cells. Whether estrogen receptors are unique to
the McCune-Albright syndrome or, alternatively, a property of any
activated, dedifferentiated, or neoplastic bone cells is unclear.

Viljoen et al. (1988) described a severely affected man, aged about 30,
with massive craniofacial hyperostosis. They raised the question of
whether this represents the severe end of the scale for polyostotic
fibrous dysplasia, or whether it is a distinct entity. It seems likely
that this was a severe expression of polyostotic fibrous dysplasia
(McCune-Albright syndrome). McKusick (1988) studied a patient with
severe craniofacial hyperostosis who had other, more characteristic
features of polyostotic fibrous dysplasia, including cafe-au-lait
pigmentation, which was absent in the case of Viljoen et al. (1988);
this patient was later found by Schwindinger et al. (1992) to have a
mutation in the GNAS1 gene (139320.0009). There are other definite cases
of patients with very severe craniofacial involvement (Nager et al.,
1982; Nager and Holliday, 1984). Such is also evident from inspection of
the descriptions in the classic monograph of Albright and Reifenstein
(1948). For example, they produced a picture (their Figure 145) of a
skeleton thought by von Recklinghausen (1891) to represent
hyperparathyroidism (osteitis fibrosa generalisata of von
Recklinghausen). That this was severe Albright polyostotic fibrous
dysplasia was suggested by the shepherd's crook deformity of the femora
and the asymmetric bulge of the occipital area of the skull. Taconis
(1988) reported 2 cases of osteosarcomatous transformation, 1 in the
skull of a 25-year-old man and 1 in the iliac bone of a 38-year-old man.

Taconis (1988) stated that the incidence of malignancy of the bone
lesions may be lower than previously suggested. Malignant transformation
occurs in both monostotic and polyostotic disease but is more common in
the latter form. Although radiation therapy is often an inciting cause,
this was not the case in either of these patients, who had received no
radiation therapy.

Candeliere et al. (1995) reported a 7-year-old boy with McCune-Albright
syndrome in whom they identified high levels of expression of the FOS
(164810) oncogene in bone lesions. Increased expression of the FOS
oncogene was presumably a consequence of increased adenylate cyclase
activity and may have been important in the pathogenesis of the bone
lesions. Genetic analysis identified the R201H mutation in the GNAS1
gene (139320.0013).

- Skin

The involvement of the skin consists predominantly of large cafe-au-lait
spots with irregular margins, giving them a 'coast of Maine'
configuration as opposed to the more regularly outlined 'coast of
California' cafe-au-lait spots of neurofibromatosis (162200). Like the
bony lesions, the pigmentary lesions of the skin may be limited
predominantly to one side and stop sharply at the midline. The nape of
the neck is a commonly involved site. (The cafe-au-lait spots of
neurofibromatosis are for the most part smaller, more regular, and more
uniformly distributed, and are accompanied by axillary freckling and
usually by skin tumors.)

- Endocrine

The leading endocrinologic feature is precocious puberty, which occurs
in over half of female cases. Menstruation may occur in the first months
of life. Precocious puberty has been reported also in males with this
syndrome; testicular biopsy has revealed the full process of
spermatogenesis with mature sperm in patients as young as 6 years
(Benedict, 1966; Giovannelli et al., 1978). Probably the second most
common endocrinopathy is hyperthyroidism (Lichtenstein and Jaffe, 1942;
Hamilton and Maloof, 1973). Excessive secretion of growth hormone (GH1;
139250) with gigantism, hyperadrenocorticism with Cushing syndrome, and
gynecomastia have been observed. In specific instances, it has been
demonstrated that the Cushing syndrome is due to multinodular change in
the adrenals and the hyperthyroidism to multinodular toxic goiter
(Hamilton and Maloof, 1973).

Falconer et al. (1942) reported pituitary gigantism in association with
McCune-Albright syndrome. Wrong (1992) stated that he saw this patient,
a boy born in Nottingham in 1930, in 1954; the patient was still alive,
though severely disabled by bone disease, in the late 1960s at the age
of almost 40. Premawardhana et al. (1992) described a 26-year-old woman
with acromegaly due to a pituitary adenoma who developed secondary
hypothyroidism and hypoadrenalism, in a setting of McCune-Albright
syndrome. Cremonini et al. (1992) described acromegaly and
hyperprolactinemia due to pituitary adenoma in a 35-year-old woman with
McCune-Albright syndrome.

Malchoff et al. (1994) reported a 27-year-old woman with McCune-Albright
syndrome who had an unusual clinical course. She presented at the age of
3 years with vaginal bleeding, had breast development at age 4 years,
and had a second episode of vaginal bleeding at age 5 years 7 months.
She had no pigmentary skin lesions, and 2 sets of radiographs of the
chest, pelvis, skull, and long bones were normal. She was treated for 24
months with medroxyprogesterone acetate, and precocity resolved. She
progressed normally through puberty, starting at age 10 years, and had
normal menses, starting at age 12 years. At age 25 years, she delivered
a normal daughter. A chest x-ray at age 27 years after minor trauma
identified a single lesion of fibrous dysplasia in the left seventh rib.
Radiographs of other bones were normal. Studies of the GNAS1 gene showed
an R201H mutation.

Tinschert et al. (1999) reported a 37-year-old man with McCune-Albright
syndrome causing gigantism and fibrous dysplasia with hypersecretion of
growth hormone and prolactin (176760), with no evidence of pituitary
tumor. The patient had an R201H mutation which ranged from 0% in buccal
mucosa, blood, and skin melanocytes to 45% in a frozen section of the
middle nasal concha.

Coutant et al. (2001) reported a 3.8-year-old boy with McCune-Albright
syndrome associated with abnormal prepubertal testis enlargement and no
sexual precocity. Other endocrine tests showed excessive GH secretion
and moderate adrenal androgen hypersecretion. These findings were
consistent with the occurrence of an activating mutation of the GNAS1
gene mainly expressed in Sertoli cells and weakly expressed or absent in
Leydig cells. Abnormal prepubertal testicular enlargement extends the
clinical spectrum of MAS, suggesting that determination of serum inhibin
B (see 147290) and anti-mullerian hormone (600957) should be considered
in boys with this syndrome. DNA sequence analysis from bone and testis
tissues detected the R201H mutation.

Akintoye et al. (2002) estimated the prevalence of GH excess in MAS,
characterized the clinical and endocrine manifestations, and described
the response to treatment. Twelve patients (21%) had GH excess, based on
failure to suppress serum GH on oral glucose tolerance test. Vision and
hearing deficits were more common in patients with GH excess (33%) than
in those without (4%). Patients with a history of precocious puberty and
GH excess who had reached skeletal maturity achieved normal adult height
despite a history of early epiphyseal fusion. All 9 patients tested had
an increase in serum GH after TRH (613879), 11 of 12 (92%) had
hyperprolactinemia, and all 8 tested had detectable or elevated
nighttime GH levels. Pituitary adenoma was detected in 4 of 12 (33%)
patients. GH excess is common in MAS and results in a distinct clinical
phenotype characterized by inappropriately normal stature, TRH
responsiveness, prolactin (176760) cosecretion, small or absent
pituitary tumors, a consistent but inadequate response to treatment with
cabergoline, and an intermediate response to long-acting octreotide.

Laven et al. (2001) presented the first longitudinal assessment of
ovarian dysfunction in an adult patient with McCune-Albright syndrome.
Their report provided evidence for persistent autonomous unilateral
ovarian dysfunction during early adulthood in McCune-Albright syndrome
not compatible with normal fertility. Laven et al. (2004) presented a
case of an adult MAS patient with persistent unilateral autonomous
ovarian activity whose ovarian and endometrial function was restored by
removal of the affected ovary.

Obuobie et al. (2001) studied the GH and insulin-like growth hormone I
(IGF1; 147440) profiles in a patient with confirmed McCune-Albright
syndrome and GH hypersecretion throughout a successful pregnancy and
postpartum period. Prepregnancy, the IGF I level was 60.6 nmol/L
(normal, 18.0-43.1) and the daytime GH profile measured using assay A
was 9.6-14.0 mU/L. At 13 weeks' gestation there was a decline of IGF I
to 33.9 nmol/L and in the daytime GH profile (assay A) to 5.4-6.8 mU/L.
At 24 weeks, IGF I had risen to 51.6 nmol/L. At 36 weeks, IGF I was
still elevated at 56.6 nmol/L, with a daytime GH profile of 16.6-17.7
mU/L using assay A. At 12 weeks postpartum, the daytime GH profile with
assay B was 5.6-8.6 mU/L. The authors concluded that GH suppression
during pregnancy in acromegaly associated with McCune-Albright syndrome
is best shown with assay B, which discriminates between GH and human
placental lactogen (HPL; 150200). They also stated that GH secretion in
a pregnant acromegalic with the McCune-Albright syndrome may not be
entirely autonomous, as seen in classic acromegaly, but may be
associated with a degree of negative feedback control that could be
exerted by a circulating factor of placental origin, probably HPL or
placental GH (GH2; 139240).

DiGeorge (1975) reviewed unusual features of the syndrome and the
evidence that the endocrinopathy represents autonomous function of the
endocrine glands. Two main hypotheses had been stated: (1) excessive
secretion of the hypothalamic releasing hormones is involved in the
endocrinopathy of this disorder (Hall and Warrick, 1972); and (2) this
disorder represents multiple, circumscribed embryonic alterations in a
variety of tissues resulting from clones of cells characterized by
autonomous behavior, and perhaps aberrant behavior, toward otherwise
normal stimuli. The latter hypothesis appeared to be the more compatible
with the skeletal, cutaneous, and endocrinologic features and with the
mosaic hypothesis of Happle (1986); its validity was proved by
demonstration of mosaicism for mutations in the GNAS1 gene.

Majzoub and Scully (1993) described a 6-year-old boy who had apocrine
sweat, facial acne, Tanner stage 2 pubic hair, and midpubertal-sized
testes and penis, all indicative of precocious puberty, in association
with osseous changes of this disorder.

A patient, aged 50 years, with McCune-Albright syndrome had a large
syrinx (syringomyelia) causing neurologic manifestations in the arms and
legs (McKusick, 1988). Because of a linear midline pigmentation in the
high cervical area posteriorly, in the same area of the syrinx, the
possibility can be raised that the syrinx, which extended from C2 to
T11, was a primary manifestation of the syndrome. The patient also had
extensive involvement of the base of the skull with Arnold-Chiari
syndrome (i.e., extension of cerebellar tissue through the foramen
magnum). He had had hyperthyroidism, as reported by Hamilton and Maloof
(1973). (The same patient had severe craniofacial hyperostosis and was
demonstrably mosaic for a specific GNAS1 mutation, i.e., arg201-to-his
(139320.0009).)

Abs et al. (1990) described a case of atypical McCune-Albright syndrome;
a 36-year-old woman had acromegaly due to a pituitary adenoma, a toxic
multinodular goiter that was associated with spontaneous normalization
of thyroid function, and asymptomatic polyostotic fibrous dysplasia.
There was no skin pigmentation and no sexual precocity. See 139320.0009
for discussion of the molecular basis of the association of pituitary
tumor with McCune-Albright syndrome. Chanson et al. (1994) reported 5
patients with McCune-Albright syndrome and acromegaly. In all,
acromegaly began before the age of 20 years and was recognized after the
diagnosis of fibrous dysplasia, which was polyostotic in 3 and
monostotic in 2. Bone fibrous dysplasia always involved the base of the
skull and in 4 patients prevented surgical removal of the pituitary
adenoma, which was visualized easily by MRI.

Yoshimoto et al. (1991) described the extraordinary case of a female
infant who at birth had cutaneous pigmentation, hyperthyroidism, and
Cushing syndrome.

Mastorakos et al. (1997) described a 6-year-old girl with MAS and
hyperthyroidism and reviewed the previously reported 63 patients with
MAS and thyroid disorders.

Kirk et al. (1999) presented 5 children (4 girls) with features of
McCune-Albright syndrome who had Cushing syndrome in the infantile
period (under 6 months of age). In 2 children, spontaneous resolution
occurred, but the remaining 3 required bilateral adrenalectomy. In
addition, all 4 girls experienced precocious puberty, and 3 children
demonstrated radiologic evidence of nephrocalcinosis. In 1 patient,
laparotomy, performed at 7 weeks of age because of vomiting and
abdominal distention, revealed multiloculated ovarian cysts. Bilateral
adrenalectomy was performed at 3 months for nodular hyperplasia.
Irregular vaginal bleeding in association with breast development
occurred by 11 months of age. Thyrotoxicosis subsequently developed, and
the patient had a number of pathologic fractures of both femurs through
polyostotic lesions and had marked spinal deformity. Kirk et al. (1999)
postulated that the hypercalcemia and hypercalciuria leading to renal
stones are secondary to the effects of cortisol on bone turnover.

Yang et al. (1999) reported a case of thyroid cancer in McCune-Albright
syndrome. Collins et al. (2003) reported a second case and reviewed both
cases, extending the phenotypic spectrum of the disorder.

- Phenotypic Variation

Cole et al. (1983) reported the case of a French-Canadian boy, of
nonconsanguineous parents, who had unusual facial appearance (depressed
nasal bridge, synophrys, and forehead hirsutism), 'coast of Maine'
pigmented patches, myelofibrosis, recurrent femoral fractures and
widespread fibrous dysplasia of bone leading to the suggested
designation 'panostotic fibrous dysplasia.' Biochemical findings
included elevated serum alkaline phosphatase (bone isozyme) and
1,25-(OH)2 vitamin D and low serum phosphorus levels. Increased turnover
of bone was indicated by urinary excretion rates of hydroxyproline,
glycylproline, and gamma-carboxyglutamic acid. Progressive cortical
thinning and loss of bony trabeculae were demonstrated by serial x-rays
and supported by bone biopsy. No precisely similar case was known.
Candeliere et al. (1995) demonstrated that this patient, then a
14-year-old boy, had an arg201-to-cys mutation in the GNAS1 gene
(139320.0008). Thus, this was an unusually severe form of
McCune-Albright syndrome not fundamentally different from that disorder
or perhaps from monostotic fibrous dysplasia. Cole (1996) pointed out
that the patient with 'idiopathic hyperphosphatasia with dermal
pigmentation' reported by Dohler et al. (1986) appears to have had the
same disorder as the patient reported by Cole et al. (1983).

De Sanctis et al. (1999) reported the diagnostic clinical features and
their long-term evolution in 32 patients with McCune-Albright syndrome.
Almost all patients had skin changes at birth. There was a 50%
probability of bone dysplasia at 8 years of age and a 50% probability of
precocious puberty in females at 4 years.

Coutant et al. (2001) reported a 3.8-year-old boy with McCune-Albright
syndrome associated with abnormal prepubertal testis enlargement and no
sexual precocity. Physical examination showed cafe-au-lait skin lesions,
enlarged testes, prepubertal sized penis, and no pubic or axillary hair.
Skeletal radiography disclosed fibrous dysplasia. The serum testosterone
level was 0.58 nmol/L and remained below 1.4 nmol/L during the 4-year
follow-up. By contrast, serum inhibin B (see 147290) and anti-mullerian
hormone (600957) concentrations were abnormally increased up to 255
pg/mL (childhood range, 35-180) and 792 pmol/L (childhood range,
309-566), respectively. The luteinizing hormone (LH; 152780) response to
a gonadotropin-releasing hormone (GnRH; 152760) test was in the
prepubertal range, whereas the follicle-stimulating hormone (FSH;
136530) response was blunted. This abnormal hormone concentration
profile indicated autonomous hyperfunction of Sertoli cells, with no
evidence of Leydig cell activation. Testicular histology showed tubules
with marked Sertoli cell hyperplasia and very rare germinal cells, and
interstitial tissue containing mesenchymal cells but no mature Leydig
cells. DNA sequence analysis from bone and testis tissues detected the
known activating mutation in MAS that results in the arg201-to-his
mutation in the GNAS1 protein (139320.0009).

OTHER FEATURES

Zacharin et al. (2011) reported 4 unrelated patients with MAS who had
multiple hamartomatous gastrointestinal polyps in the stomach and/or
duodenum. Two of the patients were noted to have perioral freckling in
their early teens, reminiscent of Peutz-Jeghers syndrome (PJS; 175200)
and were thus examined endoscopically. The polyps showed a branching
pattern with prominent cores of smooth muscle covered by
well-differentiated epithelium. Molecular analysis of peripheral blood
identified activating mutations in the GNAS gene in 3 of the 4 patients;
none of the patients had STK11 (602216) mutations. Molecular analysis of
the gastrointestinal polyps showed no GNAS mutation in 1 patient, LOH of
the GNAS locus in 1 patient, the same GNAS mutation as found in
peripheral blood in 1 patient, and heterozygosity for a GNAS activating
mutation only in the polyp in the patient without a mutation in
peripheral blood. Zacharin et al. (2011) concluded that patients with
MAS should undergo routine endoscopy, as gastrointestinal polyps may be
a common manifestation of the disorder.

INHERITANCE

Few convincing instances of familial occurrence of POFD have been
reported. Hibbs and Rush (1952) reported the case of a 50-year-old woman
with typical skin pigmentation and involvement of multiple bones. The
daughter had no skin pigmentation (which is absent in some cases) but
had a pathologic fracture of the left radius and radiologic and
histologic changes interpreted as those of fibrous dysplasia. Firat and
Stutzman (1968) described hyperthyroidism in 1 patient who also had
pituitary gigantism and hyperparathyroidism in 2 others. The last 2
cases were mother and daughter. The fibrous dysplasia was limited to the
jaw.

Reitzik and Lownie (1975) described a family in which many members had
craniofacial POFD in an autosomal dominant pedigree pattern. This may
have represented, however, an entity distinct from MAS. Alvarez-Arratia
et al. (1983) presented a family that had several members in at least 3
generations with the bony and cutaneous lesions of polyostotic fibrous
dysplasia.

Happle (1986) made the intriguing suggestion that this disorder is
caused by an autosomal dominant lethal gene that is compatible with
viability of the conceptus only when it occurs in the mosaic state,
having arisen by somatic mutation. Endo et al. (1991) described
monozygotic twin girls of whom one showed major signs of MAS: precocious
puberty, cafe-au-lait nevi, and polyostotic fibrous dysplasia. The lack
of fully convincing familial cases, except for the occurrence in
monozygotic twins (Lemli, 1977), is consistent with the Happle
hypothesis. (In the twins reported by Lemli (1977), one had classic
signs of McCune-Albright syndrome and the other had only radiologic
signs of bone disease and elevated serum alkaline phosphatase.) The
frequency of the disorder is about equal in males and females.

Feuillan et al. (1991) reported the cases of 2 girls with precocious
puberty initially diagnosed at the ages of 1 and 4 years. Both were
unresponsive to treatment with the LHRH (luteinizing hormone-releasing
hormone; 152760) agonist deslorelin for 5 years. In this respect they
resembled patients with the McCune-Albright syndrome, but they had none
of the other manifestations of MAS. Feuillan et al. (1991) suggested
that although the underlying defect was absent in bone and skin, it was
expressed in the ovaries of the 2 girls. This suggestion is consistent
with the view that the McCune-Albright syndrome is a somatic mutation
disorder.

CLINICAL MANAGEMENT

Plotkin et al. (2003) investigated the effects of intravenous
pamidronate treatment in 18 children and adolescents with polyostotic
fibrous dysplasia who were treated for 1.2 to 9.1 years. Although not
quantitatively examined, pamidronate appeared to be effective in
reducing bone pain. However, there was no radiographic evidence of
filling of lytic lesions or thickening of the bone cortex surrounding
the lesions in any patient.

Feuillan et al. (2007) studied the effectiveness of the aromatase
inhibitor letrozole in decreasing pubertal progression in girls with MAS
and assessed the response of indices of bone turnover associated with
the patients' polyostotic fibrous dysplasia. Girls had decreased rates
of growth (p less than 0.01) and bone age advance (p less than 0.004)
and cessation or slowing in their rates of bleeding over 12 to 36 months
of therapy. Mean ovarian volume, estradiol, and indices of bone
metabolism fell after 6 months (p less than 0.05) but tended to rise by
24 to 36 months. Feuillan et al. (2007) concluded that letrozole may be
effective therapy in some girls with MAS and/or gonadotropin-independent
precocious puberty. Possible adverse effects include ovarian enlargement
and cyst formation.

Mieszczak et al. (2008) determined the safety and efficacy of the
aromatase inhibitor anastrozole for the treatment of precocious puberty
in girls with McCune-Albright syndrome. Although it appeared safe,
anastrozole for 1 year was ineffective in halting vaginal bleeding and
attenuating rates of skeletal maturation and linear growth in girls with
McCune-Albright syndrome. The authors concluded that pharmacologic
strategies other than anastrozole should be pursued for the treatment of
precocious puberty in this population.

MOLECULAR GENETICS

The mystery of the etiology and pathogenesis of polyostotic fibrous
dysplasia appears to have been solved by the identification of
activating mutations in the GNAS1 gene (139320) which render the gene
functionally constitutive (Weinstein et al., 1991; Schwindinger et al.,
1992). Similar mutations leading to constitutive activation of this gene
had been identified in some human growth hormone secreting pituitary
tumors and human thyroid tumors. Furthermore, the demonstration of the
mutation in peripheral blood leukocytes but not in DNA from biopsies of
clinically normal skin supports the proposal of Happle (1986) that this
is a disorder of mosaicism resulting from postzygotic somatic cell
mutation.

Kitoh et al. (1999) found a mutation in GNAS1 in endosteal, but not in
periosteal, cells taken from a cystic lesion of the humerus of an
11-year-old boy with polyostotic fibrous dysplasia.

Bianco et al. (1998) isolated progenitor cells from the stromal system
of the bone marrow involved in fibrous dysplasia in patients with
McCune-Albright syndrome and analyzed these cells in culture. Analysis
of the GNAS1 gene from individual colonies provided direct evidence for
the presence of 2 different genotypes within single fibrous dysplastic
lesions: marrow stromal cells containing 2 normal GNAS1 alleles, and
those containing a normal allele and an allele with an activating
mutation. Transplantation of clonal populations of normal cells into the
subcutis of immunocompromised mice resulted in normal ossicle formation.
In contrast, transplantation of clonal populations of mutant cells
always led to the loss of transplanted cells from the transplantation
site and no ossicle formation. However, transplantation of a mixture of
normal and mutant cells reproduced an abnormal ectopic ossicle
recapitulating human fibrous dysplasia and providing an in vivo cellular
model of this disease. The results provided experimental evidence for
the need of both normal and mutant cells in the development of
McCune-Albright syndrome fibrous dysplastic lesions in bone. This study
confirmed the hypothesis of Happle (1986). It also confirmed the
editorial comment of DiGeorge (1975) concluding with the remark that MAS
is 'a rare disorder, yes; an unimportant one, never' (Olsen, 1998).

Bianco et al. (2000) analyzed a series of 8 consecutive cases of
isolated fibrous dysplasia without the classic features of
McCune-Albright syndrome and identified arg201 mutations in the GNAS1
gene in all of them. Histologic findings in these cases were not
distinguishable from those observed in MAS-related fibrous dysplasia and
included subtle changes in cell shape and collagen texture putatively
ascribed to excess endogenous cAMP. Unmineralized osteoid changes
characteristic of osteomalacia were prominent in lesional fibrous
dysplasia. Bianco et al. (2000) concluded that the findings support the
view that fibrous dysplasia, MAS, and nonskeletal isolated endocrine
lesions associated with GNAS1 mutations represent a spectrum of
phenotypic expressions, probably reflecting different patterns of
somatic mosaicism, of the same basic disorder.

Akintoye et al. (2002) noted that the molecular etiology of MAS is
postzygotic activating mutations of the GNAS1 gene product, the alpha
subunit of the Gs protein. The term 'GSP oncogene' has been assigned to
these mutations due to their association with certain neoplasms.

Collins et al. (2003) performed molecular analysis of thyroid carcinomas
from 2 McCune-Albright syndrome patients and demonstrated that foci of
malignancy and adjacent areas of hyperplasia and, in 1 case, some areas
of normal thyroid harbored an activating mutation of GNAS1 at the arg201
codon (139320.0008 and 139320.0009, respectively). The authors concluded
that these 2 cases of thyroid carcinoma in MAS supported the hypothesis
that activation of the G(s) signaling cascade alone is insufficient for
malignant transformation of thyroid or other endocrine cells.

Using a PCR-based sensitive method, Lumbroso et al. (2004) reported a
systematic search for Gs-alpha arg201 mutations in patients presenting
with at least 1 of the signs of MAS. They studied 113 patients (98 girls
and 15 boys), 24% presenting the classic triad, 33% with 2 signs, and
40% with only 1 classic sign. Overall, mutation of the arg201 codon was
identified in 43% of the patients. When an affected tissue was
available, the mutation was found in more than 90% of the patients,
whatever the number of signs. Skin was a noteworthy exception because
only 3 of 11 skin samples were positive. The mutation was detected in
46% of blood samples in patients presenting the classic triad, whereas
this figure fell to 21% and 8% in patients with 2 and 1 sign,
respectively. The authors concluded that affections as clinically
different as monostotic fibrous dysplasia, isolated peripheral
precocious puberty, neonatal liver cholestasis, and the classic MAS all
appear to be components of a wide spectrum of diseases based on the same
molecular defect.

HISTORY

This disorder was first described by McCune and Bruch (1937) and
Albright et al. (1937, 1938). Affected persons came to the attention of
Fuller Albright because of the similarity of the skeletal changes to
those of osteitis fibrosa cystica resulting from hyperparathyroidism
(Axelrod, 1970). Lichtenstein (1938) introduced the designation
'polyostotic fibrous dysplasia' for the skeletal aspect of the syndrome.

Nerlich et al. (1991) suggested that Thomas Hasler, the 'Tegernsee
giant,' had a combination of juvenile gigantism and polyostotic fibrous
dysplasia. It would not be surprising if the two occurred together in
light of the fact that the same somatic mutation is found in PFD and in
growth hormone-secreting tumors of the pituitary (see 102200)
(Schwindinger et al., 1991).

*FIELD* SA
Comite et al. (1984); Feuillan et al. (1986); Nakagawa et al. (1985);
Shires et al. (1979); Wirth et al. (1971)
*FIELD* RF
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A. M.; Fisher, L. W.; Robey, P. G.: Mutations of the GNAS1 gene,
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*FIELD* CS
INHERITANCE:
Somatic mosaicism

HEAD AND NECK:
[Head];
Cranial foramen impingement;
Craniofacial hyperostosis;
[Face];
Facial asymmetry;
[Ears];
Deafness;
[Eyes];
Blindness

ABDOMEN:
[Gastrointestinal];
Gastrointestinal polyps

SKELETAL:
Polyostotic fibrous dysplasia;
Pathologic fracture

SKIN, NAILS, HAIR:
[Skin];
Large cafe au lait spots with irregular margins

ENDOCRINE FEATURES:
Hyperthyroidism;
Hyperparathyroidism;
Cushing syndrome;
Precocious puberty;
Acromegaly;
Hyperprolactinemia

NEOPLASIA:
Pituitary adenoma

MISCELLANEOUS:
Variable phenotype;
Activating or gain-of-function GNAS1 mutations in patients with the
McCune-Albright syndrome are present in the mosaic state, resulting
from a postzygotic somatic mutation appearing early in the course
of development which yields a monoclonal population of mutated cells
within variously affected tissues

MOLECULAR BASIS:
Caused by somatic mutation in the guanine nucleotide-binding protein,
alpha-stimulating activity polypeptide 1 gene (GNAS1, 139320.0008)

*FIELD* CN
Cassandra L. Kniffin - updated: 8/9/2011
Ada Hamosh - updated: 2/8/2000
Kelly A. Przylepa - revised: 11/16/1999

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 03/05/2012
joanna: 12/29/2011
ckniffin: 8/9/2011
joanna: 4/12/2000
joanna: 2/8/2000
joanna: 11/22/1999
joanna: 11/16/1999

*FIELD* CN
Cassandra L. Kniffin - updated: 8/9/2011
John A. Phillips, III - updated: 12/20/2010
John A. Phillips, III - updated: 3/24/2008
Cassandra L. Kniffin - updated: 2/19/2008
John A. Phillips, III - updated: 8/20/2006
Marla J. F. O'Neill - updated: 9/2/2005
John A. Phillips, III - updated: 7/26/2005
John A. Phillips, III - updated: 7/14/2005
John A. Phillips, III - updated: 3/31/2005
John A. Phillips, III - updated: 4/8/2003
John A. Phillips, III - updated: 8/17/2001
John A. Phillips, III - updated: 7/20/2001
John A. Phillips, III - updated: 7/16/2001
Victor A. McKusick - updated: 4/11/2000
Ada Hamosh - updated: 2/10/2000
Michael J. Wright - updated: 12/16/1999
Victor A. McKusick - updated: 8/5/1999
Victor A. McKusick - updated: 5/18/1998

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
alopez: 08/17/2011
ckniffin: 8/9/2011
carol: 4/20/2011
terry: 1/13/2011
alopez: 12/20/2010
terry: 2/6/2009
carol: 12/19/2008
terry: 9/26/2008
carol: 3/24/2008
carol: 2/28/2008
ckniffin: 2/19/2008
alopez: 8/20/2006
terry: 12/14/2005
wwang: 9/2/2005
alopez: 7/26/2005
alopez: 7/14/2005
alopez: 3/31/2005
tkritzer: 4/14/2003
terry: 4/8/2003
carol: 2/27/2003
cwells: 8/22/2001
cwells: 8/17/2001
cwells: 8/14/2001
cwells: 7/20/2001
mcapotos: 7/18/2001
mcapotos: 7/16/2001
mcapotos: 5/2/2000
terry: 4/11/2000
mcapotos: 4/6/2000
terry: 2/10/2000
carol: 2/10/2000
alopez: 12/16/1999
carol: 8/19/1999
jlewis: 8/19/1999
terry: 8/5/1999
carol: 2/23/1999
carol: 2/8/1999
terry: 2/2/1999
carol: 6/9/1998
terry: 5/18/1998
mark: 10/19/1997
mark: 6/11/1995
carol: 1/30/1995
pfoster: 9/7/1994
davew: 8/1/1994
terry: 5/16/1994
mimadm: 4/18/1994

MIM 219080
*RECORD*
*FIELD* NO
219080
*FIELD* TI
#219080 ACTH-INDEPENDENT MACRONODULAR ADRENAL HYPERPLASIA; AIMAH
;;ACTH-INDEPENDENT MACRONODULAR ADRENOCORTICAL HYPERPLASIA;;
read moreADRENOCORTICOTROPIC HORMONE-INDEPENDENT MACRONODULAR ADRENAL HYPERPLASIA;;
CORTICOTROPIN-INDEPENDENT MACRONODULAR ADRENAL HYPERPLASIA;;
ACTH-INDEPENDENT CUSHING SYNDROME;;
CUSHING SYNDROME, ADRENAL, DUE TO AIMAH
*FIELD* TX
A number sign (#) is used with this entry because ACTH-independent
macronodular adrenal hyperplasia (AIMAH) can be caused by somatic
mutation in the GNAS1 gene (139320) on chromosome 20q13. Bilateral
adrenocortical nodular hyperplasia can also be found in McCune-Albright
syndrome (174800), which is also caused by mutation in the GNAS1 gene.

DESCRIPTION

ACTH-independent macronodular adrenal hyperplasia (AIMAH) is an
endogenous form of adrenal Cushing syndrome characterized by multiple
bilateral adrenocortical nodules that cause a striking enlargement of
the adrenal glands. Although some familial cases have been reported, the
vast majority of AIMAH cases are sporadic. Patients typically present in
the fifth and sixth decades of life, approximately 10 years later than
most patients with other causes of Cushing syndrome (Swain et al., 1998;
Christopoulos et al., 2005).

Approximately 10 to 15% of adrenal Cushing syndrome is due to primary
bilateral ACTH-independent adrenocortical pathology. The 2 main subtypes
are AIMAH and primary pigmented nodular adrenocortical disease (PPNAD,
see 610489), which is often a component of the Carney complex (160980)
and associated with mutations in the PRKAR1A gene (188830) on chromosome
17q23-q24. AIMAH is rare, representing less than 1% of endogenous causes
of Cushing syndrome (Swain et al., 1998; Christopoulos et al., 2005).

Cushing 'disease' (219090) is an ACTH-dependent disorder caused in most
cases by pituitary adenomas that secrete excessive ACTH.

CLINICAL FEATURES

Kirschner et al. (1964) first reported AIMAH in a 40-year-old woman with
long-standing Cushing syndrome (Christopoulos et al., 2005).

Findlay et al. (1993) reported a mother and daughter who each presented
with clinical features of Cushing syndrome at age 38 years and were
found to have AIMAH.

Minami et al. (1996) reported 2 Japanese sibs with Cushing syndrome due
to AIMAH. The proband was a 69-year-old woman who presented with easy
bruising, fatigability, muscle weakness, hypertension, and cognitive
decline. She had truncal obesity, moon facies, muscle wasting, and
pretibial edema. Serum cortisol was elevated and did not respond to
dexamethasone; CT scan showed bilateral adrenal enlargement. The patient
died of subarachnoid hemorrhage and postmortem examination confirmed
AIMAH. Family history revealed an older brother with AIMAH who had died
postoperatively. Two additional sibs showed bilateral enlargement of the
adrenal glands as well as impaired response to dexamethasone, although
they were not clinically Cushingoid.

Swain et al. (1998) reported 9 unrelated patients with AIMAH who
underwent curative bilateral adrenalectomy. The mean age was 56 years.
All patients had increased serum cortisol, decreased serum ACTH, and
failed to show suppression of cortisol excretion following dexamethasone
administration. All patients except 1 had hypertension; subtle signs or
symptoms consistent with Cushing syndrome were noted in patients'
histories dating back up to 20 years. Pathologic examination showed
bilateral adrenal cortical nodules that were yellow and ranged in size
from 1 to 4.2 cm within enlarged adrenal glands weighing from 16.7 to
218 g combined. Microscopic analysis showed hyperplastic nodules
composed of clear cells in cord-like arrangements and compact
eosinophilic cells occasionally interspersed with atrophic nonnodular
cortex. Swain et al. (1998) cited studies (Aiba et al., 1991; Sasano et
al., 1994; Morioka et al., 1997; Koizumi et al., 1994) indicating that
AIMAH nodules show impaired steroidogenesis, suggesting a primary
intrinsic alteration in the adrenal cells. Importantly, none of the
patients developed Nelson syndrome (pituitary tumor) after adrenalectomy
and none showed any sign of malignancy. Swain et al. (1998) concluded
that AIMAH is a distinct and legitimate disease entity.

Doppman et al. (2000) reported the radiographic findings of 11 patients
with AIMAH and noted that the adrenal glands are often massive with
combined weights up to 300 g and individual nodules up to 5 cm in
diameter. One male patient reportedly had a brother with
surgically-proven AIMAH. The authors commented that the clinical
manifestations of Cushing syndrome are mild in many patients with AIMAH.

Nies et al. (2002) reported a family in which 3 female members had
clinically symptomatic AIMAH. Three deceased female family members were
reportedly affected. Although the father, who was determined to be an
obligate carrier, had no overt symptoms, his adrenal glands showed
nodular hyperplasia and he had impaired cortisol suppression on
dexamethasone administration. Nies et al. (2002) suggested autosomal
dominant inheritance.

Lee et al. (2005) reported 2 Asian sisters who developed AIMAH at ages
46 and 58 years, respectively. Both patients had typical Cushingoid
features, including moon facies, buffalo hump, and central obesity; 1
had purple striae. Both had increased serum cortisol and bilateral
adrenal masses, and both had meningiomas, which may or may not have been
related. Pituitary tumors were not present.

PATHOGENESIS

- Aberrant Hormone Receptors

Several groups have shown that cortisol hypersecretion in AIMAH can be
regulated by hormones other than ACTH via the ectopic expression or the
overactive eutopic expression of several membrane-bound hormone
receptors in the adrenal cortex. These include gastric inhibitory
polypeptide receptor (GIPR; 137241), various vasopressin receptors
(AVPR1A, 600821; AVPR1B, 600264; AVPR2; 300538), beta-adrenergic
receptors (see, e.g., ADRB1; 109630), the LH/human CG receptor (LHCGR;
152790), the serotonin 5-HT4 receptor (HTR4; 602164), and the
angiotensin receptor (AGTR1; 106165) (Christopoulos et al., 2005).

Hamet et al. (1987) reported a 41-year-old male with what they termed
'food-dependent Cushing syndrome.' Cortisol was low in the morning and
when the patient fasted, yet increased significantly after meals. Hamet
et al. (1987) postulated that a humoral factor induced by eating
stimulated the adrenal secretion of cortisol in this patient.
Independently, Lacroix et al. (1992) and Reznik et al. (1992) reported 2
women, aged 48 and 49 years, respectively, with AIMAH and food-dependent
Cushing syndrome. In both cases, ingestion of food resulted in increased
serum cortisol that could not be suppressed by dexamethasone. Detailed
studies showed abnormal responsiveness of the adrenal cells to
physiologic secretion of gastric inhibitory polypeptide (GIP; 137420).
De Herder et al. (1996) and Lebrethon et al. (1998) demonstrated that
food-dependent Cushing syndrome results from ectopic adrenal expression
of GIP receptors.

Lacroix et al. (1997) reported a 36-year-old woman with Cushing syndrome
due to AIMAH who had orthostatic hypotension. During upright posture,
the patient's cortisol and aldosterone levels were stimulated despite
suppression of ACTH and renin. Arginine vasopressin (AVP; 192340) was
found to increase plasma cortisol, aldosterone, and androgens in this
patient but not in controls. Following adrenalectomy, orthostatic
hypotension persisted; a prolonged vasoconstrictive response to AVP was
found in vitro in the patient's small arteries. Lacroix et al. (1997)
suggested altered adrenal and vascular responses of the AVP V1 receptor
(see 600821). Mune et al. (2002) found increased levels of AVPR1A mRNA
in adrenal tissue from 4 patients with AIMAH, suggesting that eutopic
V1A receptor overexpression is involved in the etiology. Miyamura et al.
(2002) reported a mother and son with AIMAH in whom AVP and
catecholamines promoted cortisol secretion. RT-PCR of adrenal tissue
from the mother showed abnormal expression of AVPR1B, AVPR2, and LHCGR,
none of which was observed in a normal control. In 2 sisters with AIMAH,
Lee et al. (2005) demonstrated that AVP promoted cortisol secretion
through overexpression of AVPR1A. In addition, RT-PCR analysis revealed
abnormal cDNA expression of AVPR1B and AVPR2, which are normally not
expressed in the adrenal gland.

Lacroix et al. (1997) reported a 56-year-old man with AIMAH who showed
increased serum cortisol when changing from a supine to upright posture
and in response to insulin-induced hypoglycemia, suggesting mediation by
a beta-adrenergic receptor. Treatment with propranolol was effective,
and the authors suggested that ectopic receptor expression led to
catecholamine-induced adrenal hyperplasia in this patient. Lacroix et
al. (1999) reported a woman with AIMAH that was clinically manifest
transiently during pregnancy. Studies showed that the cortisol secretion
was stimulated by luteinizing hormone (LH; 152780), HCG (118850), and by
drugs that activated 5HT-4 receptors. Long-term suppression of LH
secretion with leuprolide led to reversal of symptoms. Lacroix et al.
(1999) noted that the identification of ectopic adrenal receptors could
lead to medical treatment for such patients as alternatives to
adrenalectomy.

Cartier et al. (2003) reported overexpression of 5HT-4 receptors in
adrenal tissue from 4 of 6 patients with cisapride-responsive AIMAH.
Sequencing of the 5HT4 receptor gene in 2 patients did not reveal any
mutations.

Mircescu et al. (2000) found 1 or 2 abnormal hormone receptors in
adrenal tissue from all 6 patients with AIMAH who were studied. The
findings suggested that aberrant hormone receptors in adrenal tissue are
common in these patients.

In a review, Christopoulos et al. (2005) stated that most patients with
AIMAH, when screened, have been shown to have aberrant expression of
receptors in the adrenal gland resulting in increased cortisol
secretion; many patients show aberrant expression of more than 1
receptor. The authors suggested that dysregulation of tissue-specific
receptor expression may indicate a disruption of gene regulatory
elements in the early stages of embryogenesis since the pathology
involves the entire adrenal cortex.

MOLECULAR GENETICS

Fragoso et al. (2003) identified somatic heterozygous mutations in the
GNAS1 gene (139320.0009; 139320.0013) in adrenal tissue from 3 unrelated
patients with AIMAH. The mutations resulted in constitutive activation
of the G-protein. The mutations were not present in peripheral blood,
and none of the patients had signs of McCune-Albright syndrome. Fragoso
et al. (2003) discussed whether the patients could be considered part of
the spectrum of McCune-Albright syndrome or whether they represent
isolated cases of AIMAH associated with somatic mutations.

By cDNA microarray analysis of adrenal tissue from 8 AIMAH patients,
Bourdeau et al. (2004) found upregulation of several genes involved in
transcription, chromatin remodeling, and cell cycle and adhesion. There
were differences in gene expression between those with and without
GIP-dependent AIMAH, confirming clinical heterogeneity and suggesting
distinct diagnostic subgroups.

Bourdeau et al. (2006) did not identify mutations in the PRKAR1A gene in
14 unrelated patients with sporadic AIMAH. However, 91% of the tumor
tissue samples showed somatic loss of heterozygosity (LOH) of chromosome
2p16, where Carney complex-2 (CNC2; 605244) has been mapped, and 73% of
tissue samples showed somatic LOH of 17q22-q24, where the PRKAR1A gene
is located. Total protein kinase A activity was higher in AIMAH tissue
compared to normal adrenal glands.

*FIELD* RF
1. Aiba, M.; Hirayama, A.; Iri, H.; Ito, Y.; Fujimoto, Y.; Mabuchi,
G.; Murai, M.; Tazaki, H.; Maruyama, H.; Saruta, T.; Suda, T.; Demura,
H.: Adrenocorticotropic hormone-independent bilateral adrenocortical
macronodular hyperplasia as a distinct subtype of Cushing's syndrome:
enzyme histochemical and ultrastructural study of four cases with
a review of the literature. Am. J. Clin. Path. 96: 334-340, 1991.

2. Bourdeau, I.; Antonini, S. R.; Lacroix, A.; Kirschner, L. S.; Matyakhina,
L.; Lorang, D.; Libutti, S. K.; Stratakis, C. A.: Gene array analysis
of macronodular adrenal hyperplasia confirms clinical heterogeneity
and identifies several candidate genes as molecular mediators. Oncogene 23:
1575-1585, 2004.

3. Bourdeau, I.; Matyakhina, L.; Stergiopoulos, S. G.; Sandrini, F.;
Boikos, S.; Stratakis, C. A.: 17q22-24 chromosomal losses and alterations
of protein kinase A subunit expression and activity in adrenocorticotropin-independent
macronodular adrenal hyperplasia. J. Clin. Endocr. Metab. 91: 3626-3632,
2006.

4. Cartier, D.; Lihrmann, I.; Parmentier, F.; Bastard, C.; Bertherat,
J.; Caron, P.; Kuhn, J.-M.; Lacroix, A.; Tabarin, A.; Young, J.; Vaudry,
H.; Lefebvre, H.: Overexpression of serotonin-4 receptors in cisapride-responsive
adrenocorticotropin-independent bilateral macronodular adrenal hyperplasia
causing Cushing's syndrome. J. Clin. Endocr. Metab. 88: 248-254,
2003.

5. Christopoulos, S.; Bourdeau, I.; Lacroix, A.: Clinical and subclinical
ACTH-independent macronodular adrenal hyperplasia and aberrant hormone
receptors. Horm. Res. 64: 119-131, 2005.

6. de Herder, W. W.; Hofland, L. J.; Usdin, T. B.; de Jong, F. H.;
Uitterlinden, P.; van Koetsveld, P.; Mezey, E.; Bonner, T. I.; Bonjer,
H. J.; Lamberts, S. W. J.: Food-dependent Cushing's syndrome resulting
from abundant expression of gastric inhibitory polypeptide receptors
in adrenal adenoma cells. J. Clin. Endocr. Metab. 81: 3168-3172,
1996.

7. Doppman, J. L.; Chrousos, G. P.; Papanicolaou, D. A.; Stratakis,
C. A.; Alexander, H. R.; Nieman, L. K.: Adrenocorticotropin-independent
macronodular adrenal hyperplasia: an uncommon cause of primary adrenal
hypercortisolism. Radiology 216: 797-802, 2000.

8. Findlay, J. C.; Sheeler, L. R.; Engeland, W. C.; Aron, D. C.:
Familial adrenocorticotropin-independent Cushing's syndrome with bilateral
macronodular adrenal hyperplasia. J. Clin. Endocr. Metab. 76: 189-191,
1993.

9. Fragoso, M. C. B. V.; Domenice, S.; Latronico, A. C.; Martin, R.
M.; Pereira, M. A. A.; Zerbini, M. C. N.; Lucon, A. M.; Mendonca,
B. B.: Cushing's syndrome secondary to adrenocorticotropin-independent
macronodular adrenocortical hyperplasia due to activating mutations
of GNAS1 gene. J. Clin. Endocr. Metab. 88: 2147-2151, 2003.

10. Hamet, P.; Larochelle, P.; Franks, D. J.; Cartier, P.; Bolte,
E.: Cushing syndrome with food-dependent periodic hormonogenesis. Clin.
Invest. Med. 10: 530-533, 1987.

11. Kirschner, M. A.; Powell, R. D., Jr.; Lipsett, M. B.: Cushing's
syndrome: nodular cortical hyperplasia of adrenal glands with clinical
and pathological features suggesting adrenocortical tumor. J. Clin.
Endocr. 24: 947-955, 1964.

12. Koizumi, S.; Beniko, M.; Ikota, A.; Mizumoto, H.; Matsuya, K.;
Matsuda, A.; Sakuma, S.; Mashio, Y.; Kunita, H.; Okamoto, K.; Sasano,
H.: Adrenocorticotropic hormone-independent bilateral adrenocortical
macronodular hyperplasia: a case report and immunohistochemical studies. Endocr.
J. 41: 429-435, 1994.

13. Lacroix, A.; Bolte, E.; Tremblay, J.; Dupre, J.; Poitras, P.;
Fournier, H.; Garon, J.; Garrel, D.; Bayard, F.; Taillefer, R.; Flanagan,
R. J.; Hamet, P.: Gastric inhibitory polypeptide-dependent cortisol
hypersecretion--a new cause of Cushing's syndrome. New Eng. J. Med. 327:
974-980, 1992.

14. Lacroix, A.; Hamet, P.; Boutin, J.-M.: Leuprolide acetate therapy
in luteinizing hormone-dependent Cushing's syndrome. New Eng. J.
Med. 341: 1577-1581, 1999.

15. Lacroix, A.; Tremblay, J.; Rousseau, G.; Bouvier, M.; Hamet, P.
: Propranolol therapy for ectopic beta-adrenergic receptors in adrenal
Cushing's syndrome. New Eng. J. Med. 337: 1429-1434, 1997.

16. Lacroix, A.; Tremblay, J.; Touyz, R. M.; Deng, L. Y.; Lariviere,
R.; Cusson, J. R.; Schiffrin, E. L.; Hamet, P.: Abnormal adrenal
and vascular responses to vasopressin mediated by a V1-vasopressin
receptor in a patient with adrenocorticotropin-independent macronodular
adrenal hyperplasia, Cushing's syndrome, and orthostatic hypotension. J.
Clin. Endocr. Metab. 82: 2414-2422, 1997.

17. Lebrethon, M. C.; Avallet, O.; Reznik, Y.; Archambeaud, F.; Combes,
J.; Usdin, T. B.; Narboni, G.; Mahoudeau, J.; Saez, J. M.: Food-dependent
Cushing's syndrome: characterization and functional role of gastric
inhibitory polypeptide receptor in the adrenals of three patients. J.
Clin. Endocr. Metab. 83: 4514-4519, 1998.

18. Lee, S.; Hwang, R.; Lee, J.; Rhee, Y.; Kim, D. J.; Chung, U.;
Lim, S.-K.: Ectopic expression of vasopressin V1b and V2 receptors
in the adrenal glands of familial ACTH-independent macronodular adrenal
hyperplasia. Clin. Endocr. 63: 625-630, 2005.

19. Minami, S.; Sugihara, H.; Sato, J.; Tatsukuchi, A.; Sugisaki,
Y.; Sasano, H.; Wakabayashi, I.: ACTH independent Cushing's syndrome
occurring in siblings. Clin. Endocr. 44: 483-488, 1996.

20. Mircescu, H.; Jilwan, J.; N'Diaye, N.; Bourdeau, I.; Tremblay,
J.; Hamet, P.; Lacroix, A.: Are ectopic or abnormal membrane hormone
receptors frequently present in adrenal Cushing's syndrome? J. Clin.
Endocr. Metab. 85: 3531-3536, 2000.

21. Miyamura, N.; Taguchi, T.; Murata, Y.; Taketa, K.; Iwashita, S.;
Matsumoto, K.; Nishikawa, T.; Toyonaga, T.; Sakakida, M.; Araki, E.
: Inherited adrenocorticotropin-independent macronodular adrenal hyperplasia
with abnormal cortisol secretion by vasopressin and catecholamines:
detection of the aberrant hormone receptors on adrenal gland. Endocrine 19:
319-326, 2002.

22. Morioka, M.; Ohashi, Y.; Watanabe, H.; Komatsu, F.; Jin, T.-X.;
Suyama, B.; Tanaka, H.: ACTH-independent macronodular adrenocortical
hyperplasia (AIMAH): report of two cases and the analysis of steroidogenic
activity in adrenal nodules. Endocr. J. 44: 65-72, 1997.

23. Mune, T.; Murase, H.; Yamakita, N.; Fukuda, T.; Murayama, M.;
Miura, A.; Suwa, T.; Hanafusa, J.; Daido, H.; Morita, H.; Yasuda,
K.: Eutopic overexpression of vasopressin V1a receptor in adrenocorticotropin-independent
macronodular adrenal hyperplasia. J. Clin. Endocr. Metab. 87: 5706-5713,
2002.

24. Nies, C.; Bartsch, D. K.; Ehlenz, K.; Wild, A.; Langer, P.; Fleischhacker,
S.; Rothmund, M.: Familial ACTH-independent Cushing's syndrome with
bilateral macronodular adrenal hyperplasia clinically affecting only
female family members. Exp. Clin. Endocr. Diabetes 110: 277-283,
2002.

25. Reznik, Y.; Allali-Zerah, V.; Chayvialle, J. A.; Leroyer, R.;
Leymarie, P.; Travert, G.; Lebrethon, M.-C.; Budi, I.; Balliere, A.-M.;
Mahoudeau, J.: Food-dependent Cushing's syndrome mediated by aberrant
adrenal sensitivity to gastric inhibitory polypeptide. New Eng. J.
Med. 327: 981-986, 1992.

26. Sasano, H.; Suzuki, T.; Nagura, H.: ACTH-independent macronodular
adrenocortical hyperplasia: immunohistochemical and in situ hybridization
studies of steroidogenic enzymes. Mod. Path. 7: 215-219, 1994.

27. Swain, J. M.; Grant, C. S.; Schlinkert, R. T.; Thompson, G. B.;
van Heerden, J. A.; Lloyd, R. V.; Young, W. F.: Corticotropin-independent
macronodular adrenal hyperplasia: a clinicopathologic correlation. Arch.
Surg. 133: 541-546, 1998.

*FIELD* CS
INHERITANCE:
Isolated cases

GROWTH:
[Weight];
Truncal obesity

HEAD AND NECK:
[Face];
Round face

CARDIOVASCULAR:
[Vascular];
Hypertension

SKELETAL:
Decreased bone mineral density;
Osteoporosis;
[Spine];
Kyphosis

SKIN, NAILS, HAIR:
[Skin];
Thin skin;
Striae;
Easy bruising

MUSCLE, SOFT TISSUE:
Muscle wasting

NEUROLOGIC:
[Central nervous system];
Cognitive decline;
[Behavioral/psychiatric manifestations];
Mood changes;
Depression;
Agitation;
Anxiety;
Psychosis

ENDOCRINE FEATURES:
Cushing syndrome;
ACTH-independent hypercortisolemia;
Enlarged adrenal glands;
Macronodular adrenal hyperplasia

NEOPLASIA:
No progression to cancer

LABORATORY ABNORMALITIES:
Increased serum cortisol;
Cortisol does not decrease on dexamethasone suppression test;
Decreased serum ACTH

MISCELLANEOUS:
Adult onset (40 to 60 years old);
Variable expressivity, some patients may be clinically asymptomatic

MOLECULAR BASIS:
Caused by somatic mutation in the GNAS gene (GNAS1, 139320.0009)

*FIELD* CN
Cassandra L. Kniffin - revised: 10/17/2006

*FIELD* CD
Cassandra L. Kniffin: 10/12/2006

*FIELD* ED
joanna: 12/05/2008
joanna: 12/5/2008
joanna: 5/23/2007
ckniffin: 10/17/2006

*FIELD* CN
Cassandra L. Kniffin - reorganized: 10/18/2006
Cassandra L. Kniffin - updated: 10/17/2006
Victor A. McKusick - updated: 6/30/2006
John A. Phillips, III - updated: 4/8/2003
John A. Phillips, III - updated: 3/16/2001
John A. Phillips, III - updated: 10/30/1997

*FIELD* CD
Victor A. McKusick: 6/3/1986

*FIELD* ED
terry: 09/20/2007
carol: 10/18/2006
ckniffin: 10/17/2006
alopez: 7/5/2006
terry: 6/30/2006
ckniffin: 8/3/2005
alopez: 2/12/2004
tkritzer: 4/14/2003
tkritzer: 4/9/2003
terry: 4/8/2003
alopez: 3/16/2001
alopez: 8/30/1999
dholmes: 10/30/1997
dholmes: 10/28/1997
dholmes: 10/15/1997
mark: 12/26/1996
terry: 12/16/1996
mimadm: 2/19/1994
carol: 7/6/1993
carol: 7/2/1993
carol: 4/21/1992
supermim: 3/16/1992
supermim: 3/20/1990

MIM 603233
*RECORD*
*FIELD* NO
603233
*FIELD* TI
#603233 PSEUDOHYPOPARATHYROIDISM, TYPE IB; PHP1B
;;PHP IB
*FIELD* TX
A number sign (#) is used with this entry because
read morepseudohypoparathyroidism type Ib (PHP Ib) is caused by deletions in the
differentially methylated region (DMR) of the GNAS (139320) locus. One
deletion (139320.0031) removes the entire NESP55 DMR and exons 3 and 4
of the antisense transcript of the GNAS gene (GNASAS; 610540.0001).
PHP1B can also result from deletion in the STX gene (603666), a
long-range control element of methylation at the GNAS locus. These
methylation and imprinting defects result in the absence of expression
of the maternal Gs-alpha isoform.

DESCRIPTION

Pseudohypoparathyroidism refers to a heterogeneous group of disorders
characterized by resistance to parathyroid hormone (PTH; 168450).
Pseudohypoparathyroidism type Ib is characterized clinically by isolated
renal PTH resistance manifest as hypocalcemia, hyperphosphatemia, and
increased serum PTH. Biochemical studies show a decreased response of
urinary cAMP to exogenous PTH, but normal Gs activity in erythrocytes
because the defect is restricted to renal tubule cells. In contrast to
the findings in PHP Ia, patients with PHP Ib usually lack the physical
characteristics of Albright hereditary osteodystrophy (AHO) and
typically show no other endocrine abnormalities, although resistance to
thyroid-stimulating hormone (TSH; 188540) has been reported in PHP Ib
(Levine et al., 1983, Heinsimer et al., 1984). However, patients with
PHP Ib may rarely show some features of AHO (Mariot et al., 2008).

For a general phenotypic description, classification, and a discussion
of molecular genetics of pseudohypoparathyroidism, see PHP1A (103580).

CLINICAL FEATURES

Frame et al. (1972) reported 2 patients with renal resistance to
parathyroid hormone characterized by hypocalcemia and hyperphosphatemia
and associated with osteitis fibrosa cystica. Frame et al. (1972)
postulated that renal PTH resistance was the primary defect and that a
secondary hyperparathyroid state occurred to cause the skeletal changes
of osteitis fibrosa. The calcemic effect of both endogenous and
exogenous PTH was blunted by the presence of hyperphosphatemia.

Farfel and Bourne (1980) reported a family in which 5 patients with PHP
type I had no signs of AHO and showed normal erythrocyte Gs protein
activity.

Kidd et al. (1980) described 3 patients with PHP and bone findings
consistent with hyperparathyroidism, including elevated serum alkaline
phosphatase and subperiosteal resorption on skeletal films. None of the
patients had AHO features of short stature, brachydactyly, or mental
deficiency. The authors commented on the paradoxic occurrence of
hyperparathyroid bone disease in PHP, and suggested that this was an
extreme of a clinical spectrum of skeletal responsiveness to excess PTH.

Heinsimer et al. (1984) found that beta-adrenergic agonist-specific
binding properties of red cell membranes were 45% of controls in 5
patients with PHP Ia and 97% of controls in 5 patients with PHP Ib.
Further studies were consistent with a single defect causing deficient
hormone receptor-nucleotide complex formation and adenylate cyclase
activity in PHP Ia, whereas the biochemical lesion(s) appeared not to
affect the complex formation in PHP Ib.

Liu et al. (2000) studied 13 patients with PHP Ib, all of whom initially
presented with hypocalcemia, hyperphosphatemia, and elevated serum PTH
levels in the absence of renal insufficiency or any of the clinical or
radiologic features of Albright hereditary osteodystrophy. Serum
thyrotropin (TSH), thyroxine (T4), free T4, triiodothyronine (T3), and
25-hydroxyvitamin D levels were normal in all patients. Two patients had
overt osteitis fibrosa cystica at presentation that resolved with oral
calcium and vitamin D therapy. Two other patients had at least 1 other
affected family member.

- Clinical Variability

De Nanclares et al. (2007) reported 4 unrelated patients who were
thought to have PHP1A because of PTH and TSH resistance and mild
features of Albright hereditary osteodystrophy. Two patients showed
decreased G-alpha activity in erythrocytes. However, genetic analysis
did not reveal germline point mutations in the GNAS gene in any of the
patients; instead, all were found to have GNAS methylation defects,
which are usually associated with PHP1B. Furthermore, 1 of the patients
with normal G-alpha activity was found to have a 3.0-kb STX16 deletion
(603666.0001), which is usually associated with PHP1B. The findings
suggested that there may be an overlap between the molecular and
clinical features of PHP1A and PHP1B, and that methylation defects may
manifest as mild PHP1A.

Mariot et al. (2008) reported a girl with obvious Albright
osteodystrophy features, PTH resistance, and normal G-alpha-s
bioactivity in red blood cells (PHP Ib), yet no loss-of-function
mutation in the GNAS coding sequence. The patient had broad methylation
changes at all differentially methylated regions of the GNAS gene
leading to a paternal epigenotype on both alleles. Mariot et al. (2008)
suggested that Albright osteodystrophy features are not specific to PHP
Ia, and concluded that the decreased expression of G-alpha-s due to GNAS
epimutations is not restricted to the renal tubule but may affect
nonimprinted tissues like bone. PHP1B should be considered a
heterogeneous disorder that should lead to the study of GNAS epigenotype
in patients with PHP and no mutation in GNAS exons 1 through 13,
regardless of their physical features.

Lecumberri et al. (2010) reported a patient with PHP1B who had paternal
uniparental isodisomy of chromosome 20q. However, he also had mild
features of AHO and cognitive impairment, suggestive of PHP1A.
Erythrocyte Gs-alpha activity was slightly decreased at 81% of control
values.

INHERITANCE

PHP Ib is most often a sporadic disorder, but sex-influenced autosomal
dominant inheritance has been reported. In familial cases, PTH
resistance in PHP1B develops only after maternal inheritance of the
molecular defect, whereas paternal inheritance of the defect is not
associated with PTH resistance. This is the same situation as in PHP1A
and PPHP (612463) (Mantovani and Spada, 2006).

By analysis of 4 families with PHP1B, Juppner et al. (1998) showed that
the genetic defect is imprinted paternally, meaning that the disorder
only occurs if the defective gene is inherited from a female carrier.
Offspring of an affected father were unaffected.

Lecumberri et al. (2010) reported 2 unrelated families in which PHP1A
and PHP1B occurred coincidentally within different branches of each of
the families. In the first family, 2 sibs with PHP1A inherited a GNAS
mutation from their affected mother. A man from another branch of the
family with PHP1B was found to have paternal uniparental isodisomy of
chromosome 20q, with presumed lack of expression of the maternal allele.
The diagnosis was confusing in this patient before molecular analysis
because he had mild features of AHO and cognitive impairment, suggestive
of PHP1A. Genetic analysis confirmed that he did not have a germline
GNAS mutation. In the second family, 1 individual with PHP1A had a GNAS
mutation (139320.0011) inherited from his mother, and a second cousin
had PHP1B with an epigenetic defect at the GNAS locus. Lecumberri et al.
(2010) emphasized the importance of molecular diagnosis for proper
genetic counseling.

MAPPING

Juppner et al. (1998) performed a genomewide search using genomic DNA
from 4 kindreds with PHP Ib and established linkage to a small telomeric
region on chromosome 20q (20q13.3), which contains the GNAS1 gene.
However, no gross deletions or rearrangements of the GNAS gene were
detected by Southern blot analysis. Juppner et al. (1998) postulated
that mutations in a promoter or enhancer of the GNAS gene could explain
the kidney-specific resistance toward PTH and the resulting hypocalcemia
in patients with PHP Ib.

PATHOGENESIS

PHP Ib is caused by methylation and imprinting defects of the maternal
GNAS gene with subsequent loss of expression of the Gs-alpha protein in
renal proximal tubules. Since only the maternal allele, and not the
paternal allele, is expressed in renal tubule cells, the defect results
in complete lack of Gs-alpha activity in these cells. Patients with
PHP1B do not have mutations within GNAS exons that encode the Gs-alpha
isoform (Mantovani and Spada, 2006; Bastepe, 2008).

Hayward et al. (1998) found that a splice variant of the GNAS1 gene,
XL-alpha-s (Kehlenbach et al., 1994), is transcribed from the paternal
allele only, providing further confirmation that the chromosomal region
that comprises the GNAS locus undergoes imprinting. The authors noted
that if GNAS transcripts are derived, at least in some tissues or cells,
from only 1 parental allele, mutations in a promoter or enhancer of the
GNAS gene could explain the kidney-specific resistance toward PTH and
hypocalcemia in patients with PHP Ib.

Zheng et al. (2001) noted that kindred studies in PHP Ib suggested that
the cause of isolated renal resistance to PTH is a specific decrease in
Gs-alpha activity in renal proximal tubules due to paternal imprinting
of Gs-alpha. However, using RT-PCR assays, Zheng et al. (2001) found
that Gs-alpha transcripts were biallelically expressed in human fetal
kidney cortex. The results were in contrast to the parent-specific
expression of exon 1A and XL-alpha-s (paternal) or NESP (maternal)
mRNAs. The authors concluded that PHP1B is not due to paternal
imprinting of Gs-alpha within the renal proximal tubule, and proposed
that maternal inheritance of abnormal imprinting of upstream GNAS1 exons
might be responsible for PHP1B. However, Liu et al. (2000) stated that
Gs-alpha is biallelically expressed in all fetal tissues.

Using hot-stop PCR analysis on total RNA from 6 normal human thyroid
specimens, Liu et al. (2003) showed that the majority of the Gs-alpha
mRNA (72 +/- 3%) was derived from the maternal allele. Patients with PHP
Ib have an imprinting defect of the Gs-alpha gene resulting in both
alleles having a paternal epigenotype, which would lead to a more
moderate level of thyroid-specific Gs-alpha deficiency. The authors
found evidence of borderline TSH resistance in 10 of 22 PHP Ib patients.
The authors concluded that their study provided further evidence for
tissue-specific imprinting of Gs-alpha in humans with a potential
mechanism for borderline TSH resistance in some patients with PHP Ib.

MOLECULAR GENETICS

Liu et al. (2000) showed that the human GNAS exon 1A promoter region,
located 2.5 kb upstream from exon 1 of the Gs-alpha transcript, is
within a differentially methylated region (DMR) and is imprinted in a
manner similar to that in the mouse: the region is normally methylated
on the maternal allele and unmethylated on the paternal allele. In 13
patients with PHP1B, Liu et al. (2000) found that the exon 1A region of
GNAS was unmethylated on both alleles, consistent with an imprinting
defect. The authors proposed that the exon 1A DMR is important for
establishing or maintaining tissue-specific imprinting of Gs-alpha, and
that paternal-specific imprinting of exon 1A on both alleles would
reduce Gs-alpha expression specifically in renal proximal tubules, which
only express Gs-alpha from the maternal allele.

In affected individuals in 9 unrelated kindreds with PHP Ib, Bastepe et
al. (2001) found loss of methylation at GNAS1 exon 1A, which they called
exon A/B. Further genetic analysis of the largest PHP Ib kindred
revealed that the mutation leading to the disease, and presumably to the
methylation defect at exon 1A, most likely resided in untranscribed
GNAS1 sequences 56 kb centromeric to exon 1A.

Bastepe et al. (2001) reported a patient with PHP Ib who had paternal
uniparental isodisomy of chromosome 20q and lacked the maternal-specific
methylation pattern within GNAS1. There was no impairment of Gs-alpha
activity in fibroblasts. The authors suggested that loss of the maternal
GNAS1 gene and the resulting epigenetic changes alone could lead to PTH
resistance in the proximal renal tubules.

Jan de Beur et al. (2003) analyzed allelic expression and epigenetic
methylation of CpG islands within exon 1A of GNAS1 in patients with
sporadic PHP Ib and in affected and unaffected individuals from 5
multigenerational kindreds with familial PHP Ib. All subjects with
PTH-resistance showed loss of methylation of the exon 1A region on the
maternal GNAS1 allele and/or biallelic expression of exon 1A-containing
transcripts, consistent with an imprinting defect. Paternal transmission
of the disease-associated haplotype was associated with normal patterns
of GNAS1 methylation and PTH responsiveness. In 1 kindred, affected and
unaffected sibs had inherited the same GNAS1 allele from their affected
mother, indicating dissociation between the genetic and epigenetic GNAS1
defects. The absence of the epigenetic defect in subjects who inherited
a defective maternal GNAS1 allele suggested that the genetic mutation
may be incompletely penetrant and indicated that the epigenetic defect,
not the genetic mutation, leads to renal resistance to PTH in PHP Ib.

In affected members and obligate carriers of 12 unrelated families with
PHP Ib, Bastepe et al. (2003) identified a heterozygous 3-kb
microdeletion located approximately 220 kb centromeric of exon 1A of the
GNAS gene. The deletion also included 3 of 8 exons encoding syntaxin-16
(603666.0001). However, Bastepe et al. (2003) considered the involvement
of STX16 in the molecular pathogenesis of PHP Ib unlikely. They
postulated that the microdeletion disrupts a putative cis-acting element
required for methylation at exon 1A in the GNAS locus, and that this
genetic defect underlies the pathogenesis of PHP Ib. Four of 16
apparently sporadic patients also had the deletion. Affected individuals
with the microdeletion showed loss of exon 1A methylation, but no other
epigenetic abnormalities. In all examined cases, the deletion was
inherited from the mother, consistent with the observation that PHP Ib
develops only in offspring of female obligate carriers.

In all affected individuals and obligate carriers in a large kindred
with PHP Ib, Linglart et al. (2005) identified a 4.4-kb microdeletion
overlapping with a region of the 3-kb deletion identified by Bastepe et
al. (2003). Affected individuals exhibited loss of methylation only at
GNAS exon A/B. Linglart et al. (2005) concluded that PHP Ib comprises at
least 2 distinct conditions sharing the same clinical phenotype: one
associated with the loss of exon A/B methylation alone and, in most
cases, with a heterozygous microdeletion in the STX16 region, and the
other associated with methylation abnormalities at all GNAS DMRs,
including the DMR at exon A/B.

Among 20 unrelated PHP Ib probands, Liu et al. (2005) found that all had
loss of GNAS exon 1A imprinting (a paternal epigenotype on both
alleles). All 5 probands with familial disease had a deletion mutation
within the closely linked STX16 gene and a GNAS imprinting defect
involving only the exon 1A region. In contrast, the STX16 mutation was
absent in all sporadic cases. The majority of these patients had
abnormal imprinting of the more upstream regions in addition to the exon
1A imprinting defect, with 8 of 15 having a paternal epigenotype on both
alleles throughout the GNAS locus. In virtually all cases, the
imprinting status of the paternally methylated NESP55 and maternally
methylated NESPAS/XL-alpha-s promoters was concordant, suggesting that
their imprinting may be coregulated, whereas the imprinting of the
NESPAS/XL-alpha-s promoter region and XL-alpha-s first exon was not
always concordant, even though they are closely linked and lie within
the same DMR. The authors concluded that familial and sporadic forms of
PHP Ib have distinct GNAS imprinting patterns that occur through
different defects in the imprinting mechanism.

In affected members of 2 unrelated kindreds with PHP Ib who lacked STX16
mutations or deletions, Bastepe et al. (2005) identified heterozygosity
for a 4.7-kb deletion that removed the DMR of the GNAS gene encompassing
the NESP55 region and exons 3 and 4 of the GNAS antisense transcript
(GNASAS) (see 139320.0031 and 610540.0001). When inherited from a
female, the deletion abolished all maternal GNAS imprints and
derepressed maternally silenced transcripts, suggesting that the deleted
region contains a cis-acting element that controls imprinting of the
maternal GNAS allele.

Mantovani et al. (2007) studied GNAS differential methylation and STX16
microdeletions in genomic DNA from 10 Italian patients with sporadic PHP
Ib. Molecular analysis showed GNAS cluster imprinting defects in all of
the patients, only one of whom had a de novo STX16 deletion. All of the
patients were resistant to TSH, and all but 1 maintained normal
responsiveness to GHRH.

- Variability

In 3 brothers with a clinical diagnosis of PHP Ib, Wu et al. (2001)
identified heterozygosity for a 3-bp in-frame deletion in exon 13 of the
GNAS gene (ile382del; 139320.0033), resulting in an amino acid change in
the C terminus of the protein. The boys had hypocalcemia, increased
serum PTH, lack of cAMP response to PTH, and normal erythrocyte Gs
activity. When expressed in vitro, the mutant Gs-alpha was unable to
interact with the PTH receptor (PTHR1; 168468) but showed normal
coupling to other coexpressed heptahelical receptors. The findings were
consistent with isolated PTH resistance. Although the mother and
maternal grandfather also carried the mutation, they had no evidence of
PTH resistance, consistent with a model of paternal imprinting of the
locus.

Linglart et al. (2002) identified a heterozygous nonsense mutation in
exon 13 of the GNAS gene (Y391X; 139320.0036) in a girl with a clinical
diagnosis of PHP1C (612462). She had PTH resistance, multiple hormone
resistance, and the physical features of Albright hereditary
osteodystrophy. Biochemical studies showed decreased cAMP response to
PTH and normal erythrocyte cAMP activity. The mutation terminated the
Gs-alpha isoform only 4 amino acids before the wildtype stop codon, and
was shown to interrupt receptor coupling while retaining adenylyl
cyclase activity. The retention of erythrocyte Gs-alpha activity and
lack of cAMP response to PTH associated with a mutation in the
C-terminal receptor-coupling domain of Gs-alpha was similar to that
observed in the patient reported by Wu et al. (2001).

HISTORY

Although the selective resistance toward a single hormone (PTH) in PHP
Ib suggested inactivating mutations in the receptor for PTH, a
considerable number of PHP Ib patients were found to have no mutations
in the coding or noncoding exons of the PTHR1 (168468) gene (Schipani et
al., 1995; Bettoun et al., 1997). Furthermore, analysis of PTHR1 mRNA
provided no evidence for splice variants that could have offered an
explanation for the disorder (Suarez et al., 1995). Inactivating
mutations in the PTHR1 gene were found in patients with the Blomstrand
type of lethal metaphyseal chondrodysplasia (215045).

Fukumoto et al. (1996) reported reduced expression of the 2.4-kb
PTH/PTHrP receptor mRNA in 2 patients with PHP type Ib and higher levels
in a third. Reduced expression was also reported by Suarez et al.
(1995). Fukumoto et al. (1996) suggested that while lower levels of
PTH/PTHrP receptor transcript may explain the resistance to PTH in some
PHP type Ib patients, this cannot be a general mechanism.

Jan de Beur et al. (2000) used polymorphic markers in or near the genes
encoding PTH and its receptors to perform linkage analysis between these
loci and PHP1B. They found no linkage between the PTH gene or the PTH
receptor genes and PHP1B.

*FIELD* RF
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*FIELD* CS
INHERITANCE:
Autosomal dominant

SKELETAL:
Osteitis fibrosa cystica due to elevated parathyroid hormone (PTH)
(subset of patients)

ENDOCRINE FEATURES:
Renal resistance to PTH;
Pseudohypoparathyroidism

LABORATORY ABNORMALITIES:
Elevated serum PTH;
Hypocalcemia;
Hyperphosphatemia;
Normal erythrocyte Gs activity;
Low urinary cyclic AMP response to PTH administration

MISCELLANEOUS:
Many cases result from de novo mutations;
Endocrine abnormalities confined to kidney;
Typically no physical features of Albright hereditary osteodystrophy
(AHO);
Features of AHO may rarely be observed, including brachydactyly, short
metacarpals, and obesity (see 103580);
Associated with imprinting and epigenetic defects in the G-protein,
alpha-stimulating 1 gene (GNAS1, 139320);
See also pseudohypoparathyroidism type Ia (PHP1A, 103580)

MOLECULAR BASIS:
Caused by mutation in the GNAS complex locus gene (GNAS, 139320.0031);
Caused by mutation in the GNAS complex locus, antisense transcript
(GNASAS, 610540.0001);
Caused by mutation in the syntaxin 16 gene (STX16, 603666.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 5/18/2009
Cassandra L. Kniffin - updated: 12/15/2008

*FIELD* CD
Cassandra L. Kniffin: 8/25/2003

*FIELD* ED
joanna: 05/25/2012
joanna: 5/19/2011
ckniffin: 5/18/2009
joanna: 12/30/2008
ckniffin: 12/15/2008
ckniffin: 8/25/2003

*FIELD* CN
Cassandra L. Kniffin - updated: 5/28/2010
Cassandra L. Kniffin - updated: 2/5/2009
John A. Phillips, III - updated: 3/21/2008
George E. Tiller - updated: 10/31/2007
Marla J. F. O'Neill - updated: 11/8/2006
John A. Phillips, III - updated: 7/8/2005
Victor A. McKusick - updated: 3/16/2005
Cassandra L. Kniffin - updated: 11/10/2003
Cassandra L. Kniffin - reorganized: 8/27/2003
Victor A. McKusick - updated: 8/11/2003
Victor A. McKusick - updated: 5/9/2003
John A. Phillips, III - updated: 3/22/2002
Victor A. McKusick - updated: 6/15/2001
John A. Phillips, III - updated: 2/12/2001

*FIELD* CD
Victor A. McKusick: 10/28/1998

*FIELD* ED
terry: 03/14/2013
wwang: 6/2/2010
ckniffin: 5/28/2010
ckniffin: 5/18/2009
alopez: 4/24/2009
wwang: 2/10/2009
ckniffin: 2/5/2009
carol: 12/19/2008
ckniffin: 12/15/2008
carol: 3/21/2008
alopez: 11/5/2007
alopez: 11/2/2007
terry: 10/31/2007
carol: 6/29/2007
wwang: 11/8/2006
mgross: 11/1/2006
alopez: 7/8/2005
wwang: 6/27/2005
carol: 6/24/2005
carol: 3/16/2005
tkritzer: 11/17/2003
ckniffin: 11/10/2003
carol: 8/27/2003
ckniffin: 8/22/2003
tkritzer: 8/15/2003
terry: 8/11/2003
carol: 5/13/2003
tkritzer: 5/13/2003
terry: 5/9/2003
alopez: 10/10/2002
alopez: 3/22/2002
cwells: 6/27/2001
terry: 6/15/2001
mgross: 3/1/2001
terry: 2/12/2001
carol: 12/13/1998
carol: 11/13/1998
dkim: 11/13/1998
carol: 10/29/1998

MIM 612462
*RECORD*
*FIELD* NO
612462
*FIELD* TI
#612462 PSEUDOHYPOPARATHYROIDISM, TYPE IC; PHP1C
;;PHP IC
*FIELD* TX
A number sign (#) is used with this entry because a subset of patients
read morewith a diagnosis of pseudohypoparathyroidism type Ic (PHP1C) have been
found to carry a heterozygous mutation on the maternal allele of the
GNAS gene (139320) on chromosome 20q13.

Because the phenotype of PHP Ic is essentially identical to that of PHP
Ia (103580), except for retained erythrocyte Gs activity in PHP Ic which
may result from the location of the mutation within the GNAS gene, it is
unclear whether PHP Ic represents a subgroup of PHP Ia or whether it
constitutes a distinct entity (Bastepe, 2008).

For a general description, classification, and discussion of the
genetics of pseudohypoparathyroidism (PHP), see PHP1A (103580).

DESCRIPTION

Pseudohypoparathyroidism type Ic (PHP1C) is characterized by resistance
to parathyroid hormone (PTH; 168450) as well as to other hormones. It is
associated with a constellation of physical features referred to as
Albright hereditary osteodystrophy (AHO), which includes short stature,
obesity, round facies, subcutaneous ossifications, brachydactyly, and
other skeletal anomalies. Some patients have mental retardation.
Laboratory studies in patients with PHP Ic show a decreased cellular
cyclic AMP (cAMP) response to infused PTH, but no defect in activity of
the erythrocyte Gs protein (Mantovani and Spada, 2006).

CLINICAL FEATURES

Farfel et al. (1981) reported a family in which several affected
individuals had classic PHP type I, including PTH-resistance,
hypothyroidism, and skeletal abnormalities such as short stature and
brachydactyly. There was a decreased urinary cAMP response to PTH, but
normal erythrocyte activity of N-protein, a receptor-cyclase coupling
component. Farfel et al. (1981) postulated a defect distal to the PTH
receptor in these families.

Linglart et al. (2002) reported a girl with pseudohypoparathyroidism,
multiple hormonal resistance, and AHO, but normal erythrocyte Gs
activity. The phenotype was referred to as PHP type Ic.

Thiele et al. (2011) reported 5 patients from 4 unrelated families with
a diagnosis of PHP Ic. Two patients were dizygotic twins. All had round
face and brachymetacarpia, 3 were obese, and 2 had short stature. One
had mental retardation. All had significantly increased serum PTH, all
but 1 had decreased serum calcium, and all had increased TSH, suggesting
end-organ hormone resistance. Erythrocyte Gs-alpha activity was normal
in cellular studies. All mothers of the patients had milder features,
including short stature, round face, or brachymetacarpia, but none had
evidence of hormonal resistance; 2 were given a diagnosis of
pseudopseudohypoparathyroidism (PPHP; 612463).

MOLECULAR GENETICS

In a patient with a phenotype consistent with PHP Ic, Linglart et al.
(2002) identified a heterozygous nonsense mutation in the GNAS gene
(Y391X; 139320.0035) that terminated the protein only 4 amino acids
before the wildtype stop codon. The findings indicated that the mutation
did not affect adenylate cyclase activity, but interfered somehow with
receptor-mediated activation. Linglart et al. (2002) noted that the C
terminus is required for receptor coupling, and postulated that the
Y391X mutation in this patient interrupted receptor coupling, leading to
hormone resistance. The findings showed the limits of the erythrocyte Gs
bioassay used in the study, which was not dependent on receptor-mediated
activation.

Despite the molecular findings of Linglart et al. (2002), Bastepe (2008)
stated that it was unclear whether patients with so-called PHP Ic
represent a subgroup of PHP Ia patients with GNAS mutations that affect
receptor coupling or whether they constitute a distinct group in whom
the genetic defect lies downstream of receptor-activated cAMP
generation.

In 5 patients from 4 unrelated families with a diagnosis of PHP Ic,
Thiele et al. (2011) identified 3 different heterozygous mutations in
the GNAS gene (139320.0038; 139320.0039; 139320.00400), all of which
were inherited from a mother with mild skeletal features but no
end-organ hormonal resistance. All mutations occurred in exon 13, in the
alpha-5-helix in the C terminus. In vitro functional expression studies
showed that all the mutant proteins caused an absence or decrease of
receptor-mediated cAMP production, with normal receptor-independent cAMP
production. The findings indicated normal Gs-alpha activity, but a
selective defect in Gs-alpha-receptor coupling functions. GNAS mutations
were not found in 27 additional patients with a diagnosis of PHP Ic.
Thiele et al. (2011) concluded that these patients represented a new
subgroup of PHP.

*FIELD* RF
1. Bastepe, M.: The GNAS locus and pseudohypoparathyroidism. Adv.
Exp. Med. Biol. 626: 27-40, 2008.

2. Farfel, Z.; Brothers, V. M.; Brickman, A. S.; Conte, F.; Neer,
R.; Bourne, H. R.: Pseudohypoparathyroidism: inheritance of deficient
receptor-cyclase coupling activity. Proc. Nat. Acad. Sci. 78: 3098-3102,
1981.

3. Linglart, A.; Carel, J. C.; Garabedian, M.; Le, T.; Mallet, E.;
Kottler, M. L.: GNAS1 lesions in pseudohypoparathyroidism Ia and
Ic: genotype phenotype relationship and evidence of the maternal transmission
of the hormonal resistance. J. Clin. Endocr. Metab. 87: 189-197,
2002.

4. Mantovani, G.; Spada, A.: Mutations in the Gs alpha gene causing
hormone resistance. Best Prac. Res. Clin. Endocr. Metab. 20: 501-513,
2006.

5. Thiele, S.; de Sanctis, L.; Werner, R.; Grotzinger, J.; Aydin,
C.; Juppner, H.; Bastepe, M.; Hiort, O.: Functional characterization
of GNAS mutations found in patients with pseudohypoparathyroidism
type Ic defines a new subgroup of pseudohypoparathyroidism affecting
selectively Gs-alpha-receptor interaction. Hum. Mutat. 32: 653-660,
2011.

*FIELD* CS
INHERITANCE:
Autosomal dominant

GROWTH:
[Height];
Short stature;
[Weight];
Obesity

HEAD AND NECK:
[Face];
Round face;
Full cheeks;
[Eyes];
Cataract;
Nystagmus;
[Nose];
Low nasal bridge;
[Teeth];
Delayed tooth eruption;
Enamel hypoplasia;
[Neck];
Short neck

SKELETAL:
Osteoporosis;
[Hands];
Brachydactyly;
Short metacarpals (especially 4th and 5th);
[Feet];
Brachydactyly;
Short metatarsals (especially 4th and 5th)

SKIN, NAILS, HAIR:
[Skin];
Subcutaneous ossifications

NEUROLOGIC:
[Central nervous system];
Cognitive deficits;
Mental retardation;
Hypocalcemic tetany;
Seizures;
Basal ganglion calcification;
Calcified choroid plexus;
[Peripheral nervous system];
Hypocalcemic tetany

ENDOCRINE FEATURES:
Pseudohypoparathyroidism;
Hypogonadism;
Hypothyroidism

LABORATORY ABNORMALITIES:
Hypocalcemia;
Hyperphosphatemia;
Elevated serum parathyroid hormone (PTH) level;
Low urinary cyclic AMP response to PTH administration;
Normal erythrocyte Gs activity

MISCELLANEOUS:
Caused by inheritance of the mutation on the maternal allele (imprinting);
See also pseudohypoparathyroidism type Ia (103580)

MOLECULAR BASIS:
Caused by mutation in the G-protein, alpha-stimulating 1 gene (GNAS1,
139320.0035)

*FIELD* CD
Cassandra L. Kniffin: 12/12/2008

*FIELD* ED
joanna: 07/23/2013
joanna: 12/30/2008
ckniffin: 12/15/2008

*FIELD* CN
Cassandra L. Kniffin - updated: 11/30/2011

*FIELD* CD
Cassandra L. Kniffin: 12/10/2008

*FIELD* ED
carol: 12/01/2011
ckniffin: 11/30/2011
joanna: 3/2/2010
carol: 12/19/2008
ckniffin: 12/15/2008