RBCC

Full text data of PRKAR1A

PRKAR1A (PKR1, PRKAR1, TSE1) [Confidence: high (present in two of the MS resources)]
cAMP-dependent protein kinase type I-alpha regulatory subunit (Tissue-specific extinguisher 1; TSE1; cAMP-dependent protein kinase type I-alpha regulatory subunit, N-terminally processed)

hRBCD IPI00021831
IPI00021831 cAMP-dependent protein kinase type I-alpha regulatory chain cAMP-dependent protein kinase type I-alpha regulatory chain membrane n/a 1 1 n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 3 2 3 cytoskeleton associated n/a found at its expected molecular weight found at molecular weight

UniProt P10644
ID KAP0_HUMAN Reviewed; 381 AA.
AC P10644; Q567S7;
DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-JUL-1989, sequence version 1.
DT 22-JAN-2014, entry version 165.
DE RecName: Full=cAMP-dependent protein kinase type I-alpha regulatory subunit;
DE AltName: Full=Tissue-specific extinguisher 1;
DE Short=TSE1;
DE Contains:
DE RecName: Full=cAMP-dependent protein kinase type I-alpha regulatory subunit, N-terminally processed;
GN Name=PRKAR1A; Synonyms=PKR1, PRKAR1, TSE1;
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].
RC TISSUE=Testis;
RX PubMed=3426618; DOI=10.1016/0006-291X(87)90499-2;
RA Sandberg M., Tasken K., Oeyen O., Hansson V., Jahnsen T.;
RT "Molecular cloning, cDNA structure and deduced amino acid sequence for
RT a type I regulatory subunit of cAMP-dependent protein kinase from
RT human testis.";
RL Biochem. Biophys. Res. Commun. 149:939-945(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Testis;
RX PubMed=2310396; DOI=10.1016/0006-291X(90)91768-N;
RA Sandberg M., Skalhegg B., Jahnsen T.;
RT "The two mRNA forms for the type I alpha regulatory subunit of cAMP-
RT dependent protein kinase from human testis are due to the use of
RT different polyadenylation site signals.";
RL Biochem. Biophys. Res. Commun. 167:323-330(1990).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=1889088; DOI=10.1016/0092-8674(91)90433-Y;
RA Jones K.W., Shapero M.H., Chevrette M., Fournier R.E.;
RT "Subtractive hybridization cloning of a tissue-specific extinguisher:
RT TSE1 encodes a regulatory subunit of protein kinase A.";
RL Cell 66:861-872(1991).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Testis;
RX PubMed=8977401; DOI=10.1210/en.138.1.169;
RA Solberg R., Sandberg M., Natarajan V., Torjesen P.A., Hansson V.,
RA Jahnsen T., Tasken K.;
RT "The human gene for the regulatory subunit RI alpha of cyclic
RT adenosine 3', 5'-monophosphate-dependent protein kinase: two distinct
RT promoters provide differential regulation of alternately spliced
RT messenger ribonucleic acids.";
RL Endocrinology 138:169-181(1997).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lymph, and Uterus;
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 [6]
RP PROTEIN SEQUENCE OF 1-13, AND ACETYLATION AT MET-1.
RC TISSUE=Platelet;
RX PubMed=12665801; DOI=10.1038/nbt810;
RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A.,
RA Thomas G.R., Vandekerckhove J.;
RT "Exploring proteomes and analyzing protein processing by mass
RT spectrometric identification of sorted N-terminal peptides.";
RL Nat. Biotechnol. 21:566-569(2003).
RN [7]
RP INVOLVEMENT IN PPNAD1.
RX PubMed=12213893; DOI=10.1210/jc.2002-020592;
RA Groussin L., Jullian E., Perlemoine K., Louvel A., Leheup B.,
RA Luton J.P., Bertagna X., Bertherat J.;
RT "Mutations of the PRKAR1A gene in Cushing's syndrome due to sporadic
RT primary pigmented nodular adrenocortical disease.";
RL J. Clin. Endocrinol. Metab. 87:4324-4329(2002).
RN [8]
RP INTERACTION WITH RFC2.
RX PubMed=15655353;
RA Gupte R.S., Weng Y., Liu L., Lee M.Y.;
RT "The second subunit of the replication factor C complex (RFC40) and
RT the regulatory subunit (RIalpha) of protein kinase A form a protein
RT complex promoting cell survival.";
RL Cell Cycle 4:323-329(2005).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-83, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [10]
RP FUNCTION, AND INTERACTION WITH PRKX.
RX PubMed=16491121; DOI=10.1038/sj.onc.1209436;
RA Glesne D., Huberman E.;
RT "Smad6 is a protein kinase X phosphorylation substrate and is required
RT for HL-60 cell differentiation.";
RL Oncogene 25:4086-4098(2006).
RN [11]
RP INTERACTION WITH AICDA.
RX PubMed=16387847; DOI=10.1073/pnas.0509969103;
RA Pasqualucci L., Kitaura Y., Gu H., Dalla-Favera R.;
RT "PKA-mediated phosphorylation regulates the function of activation-
RT induced deaminase (AID) in B cells.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:395-400(2006).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-83, AND MASS
RP SPECTROMETRY.
RC TISSUE=T-cell;
RX PubMed=19367720; DOI=10.1021/pr800500r;
RA Carrascal M., Ovelleiro D., Casas V., Gay M., Abian J.;
RT "Phosphorylation analysis of primary human T lymphocytes using
RT sequential IMAC and titanium oxide enrichment.";
RL J. Proteome Res. 7:5167-5176(2008).
RN [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-83, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [15]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-83, AND MASS
RP SPECTROMETRY.
RC TISSUE=Liver;
RX PubMed=18318008; DOI=10.1002/pmic.200700884;
RA Han G., Ye M., Zhou H., Jiang X., Feng S., Jiang X., Tian R., Wan D.,
RA Zou H., Gu J.;
RT "Large-scale phosphoproteome analysis of human liver tissue by
RT enrichment and fractionation of phosphopeptides with strong anion
RT exchange chromatography.";
RL Proteomics 8:1346-1361(2008).
RN [17]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-83, AND MASS
RP SPECTROMETRY.
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [19]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-83, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [20]
RP INTERACTION WITH RARA, AND FUNCTION.
RX PubMed=20215566; DOI=10.1210/en.2009-1338;
RA Santos N.C., Kim K.H.;
RT "Activity of retinoic acid receptor-alpha is directly regulated at its
RT protein kinase A sites in response to follicle-stimulating hormone
RT signaling.";
RL Endocrinology 151:2361-2372(2010).
RN [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-83, 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 [22]
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 [23]
RP INVOLVEMENT IN ACRDYS1, AND MUTAGENESIS OF TYR-373.
RX PubMed=21651393; DOI=10.1056/NEJMoa1012717;
RA Linglart A., Menguy C., Couvineau A., Auzan C., Gunes Y., Cancel M.,
RA Motte E., Pinto G., Chanson P., Bougneres P., Clauser E., Silve C.;
RT "Recurrent PRKAR1A mutation in acrodysostosis with hormone
RT resistance.";
RL N. Engl. J. Med. 364:2218-2226(2011).
RN [24]
RP INTERACTION WITH PJA2.
RX PubMed=21423175; DOI=10.1038/ncb2209;
RA Lignitto L., Carlucci A., Sepe M., Stefan E., Cuomo O., Nistico R.,
RA Scorziello A., Savoia C., Garbi C., Annunziato L., Feliciello A.;
RT "Control of PKA stability and signalling by the RING ligase praja2.";
RL Nat. Cell Biol. 13:412-422(2011).
RN [25]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-83, AND MASS
RP SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [26]
RP INVOLVEMENT IN CNC1.
RX PubMed=22785148; DOI=10.1507/endocrj.EJ12-0040;
RA Tung S.C., Hwang D.Y., Yang J.W., Chen W.J., Lee C.T.;
RT "An unusual presentation of Carney complex with diffuse primary
RT pigmented nodular adrenocortical disease on one adrenal gland and a
RT nonpigmented adrenocortical adenoma and focal primary pigmented
RT nodular adrenocortical disease on the other.";
RL Endocr. J. 59:823-830(2012).
RN [27]
RP INTERACTION WITH C2ORF88/SMAKAP, AND SUBCELLULAR LOCATION.
RX PubMed=23115245; DOI=10.1074/jbc.M112.395970;
RA Burgers P.P., Ma Y., Margarucci L., Mackey M., van der Heyden M.A.,
RA Ellisman M., Scholten A., Taylor S.S., Heck A.J.;
RT "A small novel A-kinase anchoring protein (AKAP) that localizes
RT specifically protein kinase A-regulatory subunit I (PKA-RI) to the
RT plasma membrane.";
RL J. Biol. Chem. 287:43789-43797(2012).
RN [28]
RP INVOLVEMENT IN CNC1.
RX PubMed=23323113; DOI=10.4132/KoreanJPathol.2012.46.6.595;
RA Park K.U., Kim H.S., Lee S.K., Jung W.W., Park Y.K.;
RT "Novel Mutation in PRKAR1A in Carney Complex.";
RL Korean J. Pathol. 46:595-600(2012).
RN [29]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [30]
RP VARIANT CNC1 CYS-74.
RX PubMed=15371594; DOI=10.1073/pnas.0405535101;
RA Veugelers M., Wilkes D., Burton K., McDermott D.A., Song Y.,
RA Goldstein M.M., La Perle K., Vaughan C.J., O'Hagan A., Bennett K.R.,
RA Meyer B.J., Legius E., Karttunen M., Norio R., Kaariainen H.,
RA Lavyne M., Neau J.-P., Richter G., Kirali K., Farnsworth A.,
RA Stapleton K., Morelli P., Takanashi Y., Bamforth J.-S.,
RA Eitelberger F., Noszian I., Manfroi W., Powers J., Mochizuki Y.,
RA Imai T., Ko G.T.C., Driscoll D.A., Goldmuntz E., Edelberg J.M.,
RA Collins A., Eccles D., Irvine A.D., McKnight G.S., Basson C.T.;
RT "Comparative PRKAR1A genotype-phenotype analyses in humans with Carney
RT complex and prkar1a haploinsufficient mice.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:14222-14227(2004).
RN [31]
RP VARIANTS CNC1 ASN-9; SER-146; TYR-183; ASP-213 AND TRP-289, AND
RP CHARACTERIZATION OF VARIANTS CNC1 ASN-9; CYS-74; SER-146; TYR-183;
RP ASP-213 AND TRP-289.
RX PubMed=18241045; DOI=10.1002/humu.20688;
RA Greene E.L., Horvath A.D., Nesterova M., Giatzakis C., Bossis I.,
RA Stratakis C.A.;
RT "In vitro functional studies of naturally occurring pathogenic PRKAR1A
RT mutations that are not subject to nonsense mRNA decay.";
RL Hum. Mutat. 29:633-639(2008).
RN [32]
RP VARIANT ACRDYS1 HIS-373.
RX PubMed=22464250; DOI=10.1016/j.ajhg.2012.03.003;
RA Michot C., Le Goff C., Goldenberg A., Abhyankar A., Klein C.,
RA Kinning E., Guerrot A.M., Flahaut P., Duncombe A., Baujat G.,
RA Lyonnet S., Thalassinos C., Nitschke P., Casanova J.L., Le Merrer M.,
RA Munnich A., Cormier-Daire V.;
RT "Exome sequencing identifies PDE4D mutations as another cause of
RT acrodysostosis.";
RL Am. J. Hum. Genet. 90:740-745(2012).
RN [33]
RP VARIANTS ACRDYS1 THR-327 AND PRO-335.
RX PubMed=22464252; DOI=10.1016/j.ajhg.2012.03.004;
RA Lee H., Graham J.M. Jr., Rimoin D.L., Lachman R.S., Krejci P.,
RA Tompson S.W., Nelson S.F., Krakow D., Cohn D.H.;
RT "Exome sequencing identifies PDE4D mutations in acrodysostosis.";
RL Am. J. Hum. Genet. 90:746-751(2012).
RN [34]
RP VARIANTS ACRDYS1 ARG-285; GLU-289; VAL-328 AND LEU-335.
RX PubMed=23043190; DOI=10.1210/jc.2012-2326;
RA Linglart A., Fryssira H., Hiort O., Holterhus P.M.,
RA Perez de Nanclares G., Argente J., Heinrichs C., Kuechler A.,
RA Mantovani G., Leheup B., Wicart P., Chassot V., Schmidt D.,
RA Rubio-Cabezas O., Richter-Unruh A., Berrade S., Pereda A., Boros E.,
RA Munoz-Calvo M.T., Castori M., Gunes Y., Bertrand G., Bougneres P.,
RA Clauser E., Silve C.;
RT "PRKAR1A and PDE4D mutations cause acrodysostosis but two distinct
RT syndromes with or without GPCR-signaling hormone resistance.";
RL J. Clin. Endocrinol. Metab. 97:E2328-E2338(2012).
RN [35]
RP VARIANT ACRDYS1 ALA-239, AND CHARACTERIZATION OF VARIANT ACRDYS1
RP ALA-239.
RX PubMed=22723333; DOI=10.1210/jc.2012-1369;
RA Nagasaki K., Iida T., Sato H., Ogawa Y., Kikuchi T., Saitoh A.,
RA Ogata T., Fukami M.;
RT "PRKAR1A mutation affecting cAMP-mediated G protein-coupled receptor
RT signaling in a patient with acrodysostosis and hormone resistance.";
RL J. Clin. Endocrinol. Metab. 97:E1808-E1813(2012).
RN [36]
RP VARIANTS ACRDYS1 THR-213 AND CYS-373, AND VARIANT ASN-227.
RX PubMed=23425300; DOI=10.1111/cge.12106;
RA Muhn F., Klopocki E., Graul-Neumann L., Uhrig S., Colley A.,
RA Castori M., Lankes E., Henn W., Gruber-Sedlmayr U., Seifert W.,
RA Horn D.;
RT "Novel mutations of the PRKAR1A gene in patients with
RT acrodysostosis.";
RL Clin. Genet. 0:0-0(2013).
CC -!- FUNCTION: Regulatory subunit of the cAMP-dependent protein kinases
CC involved in cAMP signaling in cells.
CC -!- SUBUNIT: The inactive holoenzyme is composed of two regulatory
CC chains and two catalytic chains. Activation by cAMP releases the
CC two active catalytic monomers and the regulatory dimer. PRKAR1A
CC also interacts with RFC2; the complex may be involved in cell
CC survival. Interacts with AKAP4. Interacts with RARA; the
CC interaction occurs in the presence of cAMP or FSH and regulates
CC RARA transcriptional activity. Interacts with the phosphorylated
CC form of PJA2. Interacts with CBFA2T3 (By similarity). Interacts
CC with PRKX; regulates this cAMP-dependent protein kinase. Interacts
CC with C2orf88/smAKAP; this interaction may target PRKAR1A to the
CC plasma membrane. Interacts with AICDA.
CC -!- INTERACTION:
CC P03259-2:- (xeno); NbExp=5; IntAct=EBI-476431, EBI-7225021;
CC Q9H0R8:GABARAPL1; NbExp=2; IntAct=EBI-476431, EBI-746969;
CC Q9H8W4:PLEKHF2; NbExp=3; IntAct=EBI-476431, EBI-742388;
CC P17612:PRKACA; NbExp=2; IntAct=EBI-476431, EBI-476586;
CC P51817:PRKX; NbExp=2; IntAct=EBI-476431, EBI-4302903;
CC P35250:RFC2; NbExp=7; IntAct=EBI-476431, EBI-476409;
CC Q01105:SET; NbExp=2; IntAct=EBI-476431, EBI-1053182;
CC -!- SUBCELLULAR LOCATION: Cell membrane.
CC -!- TISSUE SPECIFICITY: Four types of regulatory chains are found: I-
CC alpha, I-beta, II-alpha, and II-beta. Their expression varies
CC among tissues and is in some cases constitutive and in others
CC inducible.
CC -!- PTM: The pseudophosphorylation site binds to the substrate-binding
CC region of the catalytic chain, resulting in the inhibition of its
CC activity.
CC -!- DISEASE: Carney complex 1 (CNC1) [MIM:160980]: CNC is a multiple
CC neoplasia syndrome characterized by spotty skin pigmentation,
CC cardiac and other myxomas, endocrine tumors, and psammomatous
CC melanotic schwannomas. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: Intracardiac myxoma (INTMYX) [MIM:255960]: Inheritance is
CC autosomal recessive. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: Primary pigmented nodular adrenocortical disease 1
CC (PPNAD1) [MIM:610489]: A rare bilateral adrenal defect causing
CC ACTH-independent Cushing syndrome. Macroscopic appearance of the
CC adrenals is characteristic with small pigmented micronodules
CC observed in the cortex. Clinical manifestations of Cushing
CC syndrome include facial and truncal obesity, abdominal striae,
CC muscular weakness, osteoporosis, arterial hypertension, diabetes.
CC PPNAD1 is most often diagnosed in patients with Carney complex, a
CC multiple neoplasia syndrome. However it can also be observed in
CC patients without other manifestations. Note=The disease is caused
CC by mutations affecting the gene represented in this entry.
CC -!- DISEASE: Acrodysostosis 1, with or without hormone resistance
CC (ACRDYS1) [MIM:101800]: A form of skeletal dysplasia characterized
CC by short stature, severe brachydactyly, facial dysostosis, and
CC nasal hypoplasia. Affected individuals often have advanced bone
CC age and obesity. Laboratory studies show resistance to multiple
CC hormones, including parathyroid, thyrotropin, calcitonin, growth
CC hormone-releasing hormone, and gonadotropin. However, not all
CC patients show endocrine abnormalities. Note=The disease is caused
CC by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the cAMP-dependent kinase regulatory chain
CC family.
CC -!- SIMILARITY: Contains 2 cyclic nucleotide-binding domains.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/PRKAR1AID387.html";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/PRKAR1A";
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DR EMBL; M18468; AAB50922.1; -; mRNA.
DR EMBL; M33336; AAB50921.1; -; mRNA.
DR EMBL; S54705; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; S54707; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; S54709; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; S54711; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; Y07642; CAA68925.1; -; mRNA.
DR EMBL; BC036285; AAH36285.1; -; mRNA.
DR EMBL; BC093042; AAH93042.1; -; mRNA.
DR PIR; A34627; OKHU1R.
DR RefSeq; NP_001263218.1; NM_001276289.1.
DR RefSeq; NP_001263219.1; NM_001276290.1.
DR RefSeq; NP_001265362.1; NM_001278433.1.
DR RefSeq; NP_002725.1; NM_002734.4.
DR RefSeq; NP_997636.1; NM_212471.2.
DR RefSeq; NP_997637.1; NM_212472.2.
DR UniGene; Hs.280342; -.
DR UniGene; Hs.745160; -.
DR ProteinModelPortal; P10644; -.
DR SMR; P10644; 14-380.
DR DIP; DIP-34368N; -.
DR IntAct; P10644; 54.
DR MINT; MINT-1194164; -.
DR STRING; 9606.ENSP00000351410; -.
DR BindingDB; P10644; -.
DR PhosphoSite; P10644; -.
DR DMDM; 125193; -.
DR OGP; P10644; -.
DR REPRODUCTION-2DPAGE; IPI00021831; -.
DR PaxDb; P10644; -.
DR PeptideAtlas; P10644; -.
DR PRIDE; P10644; -.
DR DNASU; 5573; -.
DR Ensembl; ENST00000358598; ENSP00000351410; ENSG00000108946.
DR Ensembl; ENST00000392711; ENSP00000376475; ENSG00000108946.
DR Ensembl; ENST00000536854; ENSP00000445625; ENSG00000108946.
DR Ensembl; ENST00000586397; ENSP00000466459; ENSG00000108946.
DR Ensembl; ENST00000589228; ENSP00000464977; ENSG00000108946.
DR GeneID; 5573; -.
DR KEGG; hsa:5573; -.
DR UCSC; uc002jhg.4; human.
DR CTD; 5573; -.
DR GeneCards; GC17P066508; -.
DR HGNC; HGNC:9388; PRKAR1A.
DR HPA; CAB019378; -.
DR MIM; 101800; phenotype.
DR MIM; 160980; phenotype.
DR MIM; 188830; gene.
DR MIM; 255960; phenotype.
DR MIM; 610489; phenotype.
DR neXtProt; NX_P10644; -.
DR Orphanet; 950; Acrodysostosis.
DR Orphanet; 280651; Acrodysostosis with multiple hormone resistance.
DR Orphanet; 1359; Carney complex.
DR Orphanet; 615; Familial atrial myxoma.
DR Orphanet; 189439; Primary pigmented nodular adrenocortical disease.
DR PharmGKB; PA33754; -.
DR eggNOG; COG0664; -.
DR HOGENOM; HOG000196669; -.
DR HOVERGEN; HBG002025; -.
DR InParanoid; P10644; -.
DR KO; K04739; -.
DR OMA; FSAEVYT; -.
DR PhylomeDB; P10644; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_15518; Transmembrane transport of small molecules.
DR Reactome; REACT_604; Hemostasis.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P10644; -.
DR ChiTaRS; PRKAR1A; human.
DR GenomeRNAi; 5573; -.
DR NextBio; 21602; -.
DR PRO; PR:P10644; -.
DR ArrayExpress; P10644; -.
DR Bgee; P10644; -.
DR CleanEx; HS_PRKAR1A; -.
DR Genevestigator; P10644; -.
DR GO; GO:0031588; C:AMP-activated protein kinase complex; IDA:BHF-UCL.
DR GO; GO:0005952; C:cAMP-dependent protein kinase complex; IEA:Ensembl.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0031594; C:neuromuscular junction; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0030552; F:cAMP binding; IEA:UniProtKB-KW.
DR GO; GO:0004862; F:cAMP-dependent protein kinase inhibitor activity; IDA:BHF-UCL.
DR GO; GO:0008603; F:cAMP-dependent protein kinase regulator activity; IDA:BHF-UCL.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; IDA:UniProtKB.
DR GO; GO:0007202; P:activation of phospholipase C activity; TAS:Reactome.
DR GO; GO:0034199; P:activation of protein kinase A activity; TAS:Reactome.
DR GO; GO:0007596; P:blood coagulation; TAS:Reactome.
DR GO; GO:0060038; P:cardiac muscle cell proliferation; IEA:Ensembl.
DR GO; GO:0071377; P:cellular response to glucagon stimulus; TAS:Reactome.
DR GO; GO:0006112; P:energy reserve metabolic process; TAS:Reactome.
DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0007143; P:female meiosis; IEA:Ensembl.
DR GO; GO:0008543; P:fibroblast growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0035556; P:intracellular signal transduction; TAS:ProtInc.
DR GO; GO:0001707; P:mesoderm formation; IEA:Ensembl.
DR GO; GO:2000480; P:negative regulation of cAMP-dependent protein kinase activity; IDA:BHF-UCL.
DR GO; GO:0045835; P:negative regulation of meiosis; IEA:Ensembl.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0050796; P:regulation of insulin secretion; TAS:Reactome.
DR GO; GO:0006357; P:regulation of transcription from RNA polymerase II promoter; TAS:ProtInc.
DR GO; GO:0045214; P:sarcomere organization; IEA:Ensembl.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR GO; GO:0055085; P:transmembrane transport; TAS:Reactome.
DR GO; GO:0006833; P:water transport; TAS:Reactome.
DR Gene3D; 2.60.120.10; -; 2.
DR InterPro; IPR002373; cAMP/cGMP_kin.
DR InterPro; IPR012198; cAMP_dep_PK_reg_su.
DR InterPro; IPR003117; cAMP_dep_PK_reg_su_I/II_a/b.
DR InterPro; IPR018490; cNMP-bd-like.
DR InterPro; IPR018488; cNMP-bd_CS.
DR InterPro; IPR000595; cNMP-bd_dom.
DR InterPro; IPR014710; RmlC-like_jellyroll.
DR Pfam; PF00027; cNMP_binding; 2.
DR Pfam; PF02197; RIIa; 1.
DR PIRSF; PIRSF000548; PK_regulatory; 1.
DR PRINTS; PR00103; CAMPKINASE.
DR SMART; SM00100; cNMP; 2.
DR SMART; SM00394; RIIa; 1.
DR SUPFAM; SSF47391; SSF47391; 1.
DR SUPFAM; SSF51206; SSF51206; 2.
DR PROSITE; PS00888; CNMP_BINDING_1; 2.
DR PROSITE; PS00889; CNMP_BINDING_2; 2.
DR PROSITE; PS50042; CNMP_BINDING_3; 2.
PE 1: Evidence at protein level;
KW Acetylation; cAMP; cAMP-binding; Cell membrane; Complete proteome;
KW Cushing syndrome; Direct protein sequencing; Disease mutation;
KW Disulfide bond; Membrane; Nucleotide-binding; Phosphoprotein;
KW Reference proteome; Repeat.
FT CHAIN 1 381 cAMP-dependent protein kinase type I-
FT alpha regulatory subunit.
FT /FTId=PRO_0000205377.
FT INIT_MET 1 1 Removed; alternate (By similarity).
FT CHAIN 2 381 cAMP-dependent protein kinase type I-
FT alpha regulatory subunit, N-terminally
FT processed.
FT /FTId=PRO_0000421785.
FT NP_BIND 137 254 cAMP 1.
FT NP_BIND 255 381 cAMP 2.
FT REGION 1 136 Dimerization and phosphorylation.
FT MOTIF 96 100 Pseudophosphorylation motif.
FT BINDING 202 202 cAMP 1.
FT BINDING 211 211 cAMP 1.
FT BINDING 326 326 cAMP 2.
FT BINDING 335 335 cAMP 2.
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 83 83 Phosphoserine.
FT MOD_RES 101 101 Phosphoserine (By similarity).
FT DISULFID 18 18 Interchain (with C-39) (By similarity).
FT DISULFID 39 39 Interchain (with C-18) (By similarity).
FT VARIANT 9 9 S -> N (in CNC1; exhibits increased PKA
FT activity which is attributed to decreased
FT binding to cAMP and/or the catalytic
FT subunit).
FT /FTId=VAR_046894.
FT VARIANT 74 74 R -> C (in CNC1; exhibits increased PKA
FT activity which is attributed to decreased
FT binding to cAMP and/or the catalytic
FT subunit).
FT /FTId=VAR_046895.
FT VARIANT 146 146 R -> S (in CNC1; exhibits increased PKA
FT activity which is attributed to decreased
FT binding to cAMP and/or the catalytic
FT subunit).
FT /FTId=VAR_046896.
FT VARIANT 183 183 D -> Y (in CNC1; exhibits increased PKA
FT activity which is attributed to decreased
FT binding to cAMP and/or the catalytic
FT subunit).
FT /FTId=VAR_046897.
FT VARIANT 213 213 A -> D (in CNC1; exhibits increased PKA
FT activity which is attributed to decreased
FT binding to cAMP and/or the catalytic
FT subunit).
FT /FTId=VAR_046898.
FT VARIANT 213 213 A -> T (in ACRDYS1).
FT /FTId=VAR_069456.
FT VARIANT 227 227 D -> N.
FT /FTId=VAR_069457.
FT VARIANT 239 239 T -> A (in ACRDYS1; impairs response of
FT PKA to c-AMP).
FT /FTId=VAR_069458.
FT VARIANT 285 285 Q -> R (in ACRDYS1).
FT /FTId=VAR_069459.
FT VARIANT 289 289 G -> E (in ACRDYS1).
FT /FTId=VAR_069460.
FT VARIANT 289 289 G -> W (in CNC1; exhibits increased PKA
FT activity which is attributed to decreased
FT binding to cAMP and/or the catalytic
FT subunit).
FT /FTId=VAR_046899.
FT VARIANT 327 327 I -> T (in ACRDYS1).
FT /FTId=VAR_069461.
FT VARIANT 328 328 A -> V (in ACRDYS1).
FT /FTId=VAR_069462.
FT VARIANT 335 335 R -> L (in ACRDYS1).
FT /FTId=VAR_069464.
FT VARIANT 335 335 R -> P (in ACRDYS1).
FT /FTId=VAR_069463.
FT VARIANT 373 373 Y -> C (in ACRDYS1).
FT /FTId=VAR_069465.
FT VARIANT 373 373 Y -> H (in ACRDYS1).
FT /FTId=VAR_068241.
FT MUTAGEN 373 373 Y->A: Impairs response of PKA to c-AMP.
SQ SEQUENCE 381 AA; 42982 MW; 2D04F08CE8857A6D CRC64;
MESGSTAASE EARSLRECEL YVQKHNIQAL LKDSIVQLCT ARPERPMAFL REYFERLEKE
EAKQIQNLQK AGTRTDSRED EISPPPPNPV VKGRRRRGAI SAEVYTEEDA ASYVRKVIPK
DYKTMAALAK AIEKNVLFSH LDDNERSDIF DAMFSVSFIA GETVIQQGDE GDNFYVIDQG
ETDVYVNNEW ATSVGEGGSF GELALIYGTP RAATVKAKTN VKLWGIDRDS YRRILMGSTL
RKRKMYEEFL SKVSILESLD KWERLTVADA LEPVQFEDGQ KIVVQGEPGD EFFIILEGSA
AVLQRRSENE EFVEVGRLGP SDYFGEIALL MNRPRAATVV ARGPLKCVKL DRPRFERVLG
PCSDILKRNI QQYNSFVSLS V
//

MIM 101800
*RECORD*
*FIELD* NO
101800
*FIELD* TI
#101800 ACRODYSOSTOSIS 1, WITH OR WITHOUT HORMONE RESISTANCE; ACRDYS1
;;ADOHR
*FIELD* TX
read moreA number sign (#) is used with this entry because acrodysostosis-1
(ACRDYS1) is caused by heterozygous mutation in the PRKAR1A gene
(188830) on chromosome 17q24.

DESCRIPTION

Acrodysostosis-1 is a form of skeletal dysplasia characterized by short
stature, severe brachydactyly, facial dysostosis, and nasal hypoplasia.
Affected individuals often have advanced bone age and obesity.
Laboratory studies show resistance to multiple hormones, including
parathyroid, thyrotropin, calcitonin, growth hormone-releasing hormone,
and gonadotropin (summary by Linglart et al., 2011). However, not all
patients show endocrine abnormalities (Lee et al., 2012).

See also ACRDYS2 (614613), caused by mutation in the PDE4D gene (600129)
on chromosome 5q12.

CLINICAL FEATURES

Maroteaux and Malamut (1968) described acrodysostosis as a condition in
small hands and feet were associated with which peculiar facies,
including short nose, open mouth, and prognathism. Radiographs showed
cone epiphyses. Mental deficiency was also frequent.

Robinow et al. (1971) reported 9 cases and reviewed 11 from the
literature. None was familial.

Niikawa et al. (1978) described Japanese brother and sister, aged 7
months and 2 years, respectively, with severe nasal hypoplasia,
peripheral dysostosis, blue eyes, and mental retardation. The mother
showed nasal hypoplasia and irregular shortening of fingers and toes.

Butler et al. (1988) reported an affected 13-year-old boy and reviewed
the literature. They emphasized the features of nasal and maxillary
hypoplasia, peripheral dysostosis, decreased interpedicular distance,
advanced skeletal maturation, and mental retardation. They suggested
that the metacarpophalangeal pattern profile was characteristically
abnormal and useful as a diagnostic tool. The first ray in the foot may
be relatively hyperplastic. Their review suggested increased parental
age.

Viljoen and Beighton (1991) reviewed the radiologic features in 12
affected children and found that epiphyseal stippling is a consistent
and prominent characteristic during infancy.

Steiner and Pagon (1992) described an affected mother and daughter. The
mother had been diagnosed at the age of 4 years and was pictured in the
1982 edition of Smith's Recognizable Patterns of Human Malformation. At
the age of 20, she suffered from recurrent carpal tunnel syndrome. The
daughter showed cone-shaped epiphyses as in the mother.

Linglart et al. (2011) reported 3 unrelated patients with short stature,
peripheral dysostosis, nasal and maxillary hypoplasia, severe
brachydactyly, epiphyseal stippling, and advanced bone age. Laboratory
studies showed increased serum parathyroid hormone, low or normal
calcium, and increased urinary cAMP excretion. All had evidence of
multiple hormone resistance, including thyrotropin, calcitonin, growth
hormone-releasing hormone, and gonadotropin.

Michot et al. (2012) reported 5 patients with ACRDYS1. All had short
stature, severe brachydactyly, short metatarsals, metacarpals, and
phalanges, and cone-shaped epiphyses in childhood. Only 2 had mild
facial dysostosis and all had normal intellect. All had evidence of
hormone resistance, with increased parathyroid hormone (PTH) and
thyroid-stimulating hormone (TSH) and clinical hypothyroidism. Michot et
al. (2012) also identified 4 patients with acrodysostosis-2 (614613) due
to heterozygous mutations in the PDE4D gene (600129). Comparison of the
2 groups revealed interesting genotype-phenotype correlations. Those
with PRKAR1A mutations had hormone resistance, short stature, normal
intellect, and no facial dysostosis, whereas those with PDE4D mutations
had characteristic facial features, namely midface hypoplasia with the
nasal hypoplasia, moderate intellectual disability with speech delay,
and lack of hormone resistance in 3 of the 4.

Lee et al. (2012) reported 2 unrelated patients with acrodysostosis-1.
One had mild short stature, small hands, midface hypoplasia, lumbar
stenosis, and mild developmental disability, but no evidence of
endocrine dysfunction. The other patient, who had previously been
reported by Graham et al. (2001) (case 1), had mild short stature, small
hands with severe brachydactyly, cone-shaped epiphyses, midface
hypoplasia, lumbar stenosis, and mild developmental disability. He had
congenital and persistent hypothyroidism with hypoplastic thyroid gland,
unilateral undescended testes, and moderate mixed hearing loss. He also
had dextrocardia, Kartagener syndrome (244400), and multiple orthopedic
problems. Lee et al. (2012) also reported 3 unrelated patients with
ACRDYS2. In a comparison of the phenotypes, Lee et al. (2012) concluded
that it was difficult to distinguish between the patients clinically.
Both groups had mild short stature with brachydactyly, facial
dysostosis, and spinal stenosis; both groups had variable endocrine
abnormalities; and 4 of the 5 patients had some degree of developmental
disability.

INHERITANCE

Jones et al. (1975) found elevated average paternal age in this
disorder, thus supporting autosomal dominant inheritance.

Butler et al. (1988) found a pattern of autosomal dominant inheritance
in 2 families (Niikawa et al., 1978; Frey et al., 1982).

Hernandez et al. (1991) described an affected mother and daughter, as
did Steiner and Pagon (1992).

MOLECULAR GENETICS

In 3 unrelated patients with acrodysostosis with hormone resistance,
Linglart et al. (2011) identified a de novo truncating mutation in the
PRKAR1A gene (R368X; 188830.0015). The mutation resulted in decreased
protein kinase A sensitivity to cAMP, resulting in multiple hormone
resistance and skeletal anomalies.

Michot et al. (2012) identified a heterozygous de novo R368X mutation in
4 unrelated patients with acrodysostosis and a de novo heterozygous
Y373H mutation (188830.0016) in another patient with the disorder.

Lee et al. (2012) identified different de novo heterozygous missense
mutations in the PRKAR1A gene (R335P, 188830.0017 and I327T,
188830.0018) in 2 unrelated patients with acrodysostosis-1. The
mutations were identified by exome sequencing and confirmed by Sanger
sequencing. Lee et al. (2012) suggested that the mutations would cause
reduced cAMP binding, reduced PKA activation, and decreased downstream
signaling.

- Exclusion Studies

Because of the similarity between acrodysostosis and Albright hereditary
osteodystrophy (AHO; 103580), both of which show shortening of the
tubular bones of the hands and feet with cone-shaped epiphyses, Wilson
et al. (1997) looked for abnormalities in the alpha subunit of the
signal transducing protein, Gs, and in the GNAS1 gene (139320). In 2
unrelated patients with acrodysostosis, they found that Gs-alpha
bioactivity in erythrocyte membranes was normal. Mutation analysis of
the GNAS1 gene showed no sequence variation in 12 of the 13 exons
examined. The results were interpreted as indicating that, at least in a
proportion of patients with acrodysostosis, the condition is
etiologically distinct from AHO.

*FIELD* SA
Arkless and Graham (1967); Smith (1982)
*FIELD* RF
1. Arkless, R.; Graham, C. B.: An unusual case of brachydactyly. Am.
J. Roentgen. 99: 724-735, 1967.

2. Butler, M. G.; Rames, L. J.; Wadlington, W. B.: Acrodysostosis:
report of a 13-year-old boy with review of literature and metacarpophalangeal
pattern profile analysis. Am. J. Med. Genet. 30: 971-980, 1988.

3. Frey, V. G.; Martin, J.; Diefel, K.: Die Akrodysostose--eine autosomal-dominant
verebte periphere Dysplasie. Kinderarztl. Prax. 3: 149-153, 1982.

4. Graham, J. M., Jr.; Krakow, D.; Tolo, V. T.; Smith, A. K.; Lachman,
R. S.: Radiographic findings and Gs-alpha bioactivity studies and
mutation screening in acrodysostosis indicate a different etiology
from pseudohypoparathyroidism. Pediat. Radiol. 31: 2-9, 2001.

5. Hernandez, R. M.; Miranda, A.; Kofman-Alfaro, S.: Acrodysostosis
in two generations: an autosomal dominant syndrome. Clin. Genet. 39:
376-382, 1991.

6. Jones, K. L.; Smith, D. W.; Harvey, M. A. S.; Hall, B. D.; Quan,
L.: Older paternal age and fresh gene mutation: data on additional
disorders. J. Pediat. 86: 84-88, 1975.

7. Lee, H.; Graham, J. M., Jr.; Rimoin, D. L.; Lachman, R. S.; Krejci,
P.; Tompson, S. W.; Nelson, S. F.; Krakow, D.; Cohn, D. H.: Exome
sequencing identifies PDE4D mutations in acrodysostosis. Am. J. Hum.
Genet. 90: 746-751, 2012.

8. Linglart, A.; Menguy, C.; Couvineau, A.; Auzan, C.; Gunes, Y.;
Cancel, M.; Motte, E.; Pinto, G.; Chanson, P.; Bougneres, P.; Clauser,
E.; Silve, C.: Recurrent PRKAR1A mutation in acrodysostosis with
hormone resistance. New Eng. J. Med. 364: 2218-2226, 2011.

9. Maroteaux, P.; Malamut, G.: L'acrodysostose. Presse Med. 76:
2189-2192, 1968.

10. Michot, C.; Le Goff, C.; Goldenberg, A.; Abhyankar, A.; Klein,
C.; Kinning, E.; Guerrot, A. M.; Flahaut, P.; Duncombe, A.; Baujat,
G.; Lyonnet, S.; Thalassinos, C.; Nitschke, P.; Casanova, J.-L.; Le
Merrer, M.; Munnich, A.; Cormier-Daire, V.: Exome sequencing identifies
PDE4D mutations as another cause of acrodysostosis. Am. J. Hum. Genet. 90:
740-745, 2012.

11. Niikawa, N.; Matsuda, I.; Ohsawa, T.; Kajii, T.: Familial occurrence
of a syndrome with mental retardation, nasal hypoplasia, peripheral
dysostosis, and blue eyes in Japanese siblings. Hum. Genet. 42:
227-232, 1978.

12. Robinow, M.; Pfeiffer, R. A.; Gorlin, R. J.; McKusick, V. A.;
Renuart, A. W.; Johnson, G. F.; Summitt, R. L.: Acrodysostosis: a
syndrome of peripheral dysostosis, nasal hypoplasia, and mental retardation. Am.
J. Dis. Child. 121: 195-203, 1971.

13. Smith, D. W.: Recognizable Patterns of Human Malformation: Genetic,
Embryologic and Clinical Aspects. Philadelphia: W. B. Saunders (pub.)
(3rd ed.): 1982. Pp. 322-323.

14. Steiner, R. D.; Pagon, R. A.: Autosomal dominant transmission
of acrodysostosis. Clin. Dysmorph. 1: 201-206, 1992.

15. Viljoen, D.; Beighton, P.: Epiphyseal stippling in acrodysostosis. Am.
J. Med. Genet. 38: 43-45, 1991.

16. Wilson, L. C.; Oude Luttikhuis, M. E. M.; Baraitser, M.; Kingston,
H. M.; Trembath, R. C.: Normal erythrocyte membrane Gs-alpha bioactivity
in two unrelated patients with acrodysostosis. J. Med. Genet. 34:
133-136, 1997.

*FIELD* CS
INHERITANCE:
Autosomal dominant

GROWTH:
[Height];
Short stature;
Brachymelic dwarfism (upper limbs greater than lower limbs);
[Other];
Growth retardation, mild to moderate, prenatal onset

HEAD AND NECK:
[Head];
Brachycephaly;
[Face];
Hypoplastic maxilla;
Prognathism;
[Ears];
Hearing loss;
[Eyes];
Epicanthal folds;
Hypertelorism;
Optic atrophy;
Strabismus;
Blue eyes (Japanese patients);
[Nose];
Low nasal bridge;
Broad, upturned nose;
Dimpled nasal tip;
[Teeth];
Malocclusion;
Delayed tooth eruption;
Hypodontia

GENITOURINARY:
[Internal genitalia, male];
Cryptorchidism

SKELETAL:
Advanced bone age;
Epiphyseal stippling in neonates (lumbosacral and cervical bodies,
carpus, tarsus, proximal humerus, terminal phalanges, knees, hips);
[Skull];
Calvarial hyperostosis;
Hypoplastic maxilla;
[Spine];
Spinal canal stenosis;
Scoliosis;
Narrow interpediculate distances;
Small vertebrae;
[Limbs];
Radial head dislocation;
[Hands];
Short, broad hands;
Short metacarpals;
Short phalanges;
Cone-shaped epiphyses;
[Feet];
Large halluces;
Short metatarsals

SKIN, NAILS, HAIR:
[Skin];
Dorsal hand wrinkling;
Pigmented nevi

NEUROLOGIC:
[Central nervous system];
Mental retardation (IQ 24-85) (variable);
Hydrocephalus

ENDOCRINE FEATURES:
Multiple hormone resistance;
Irregular menses;
Hypogonadism

LABORATORY ABNORMALITIES:
Increased serum parathyroid hormone;
Low or normal serum calcium;
Normal or increased serum phosphate;
Increased urinary cAMP excretion;
Increased serum thyrotropin;
Increased serum calcitonin

MISCELLANEOUS:
Epiphyseal stippling is gone by 8 months of age;
Majority of cases are sporadic;
Associated with advanced paternal age;
Not all patients have facial dysmorphism

MOLECULAR BASIS:
Caused by mutation in the cAMP-dependent regulatory subunit 1 of protein
kinase A gene (PRKAR1A, 188830.0015)

*FIELD* CN
Cassandra L. Kniffin - updated: 5/1/2012
Cassandra L. Kniffin - updated: 7/11/2011
Kelly A. Przylepa - revised: 12/31/2002

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

*FIELD* ED
joanna: 05/08/2012
ckniffin: 5/1/2012
joanna: 12/30/2011
ckniffin: 7/11/2011
joanna: 1/7/2003
joanna: 12/31/2002

*FIELD* CN
Cassandra L. Kniffin - updated: 5/1/2012
Cassandra L. Kniffin - updated: 7/11/2011
Victor A. McKusick - updated: 3/6/1997

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

*FIELD* ED
carol: 05/04/2012
ckniffin: 5/1/2012
wwang: 7/13/2011
ckniffin: 7/11/2011
alopez: 3/18/2004
ckniffin: 8/27/2003
mark: 3/6/1997
terry: 3/5/1997
davew: 8/1/1994
mimadm: 3/11/1994
carol: 12/6/1993
carol: 11/11/1993
supermim: 3/16/1992
carol: 5/29/1991

MIM 160980
*RECORD*
*FIELD* NO
160980
*FIELD* TI
#160980 CARNEY COMPLEX, TYPE 1; CNC1
;;CARNEY MYXOMA-ENDOCRINE COMPLEX;;
CARNEY SYNDROME; CAR;;
read moreMYXOMA, SPOTTY PIGMENTATION, AND ENDOCRINE OVERACTIVITY;;
NAME SYNDROME;;
LAMB SYNDROME
*FIELD* TX
A number sign (#) is used with this entry because Carney complex type 1
(CNC1) is caused by mutation in the protein kinase A regulatory
subunit-1-alpha gene (PRKAR1A; 188830) on chromosome 17q.

Carney complex type 2 (CNC2; 605244) has been mapped to chromosome 2p16,
indicating genetic heterogeneity. See also isolated primary pigmented
nodular adrenocortical disease (PPNAD1; 610489) and isolated cardiac
myxoma (255960), both of which are manifestations of the Carney complex
that can be seen in isolation.

A family with features of the Carney complex and distal arthrogryposis
(608837) associated with a mutation in the MYH8 gene (160741) has also
been reported.

DESCRIPTION

Carney complex is an autosomal dominant multiple neoplasia syndrome
characterized by cardiac, endocrine, cutaneous, and neural myxomatous
tumors, as well as a variety of pigmented lesions of the skin and
mucosae. Carney complex may simultaneously involve multiple endocrine
glands, similar to classic MEN syndromes (MEN1; 131100 and MEN2;
171400). Carney complex shows some similarities to McCune-Albright
syndrome (MAS; 174800), a sporadic condition that is also characterized
by multiple endocrine and nonendocrine tumors, and shares skin
abnormalities and some nonendocrine tumors with the lentiginoses and
certain of the hamartomatoses, particularly Peutz-Jeghers syndrome (PJS;
175200). Carney complex is often associated with the unusual large-cell
calcifying Sertoli cell tumor and psammomatous melanotic schwannomas
(Kirschner et al., 2000; Stratakis et al., 2001).

CLINICAL FEATURES

Rees et al. (1973) reported a young man with red hair and fair skin who
had multiple lentigines and a left atrial myxoma. Autosomal dominant
inheritance was suggested. Follow-up of this patient by Atherton et al.
(1980) referred to a palatal tumor with characteristics of myxoid
neurofibroma.

Atherton et al. (1980) reported a 10-year-old boy with cutaneous
pigmented lesions, subcutaneous myxoid neurofibromata, and atrial
myxoma. At birth, 3 pigmented lesions were noted on the neck, trunk, and
thigh; a large number of pigmented lesions developed in the first few
weeks of life. He developed several myxoid neurofibromata on the ear,
chin, and anterior chest, as well as 2 cardiac atrial myxomas. The boy
had blue eyes and hair of a distinctive rust-red color. Both parents had
multiple freckles, although less so than the patient. Atherton et al.
(1980) suggested the designation 'NAME syndrome' as an acronym for nevi,
atrial myxoma, myxoid neurofibromata, and ephelides (freckles). Koopman
and Happle (1991) suggested that the acronym NAME could stand for nevi,
atrial myxoma, mucinosis of the skin, and endocrine overactivity.

Proppe and Scully (1980) reported familial occurrence of large-cell
calcifying Sertoli cell tumor of the testes and cardiac myxoma. In a
follow-up of a family reported by Proppe and Scully (1980), Carney et
al. (1986) noted that 2 affected brothers also had nodular
adrenocortical hyperplasia. Their mother had skin pigmentation and left
atrial myxoma.

Schweizer-Cagianut et al. (1980) reported a brother and sister with
Cushing syndrome associated with primary adrenocortical micronodular
dysplasia. The brother also had fibromas of the skin, suggesting the
diagnosis of neurofibromatosis type 1 (NF1; 162200), but cafe-au-lait
spots were absent. The sister had a documented intracranial bleed,
fibromas of the eyelid, and microcalcification of the breasts.
Functional tests suggested an intrinsic defect in the adrenals and no
hypothalamic-pituitary dysfunction. In a follow-up report of the same
family, Schweizer-Cagianut et al. (1982) noted that an older brother had
died at age 5 years of atrial myxoma; he had a hemangioma of the right
groin. On autopsy at age 36 years, the affected sister was found to have
a cardiac myxoma. The fibroma of her eyelid was reinterpreted as a
myxoma; both breasts contained multiple small benign fibroadenomas with
an unusual myxomatous and vascularized stroma, and she was noted to have
had finely freckled pigmentation around the mouth and lips.
Schweizer-Cagianut et al. (1982) concluded that the family had a
syndrome comprising adrenocortical nodular dysplasia, Cushing syndrome,
and myxomatous tumors.

Barlow et al. (1983) described 2 sisters with the combination of Cushing
syndrome, cardiac myxomas, other myxoid tumors, and spotty facial and
labial pigmentation.

Carney et al. (1985) presented evidence for the existence of a distinct
familial syndrome consisting of spotty cutaneous pigmentation, myxomas
of the heart and elsewhere, and Cushing syndrome resulting from nodular
adrenocortical dysplasia. In their family, a brother of the patient had
pigmented spots of the face and lips, had multiple nodular and
pedunculated myxomas of the skin, and at age 21 was found to have
acromegaly caused by pituitary adenoma. Successful hypophysectomy was
performed. A single pigmented macule was found in the mouth in only 2 of
40 patients, in contrast to the Peutz-Jeghers syndrome in which buccal
spotting is a standard feature. Pigmented skin lesions were identified
on the face, eyelids, ears, and vermilion borders of the lips,
conjunctiva or sclera, vulva, back of hands and fingers, anal verge, and
glans penis. Testicular tumors were identified in 9 of 17 male patients;
they were bilateral in 7 patients and multicentric in each affected
testis. The testicular tumors were large-cell calcifying Sertoli cell
tumor, Leydig cell tumor, or adrenocortical rest tumor. Sexual precocity
occurred with the first 2 types. Two patients had an unusual tumor
referred to as a 'calcifying pigmented neuroectodermal tumor.'

Wilsher et al. (1986) described an affected mother and her son and
daughter. The mother had left and right atrial myxomata, and the
daughter had a left ventricular myxoma, subcutaneous myxoid
neurofibromata, and mammary fibroadenosis. Although the son had no
evidence of cardiac myxoma, photos demonstrated that all 3 had melanin
spots around the lips and over the bridge of the nose.

Vidaillet et al. (1987) found 5 cases of what they termed 'syndrome
myxoma' out of a total of 75 patients with cardiac myxoma seen at the
Mayo Clinic between January 1954 and December 1985. They compared 49
cases of syndrome myxoma with cases of sporadic myxoma; the former
showed a younger age, a higher frequency of familial occurrence,
ventricular location of tumor (13% vs 0%), multiple tumors (50% vs 1%),
and recurrent tumor (18% vs 0%).

Young et al. (1989) provided a 50-year follow-up report of a woman seen
at the Mayo Clinic at the age of 17 for Cushing syndrome associated with
adrenal dysfunction. The adrenals were mottled brown in appearance and
contained nodules composed of large adrenocortical cells with moderately
intense brown cytoplasmic pigment. A photograph taken at that time
showed spotty pigmentation involving the face and vermilion borders of
the lips as well as the chest and shoulders. A fraternal twin of this
woman had the same features of Cushing syndrome and spotty facial and
labial pigmentation. He was found to have abnormal adrenal glands with
2- to 3-mm reddish brown bulging nodules and coarsely granular brown
pigment. Both daughters of the proband had spotty facial pigmentation; 1
also had primary pigmented nodular adrenal cortical disease and a
nasopharyngeal schwannoma. Several other members of the family had
spotty facial pigmentation.

Handley et al. (1992) described the Carney syndrome in a mother and her
son and daughter. All 3 had varying degrees of centrofacial/mucosal
lentigines and cutaneous myxoid tumors. The mother had myxoid mammary
fibroadenomatosis and a left atrial myxoma; her daughter developed a
prolactin-secreting pituitary adenoma; the son had bilateral large-cell
calcified Sertoli cell testicular tumors and an axillary psammomatous
melanotic schwannoma.

In a review of 53 patients with Carney complex from 12 families,
Stratakis et al. (1997) identified 2 patients with thyroid carcinoma (1
papillary and 1 follicular; 3.8%) and 1 with a follicular adenoma.
Detailed laboratory studies of the thyroid gland of 5 affected adults
and 6 affected children showed normal results, but thyroid
ultrasonography showed hypoechoic, cystic, solid, or mixed lesions in 3
of the 5 adults (60%) and 4 of the 6 children (67%). Thyroid gland
abnormalities were documented in 5 sibs and 1 parent-child pair.
Stratakis et al. (1997) concluded that thyroid gland pathology is common
in patients with Carney complex, and includes a spectrum of
abnormalities ranging from follicular hyperplasia and/or cystic changes
to carcinoma.

Nwokoro et al. (1997) reported an extensively affected family. The
proband was a 34-year-old woman with multiple nevi, diffuse facial
lentigines, and labial pigmentation present from an early age. Right
ventricular myxomas were resected at the age of 30. She also had
invasive follicular carcinoma of the thyroid gland, Barrett metaplasia
of the esophagus, neoplastic colonic polyps, bipolar affective disorder,
and atypical mesenchymal neoplasm of the uterine cervix distinct from
the myxoid uterine leiomyoma usually seen in this syndrome. Diagnosis of
Carney syndrome was established in her 9-year-old son, and there was a
probable diagnosis in her 12-year-old daughter. Various endocrine
manifestations occurred in at least 9 relatives in 3 generations.
Pituitary microadenoma and calcifying testicular tumor were present in 1
relative each.

Legius et al. (1998) reported a 41-year-old man with the Carney complex.
Clinical features included a pigmented schwannoma on a lumbar nerve root
with microscopically demonstrated psammoma bodies (melanocytic
schwannoma), atrial myxoma resulting in a cerebellar ischemic stroke,
and melanin spots on the vermilion border of the lips, eyelids, and back
of the hands. He also had a left nonfunctional adrenal adenoma,
macroorchidism, and reduced fertility.

Goldstein et al. (1999) reported a 40-year-old man who was a member of a
family segregating for Carney complex, but was initially not thought to
be affected. However, a review of pathologic studies and haplotype
analysis based on genotyping studies with 17q2 microsatellites showed
that he was affected. He presented with recurrent neurofibroma, a tumor
that had not been considered a component of Carney complex. Subsequent
review revealed findings consistent with cutaneous myxoma.
Echocardiography displayed interatrial septal thickening. In addition,
he was noted to have abnormal facial and eyelid hyperpigmented spots
with involvement of the buccal mucosa.

INHERITANCE

Carney et al. (1986) suggested autosomal dominant inheritance. At least
one manifestation of the syndrome occurred in 3 successive generations
of an affected family. Both males and females were affected, and 5 of 11
children of affected persons had the disorder, although no male-to-male
transmission had been reported until the report of Koopman and Happle
(1991).

DIAGNOSIS

Kennedy et al. (1987) emphasized the diagnostic usefulness of
ophthalmologic abnormalities in Carney complex. Of 63 patients studied,
eyelid myxomas were present in 16%, facial and eyelid lentigines in 70%,
and pigmented lesions on the caruncle or conjunctival semilunar fold in
27%. Spotty pigmentation of the skin involved the vermilion border of
the lips but only infrequently affected the buccal mucosa.

Bandelin et al. (2008) reported a 32-year-old woman who presented with
clinical hypercortisolism, including a 30-lb weight gain, central
obesity, oligomenorrhea, hirsutism, and hypertension with hypokalemia.
The patient reported easy bruisability, and her surgical history
included bilateral breast fibrous adenomas within a myxoid stroma. An
adrenal computed tomography (CT) revealed bilateral nodularity; a
positron emission tomography (PET)-CT demonstrated
F(18)-fluorodeoxyglucose uptake in both adrenals. Bandelin et al. (2008)
stated that, to their knowledge, this was the first report of PET-CT
imaging of the adrenal glands in primary pigmented nodular
adrenocortical disease. They concluded that PET-CT imaging may be useful
in the evaluation of patients with ACTH-independent hypercortisolism,
and that, apparently, not all F18-fluorodeoxyglucose-avid adrenal glands
contain malignancies.

MAPPING

Stratakis et al. (1996) first identified a locus for Carney complex on
chromosome 2q, which is now designated CNC2. In a family with Carney
complex, Basson et al. (1997) excluded linkage to the CNC2 locus
identified by Stratakis et al. (1996), indicating genetic heterogeneity
of this disorder.

By studies of 4 kindreds with Carney complex, Casey et al. (1998) found
linkage to a 17-cM locus on chromosome 17q2 (maximal pairwise lod scores
of 5.9, 1.5, 1.8, and 2.9 in each family, respectively).

MOLECULAR GENETICS

In patients with Carney complex, Kirschner et al. (2000) identified
mutations in the PRKAR1A gene (188830.00001-188830.0003).

Kirschner et al. (2000) identified 15 distinct PRKAR1A mutations in
affected members of 22 (41%) of 54 kindreds with Carney complex. Six
families showed linkage to CNC2.

In affected members of 3 unrelated families, Casey et al. (2000)
identified PRKAR1A frameshift mutations resulting in haploinsufficiency
of R1-alpha (188830.0005-188830.0007).

- Loss of Heterozygosity Studies

Stratakis et al. (1998) noted that the lesions in patients with CNC are
similar to those seen in Peutz-Jeghers syndrome and other lentiginosis
syndromes. In tumors and cell lines from 2 CNC families excluded from
the CNC2 locus, Stratakis et al. (1998) found no evidence for loss of
heterozygosity (LOH) involving the Peutz-Jeghers syndrome locus on 19p13
(STK11; 602216) or Cowden disease (158350)/Bannayan-Zonana syndrome
(153480) locus on 10q23 (PTEN; 601728). Studies of 16 additional CNC
patients also did not show LOH at these loci in tumors that were
histologically identical to those seen in Peutz-Jeghers syndrome. The
authors concluded that despite substantial clinical overlap among CNC,
Peutz-Jeghers syndrome, Cowden disease, and Bannayan-Zonana syndrome,
LOH for the STK11 and PTEN loci is an infrequent event in CNC-related
tumors.

Pack et al. (2000) investigated the pituitary glands of 8 patients with
CNC1 and acromegaly. Tumor DNA from 4 tumors was used for comparative
genomic hybridization. All 8 tumors stained for both growth hormone (GH;
139250) and prolactin (PRL; 176760), and some for other hormones, as
well as the guanine nucleotide-binding protein alpha-subunit (GNAS;
139320), which is mutated in McCune-Albright syndrome. Evidence for
somatomammotroph hyperplasia was present in proximity to adenoma tissue
in 5 of 8 patients; in the remaining 3, only adenoma tissue was
available for study. Comparative genomic hybridization showed multiple
changes involving losses of chromosomal regions 6q, 7q, 11p, and 11q,
and gains of 1pter-p32, 2q35-qter, 9q33-qter, 12q24-qter, 16, 17, 19p,
20p, 20q, 22p and 22q in the most aggressive tumor, an invasive
macroadenoma; no chromosomal changes were seen in 3 microadenomas
diagnosed prospectively. The authors concluded that, in at least some
patients with CNC1, the pituitary gland is characterized by somatotroph
hyperplasia, which precedes GH-producing tumor formation, in a pathway
similar to that suggested for McCune-Albright syndrome-related pituitary
tumors.

PATHOGENESIS

To evaluate the role of PKA isozymes on proliferation and cell cycle,
Nesterova et al. (2008) studied the association of inactivating
mutations of PRKAR1A with tumor formation. A cell line with RI-alpha
(encoded by PRKAR1A) haploinsufficiency due to an inactivating PRKAR1A
mutation was transfected with constructs encoding PKA subunits.
Introduction of PKA subunits led to changes in proliferation and cell
cycle: a decrease in aneuploidy and G2/M for the PRKAR1A-transfected
cells, and an increase in S phase and aneuploidy for cells transfected
with PRKAR2B (176912), a known PRKAR1A mutant (RI-alpha), and the PKA
catalytic subunit (PRKACA; 601639). There were alterations in cAMP
levels, PK subunit expression, cyclins, and E2F factors; E2F1 (189971)
was shown to possibly mediate PKA effects on cell cycle by small
interfering RNA studies. cAMP levels and constitutive and stimulated
cAMP signaling were altered in transfected cells.

NOMENCLATURE

Carney et al. (1985) suggested that the acronym NAME syndrome, as well
as the acronym LAMB syndrome (lentigines, atrial myxoma, mucocutaneous
myxoma, and blue nevi) reported by Rhodes et al. (1984), could represent
this pleiotropic syndrome of cutaneous, cardiac, and endocrine
involvement.

Stratakis et al. (1998) suggested that this disorder should be called
Carney complex (CNC), as proposed by Bain (1986). In part, this is to
differentiate it from the triad of gastric leiomyosarcoma, pulmonary
chondroma, and extraadrenal paraganglioma described by Carney (1983) and
sometimes also called Carney syndrome; see 604287. Basson (1999)
indicated that he and other students of Carney complex have used the
symbol CAR for the locus. This symbol has, however, been preempted for
other usage.

Salomon et al. (1990) noted that Schweizer-Cagianut et al. (1982)
provided the first comprehensive description of Carney complex and
suggested that it be called the 'Swiss syndrome' to reflect the country
in which it was described.

HISTORY

Carney (1995) described a fascinating search, which was eventually
successful, for Harvey Cushing's case of Minnie G., who was reported in
his 1912 monograph on the pituitary and its disorders. Carney (1995)
postulated that this patient might have had 'his' syndrome. The patient,
then 23 years old, had been referred to Cushing at The Johns Hopkins
Hospital in 1910. Minnie, whose actual given name was Maita, died in
1958 at the age of 71 years. Having assembled the family pedigree,
Carney (1995) could find no evidence of other affected members in the
extended family.

*FIELD* SA
Stratakis et al. (1996)
*FIELD* RF
1. Atherton, D. J.; Pitcher, D. W.; Wells, R. S.; MacDonald, D. M.
: A syndrome of various cutaneous pigmented lesions, myxoid neurofibromata
and atrial myxoma: the NAME syndrome. Brit. J. Derm. 103: 421-429,
1980.

2. Bain, J.: Carney's complex. Mayo Clin. Proc. 61: 508 only, 1986.

3. Bandelin, P. B.; Moreno, A. J.; LeMar, H. J.; Stratakis, C. A.;
Oliver, T. G.: The use of positron emission tomography-computed tomography
scan in the evaluation of a patient with Carney complex. J. Clin.
Endocr. Metab. 93: 2946-2947, 2008.

4. Barlow, J. F.; Abu-Gazeleh, S.; Tam, G. E.; Wirtz, P. S.; Ofstein,
L. C.; O'Brien, C. P.; Woods, G. L.; Drymalski, W. G.: Myxoid tumor
of the uterus and right atrial myxomas. S. Dakota J. Med. 36: 9-13,
1983.

5. Basson, C. T.: Personal Communication. New York, N.Y. 1/27/1999.

6. Basson, C. T.; MacRae, C. A.; Korf, B.; Merliss, A.: Genetic heterogeneity
of familial atrial myxoma syndromes (Carney complex). Am. J. Cardiol. 79:
994-995, 1997.

7. Carney, J. A.: The search for Harvey Cushing's patient, Minnie
G., and the cause of her hypercortisolism. Am. J. Surg. Path. 19:
100-108, 1995.

8. Carney, J. A.: The triad of gastric epithelioid leiomyosarcoma,
pulmonary chondroma, and functioning extra-adrenal paraganglioma:
a five-year review. Medicine 62: 159-169, 1983.

9. Carney, J. A.; Gordon, H.; Carpenter, P. C.; Shenoy, B. V.; Go,
V. L. W.: The complex of myxomas, spotty pigmentation, and endocrine
overactivity. Medicine 64: 270-283, 1985.

10. Carney, J. A.; Headington, J. T.; Su, W. P. D.: Cutaneous myxomas:
a major component of the complex of myxomas, spotty pigmentation,
and endocrine overactivity. Arch. Derm. 122: 790-798, 1986.

11. Carney, J. A.; Hruska, H. S.; Beauchamp, G. D.; Gordon, H.: Dominant
inheritance of the complex of myxomas, spotty pigmentation, and endocrine
overactivity. Mayo Clin. Proc. 61: 165-172, 1986.

12. Casey, M.; Mah, C.; Merliss, A. D.; Kirschner, L. S.; Taymans,
S. E.; Denio, A. E.; Korf, B.; Irvine, A. D.; Hughes, A.; Carney,
J. A.; Stratakis, C. A.; Basson, C. T.: Identification of a novel
genetic locus for familial cardiac myxomas and Carney complex. Circulation 98:
2560-2566, 1998.

13. Casey, M.; Vaughan, C. J.; He, J.; Hatcher, C. J.; Winter, J.
M.; Weremowicz, S.; Montgomery, K.; Kucherlapati, R.; Morton, C. C.;
Basson, C. T.: Mutations in the protein kinase A R1-alpha regulatory
subunit cause familial cardiac myxomas and Carney complex. J. Clin.
Invest. 106: R31-R38, 2000. Note: Erratum: J. Clin. Invest. 107:
235 only, 2001.

14. Goldstein, M. M.; Casey, M.; Carney, J. A.; Basson, C. T.: Molecular
genetic diagnosis of the familial myxoma syndrome (Carney complex). Am.
J. Med. Genet. 86: 62-65, 1999.

15. Handley, J.; Carson, D.; Sloan, J.; Walsh, M.; Thornton, C.; Hadden,
D.; Bingham, E. A.: Multiple lentigines, myxoid tumours and endocrine
overactivity; four cases of Carney's complex. Brit. J. Derm. 126:
367-371, 1992.

16. Kennedy, R. H.; Waller, R. R.; Carney, J. A.: Ocular pigmented
spots and eyelid myxomas. Am. J. Ophthal. 104: 533-538, 1987.

17. Kirschner, L. S.; Carney, J. A.; Pack, S. D.; Taymans, S. E.;
Giatzakis, C.; Cho, Y. S.; Cho-Chung, Y. S.; Stratakis, C. A.: Mutations
of the gene encoding the protein kinase A type I-alpha regulatory
subunit in patients with the Carney complex. Nature Genet. 26: 89-92,
2000.

18. Kirschner, L. S.; Sandrini, F.; Monbo, J.; Lin, J.-P.; Carney,
J. A.; Stratakis, C. A.: Genetic heterogeneity and spectrum of mutations
of the PRKAR1A gene in patients with the Carney complex. Hum. Molec.
Genet. 9: 3037-3046, 2000.

19. Koopman, R. J. J.; Happle, R.: Autosomal dominant transmission
of the NAME syndrome (nevi, atrial myxoma, mucinosis of the skin and
endocrine overactivity). Hum. Genet. 86: 300-304, 1991.

20. Legius, E.; Daenen, W.; Vandenbergh, V.; Verbeeck, G.; Bex, M.;
Fryns, J. P.: Syndrome of myxomas, spotty skin pigmentation, and
endocrine overactivity (Carney complex). Genet. Counsel. 9: 287-290,
1998.

21. Nesterova, M.; Bossis, I.; Wen, F.; Horvath, A.; Matyakhina, L.;
Stratakis, C. A.: An immortalized human cell line bearing a PRKAR1A-inactivating
mutation: effects of overexpression of the wild-type allele and other
protein kinase A subunits. J. Clin. Endocr. Metab. 93: 565-571,
2008.

22. Nwokoro, N. A.; Korytkowski, M. T.; Rose, S.; Gorin, M. B.; Stadler,
M. P.; Witchel, S. F.; Mulvihill, J. J.: Spectrum of malignancy and
premalignancy in Carney syndrome. Am. J. Med. Genet. 73: 369-377,
1997.

23. Pack, S. D.; Kirschner, L. S.; Pak, E.; Zhuang, Z.; Carney, J.
A.; Stratakis, C. A.: Genetic and histologic studies of somatomammotropic
pituitary tumors in patients with the 'complex of spotty skin pigmentation,
myxomas, endocrine overactivity and schwannomas' (Carney complex). J.
Clin. Endocr. Metab. 85: 3860-3865, 2000.

24. Proppe, K. H.; Scully, R. E.: Large-cell calcifying Sertoli cell
tumor of the testis. Am. J. Clin. Path. 74: 607-619, 1980.

25. Rees, J. R.; Ross, F. G. M.; Keen, G.: Lentiginosis and left
atrial myxoma. Brit. Heart J. 35: 874-876, 1973.

26. Rhodes, A. R.; Silverman, R. A.; Harrist, T. J.; Perez-Atayde,
A. R.: Mucocutaneous lentigines, cardiomucocutaneous myxomas, and
multiple blue nevi: the 'LAMB' syndrome. J. Am. Acad. Derm. 10:
72-82, 1984.

27. Salomon, F.; Froesch, E. R.; Hedinger, C. E.: Familial Cushing's
syndrome ('Carney complex'). (Letter) New Eng. J. Med. 322: 1470
only, 1990.

28. Schweizer-Cagianut, M.; Froesch, E. R.; Hedinger, C.: Familial
Cushing's syndrome with primary adrenocortical microadenomatosis (primary
adrenocortical nodular dysplasia). Acta Endocr. 94: 529-535, 1980.

29. Schweizer-Cagianut, M.; Salomon, F.; Hedinger, C. E.: Primary
adrenocortical nodular dysplasia with Cushing's syndrome and cardiac
myxomas: a peculiar familial disease. Virchows Arch. A Path. Anat.
Histol. 397: 183-192, 1982.

30. Stratakis, C. A.; Carney, J. A.; Lin, J.-P.; Papanicolaou, D.
A.; Karl, M.; Kastner, D. L.; Pras, E.; Chrousos, G. P.: Carney complex,
a familial multiple neoplasia and lentiginosis syndrome: analysis
of 11 kindreds and linkage to the short arm of chromosome 2. J. Clin.
Invest. 97: 699-705, 1996.

31. Stratakis, C. A.; Courcoutsakis, N. A.; Abati, A.; Filie, A.;
Doppman, J. L.; Carney, J. A.; Shawker, T.: Thyroid gland abnormalities
in patients with the syndrome of spotty skin pigmentation, myxomas,
endocrine overactivity, and schwannomas (Carney complex). J. Clin.
Endocr. Metab. 82: 2037-2043, 1997.

32. Stratakis, C. A.; Jenkins, R. B.; Pras, E.; Mitsiadis, C. S.;
Raff, S. B.; Stalboerger, P. G.; Tsigos, C.; Carney, J. A.; Chrousos,
G. P.: Cytogenetic and microsatellite alterations in tumors from
patients with the syndrome of myxomas, spotty skin pigmentation, and
endocrine overactivity (Carney complex). J. Clin. Endocr. Metab. 81:
3607-3614, 1996.

33. Stratakis, C. A.; Kirschner, L. S.; Carney, J. A.: Carney complex:
diagnosis and management of the complex of spotty skin pigmentation,
myxomas, endocrine overactivity, and schwannomas. (Letter) Am. J.
Med. Genet. 80: 183-185, 1998.

34. Stratakis, C. A.; Kirschner, L. S.; Carney, J. A.: Clinical and
molecular features of the Carney complex: diagnostic criteria and
recommendations for patient evaluation. J. Clin. Endocr. Metab. 86:
4041-4046, 2001.

35. Stratakis, C. A.; Kirschner, L. S.; Taymans, S. E.; Tomlinson,
I. P. M.; Marsh, D. J.; Torpy, D. J.; Giatzakis, C.; Eccles, D. M.;
Theaker, J.; Houlston, R. S.; Blouin, J.-L.; Antonarakis, S. E.; Basson,
C. T.; Eng, C.; Carney, J. A.: Carney complex, Peutz-Jeghers syndrome,
Cowden disease, and Bannayan-Zonana syndrome share cutaneous and endocrine
manifestations, but not genetic loci. J. Clin. Endocr. Metab. 83:
2972-2976, 1998.

36. Vidaillet, H. J., Jr.; Seward, J. B.; Fyke, F. E., III; Su, W.
P. D.; Tajik, A. J.: 'Syndrome myxoma': a subset of patients with
cardiac myxoma associated with pigmented skin lesions and peripheral
and endocrine neoplasms. Brit. Heart J. 57: 247-255, 1987.

37. Wilsher, M. L.; Synek, B. J. L.; Roche, A. H. G.; Holdaway, I.
M.; Neutze, J. M.; Nicholson, G. I.: A familial syndrome of cardiac
myxomas, myxoid neurofibromata, cutaneous pigmented lesions, and endocrine
abnormalities. Aust. New Zeal. J. Med. 16: 393-396, 1986.

38. Young, W. F., Jr.; Carney, J. A.; Musa, B. U.; Wulffraat, N. M.;
Lens, J. W.; Drexhage, H. A.: Familial Cushing's syndrome due to
primary pigmented nodular adrenocortical disease: reinvestigation
50 years later. New Eng. J. Med. 321: 1659-1664, 1989.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Eyes];
Conjunctival and scleral pigmentation;
Eyelid myxoma

CARDIOVASCULAR:
[Heart];
Atrial myxoma;
Ventricular myxoma;
Congestive heart failure

SKIN, NAILS, HAIR:
[Skin];
Profuse pigmented skin lesions;
Nevi;
Ephelides;
Centrofacial/mucosal lentigines;
Blue nevi;
[Hair];
Hirsuitism;
Red Hair

ENDOCRINE FEATURES:
Pigmented micronodular adrenal dysplasia;
Cushing disease;
Acromegaly;
Thyroid follicular hyperplasia

NEOPLASIA:
Myxoid subcutaneous tumors;
Primary adrenocortical nodular hyperplasia;
Testicular Sertoli cell tumor, calcified;
Pituitary adenoma;
Mammary ductal fibroadenoma;
Schwannoma;
Psammomatous melanotic schwannomas;
Thyroid carcinoma;
Pheochromocytoma

MISCELLANEOUS:
Genetic heterogeneity (see CNC2, 605244)

MOLECULAR BASIS:
Caused by mutation in the cAMP-dependent protein kinase, regulatory,
type I, alpha gene (PRKAR1A, 188830.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 10/17/2006
Kelly A. Przylepa - revised: 3/23/2001

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

*FIELD* ED
joanna: 07/23/2013
joanna: 5/22/2007
ckniffin: 10/17/2006
joanna: 4/18/2001
joanna: 3/23/2001

*FIELD* CN
John A. Phillips, III - updated: 12/10/2010
John A. Phillips, III - updated: 4/24/2009
Cassandra L. Kniffin - reorganized: 10/18/2006
Cassandra L. Kniffin - updated: 10/17/2006
John A. Phillips, III - updated: 3/20/2002
John A. Phillips, III - updated: 10/12/2001
George E. Tiller - updated: 3/5/2001
Victor A. McKusick - updated: 8/28/2000
Victor A. McKusick - updated: 10/26/1999
Victor A. McKusick - updated: 9/1/1999
Victor A. McKusick - updated: 3/11/1999
John A. Phillips, III - updated: 3/3/1999
Victor A. McKusick - updated: 2/24/1999
Victor A. McKusick - updated: 2/10/1999
Victor A. McKusick - updated: 1/25/1999
Victor A. McKusick - updated: 12/4/1998
Victor A. McKusick - updated: 1/13/1998
John A. Phillips, III - updated: 9/11/1997
Victor A. McKusick - updated: 6/25/1997
John A. Phillips, III - updated: 2/25/1997

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

*FIELD* ED
terry: 09/14/2012
alopez: 12/10/2010
terry: 10/13/2010
alopez: 4/24/2009
carol: 10/18/2006
ckniffin: 10/17/2006
tkritzer: 8/13/2004
tkritzer: 8/12/2004
terry: 8/11/2004
carol: 10/18/2002
alopez: 3/20/2002
alopez: 10/12/2001
cwells: 3/6/2001
cwells: 3/5/2001
cwells: 3/2/2001
alopez: 8/30/2000
terry: 8/28/2000
carol: 11/8/1999
terry: 10/26/1999
jlewis: 9/23/1999
terry: 9/1/1999
carol: 5/19/1999
carol: 3/11/1999
terry: 3/11/1999
carol: 3/8/1999
mgross: 3/3/1999
carol: 2/25/1999
carol: 2/24/1999
terry: 2/24/1999
carol: 2/15/1999
mgross: 2/15/1999
terry: 2/10/1999
carol: 1/25/1999
terry: 1/25/1999
carol: 12/9/1998
dkim: 12/9/1998
terry: 12/4/1998
terry: 5/12/1998
mark: 1/16/1998
terry: 1/13/1998
terry: 11/11/1997
dholmes: 11/11/1997
terry: 11/10/1997
dholmes: 10/30/1997
dholmes: 10/29/1997
dholmes: 9/26/1997
dholmes: 9/23/1997
jenny: 7/1/1997
terry: 6/25/1997
jenny: 2/25/1997
mark: 3/27/1996
terry: 3/20/1996
joanna: 1/17/1996
mark: 11/1/1995
carol: 2/7/1995
mimadm: 12/2/1994
davew: 7/14/1994
warfield: 4/21/1994
carol: 6/15/1992

MIM 188830
*RECORD*
*FIELD* NO
188830
*FIELD* TI
*188830 PROTEIN KINASE, cAMP-DEPENDENT, REGULATORY, TYPE I, ALPHA; PRKAR1A
;;TISSUE-SPECIFIC EXTINGUISHER 1; TSE1
read morePRKAR1A/RARA FUSION GENE, INCLUDED;;
PTC2 CHIMERIC ONCOGENE, INCLUDED
*FIELD* TX

DESCRIPTION

PRKAR1A is a critical component of type I protein kinase A (PKA), the
main mediator of cAMP signaling in mammals. PKA is a tetramer consisting
of 2 regulatory and 2 catalytic subunits. It is inactive in the absence
of cAMP. Activation occurs when 2 cAMP molecules bind to each regulatory
subunit, eliciting a reversible conformational change that releases
active catalytic subunits. Four distinct regulatory subunits of PKA have
been identified: RI-alpha, RI-beta (176911), RII-alpha (176910), and
RII-beta (176912). Phosphorylation mediated by the cAMP/PKA signaling
pathway is involved in the regulation of metabolism, cell proliferation,
differentiation, and apoptosis (review by Bossis and Stratakis, 2004).

CLONING

Extinction is an operational term that refers to the lack of expression
of tissue-specific traits and is generally observed in hybrid cells
formed by fusing dissimilar cell types. Killary and Fournier (1984)
studied extinction of liver-specific tyrosine aminotransferase (613018)
when rat hepatoma cells were fused with mouse fibroblasts. By microcell
hybrids, they showed that mouse chromosome 11 was specifically
responsible for extinction and that homologous human chromosome 17 had
the same activity. The tissue-specific extinguisher-1 locus (Tse1) in
the mouse represses gene expression in trans. To search for other
Tse1-responsive genes, Lem et al. (1988) screened for expression of
liver-specific mRNAs in hepatoma microcell hybrids containing mouse
chromosome 11 or human chromosome 17. Whereas most liver gene activity
was unaffected in such hybrids, phosphoenolpyruvate carboxykinase
(261650, 261680) and tyrosine aminotransferase gene expression was
coordinately repressed in these clones. Extinction of both genes was
apparently mediated by a single genetic locus that resides on human
chromosome 17.

Sandberg et al. (1987) cloned the regulatory subunit of type I
cAMP-dependent protein kinase A from a human testis cDNA library. The
cDNA encodes a deduced 381-amino acid protein. Northern blot analysis
demonstrated 1.5- and 3.0-kb mRNA transcripts in human testis and a
3.0-kb transcript in human T lymphocytes.

Boshart et al. (1991) identified the regulatory subunit RI-alpha of PKA
as the product of the TSE1 locus. The evidence consisted of concordant
expression of RI-alpha mRNA and TSE1 genetic activity, high resolution
physical mapping of the 2 genes on human chromosome 17, and the ability
of transfected RI-alpha cDNA to generate a phenocopy of TSE1-mediated
extinction. Jones et al. (1991) independently established identity of
TSE1 and the RI-alpha subunit.

MAPPING

Catalano et al. (2007) noted that the PRKAR1A gene maps to chromosome
17q24.

GENE FUNCTION

Amieux et al. (2002) presented evidence indicating that increased basal
PKA activity resulting from targeted disruption of the mouse RI-alpha
isoform affects signaling in the primitive streak, causing profound
deficits in the production of all mesoderm derivatives including the
heart. In contrast, disruption of the RII-alpha subunit did not result
in any developmental defects.

Jia et al. (2004) showed that PKA and casein kinase I (CKI; 600505)
regulate Smo (601500) cell surface accumulation and activity in response
to hedgehog (Hh; see 600725). Blocking PKA or CKI activity in the
Drosophila wing disc prevented Hh-induced Smo accumulation and
attenuated pathway activity, whereas increasing PKA activity promoted
Smo accumulation and pathway activation. Jia et al. (2004) showed that
PKA and CKI phosphorylate Smo at several sites, and that
phosphorylation-deficient forms of Smo fail to accumulate on the cell
surface and are unable to transduce the Hh signal. Conversely,
phosphorylation-mimicking Smo variants showed constitutive cell surface
expression and signaling activity. Furthermore, Jia et al. (2004) found
that the levels of Smo cell surface expression and activity correlated
with its levels of phosphorylation. Jia et al. (2004) concluded that Hh
induces progressive Smo phosphorylation by PKA and CKI, leading to
elevation of Smo cell surface levels and signaling activity.

Using immunofluorescent and confocal microscopy, Durick et al. (1998)
demonstrated that ENIGMA (605903) is localized through its PDZ domain to
the cell periphery and in some cytoskeletal components, and that ENIGMA
colocalizes with RET/PTC2. Yeast 2-hybrid analysis showed that ENIGMA
binds through its LIM2 domain to RET/PTC2 at tyr586 in a
phosphorylation-independent manner, and that this interaction, as well
as binding by SHC1 (600560), is required for RET/PTC2 mitogenic
activity.

Zhang et al. (2005) showed that in adipocytes, chronically high insulin
levels inhibit beta-adrenergic receptors (see 109630), but not other
cAMP-elevating stimuli, from activating PKA. They measured this using an
improved fluorescent reporter and by phosphorylation of endogenous CREB
(123820). Disruption of PKA scaffolding mimicked the interference of
insulin with beta-adrenergic receptor signaling. Zhang et al. (2005)
suggested that chronically high insulin levels may disrupt the close
apposition of beta-adrenergic receptors and PKA, identifying a new
mechanism for crosstalk between heterologous signal transduction
pathways.

Dodge-Kafka et al. (2005) identified a cAMP-responsive signaling complex
maintained by the muscle-specific A-kinase anchoring protein (AKAP6;
604691) that includes PKA, PDE4D3 (600129), and EPAC1 (606057). These
intermolecular interactions facilitate the dissemination of distinct
cAMP signals through each effector protein. Anchored PKA stimulates
PDE4D3 to reduce local cAMP concentrations, whereas an AKAP6-associated
ERK5 (602521) kinase module suppresses PDE4D3. PDE4D3 also functions as
an adaptor protein that recruits EPAC1, an exchange factor for the small
GTPase RAP1 (179520), to enable cAMP-dependent attenuation of ERK5.
Pharmacologic and molecular manipulations of the AKAP6 complex showed
that anchored ERK5 can induce cardiomyocyte hypertrophy. Thus,
Dodge-Kafka et al. (2005) concluded that 2 coupled cAMP-dependent
feedback loops are coordinated within the context of the AKAP6 complex,
suggesting that local control of cAMP signaling by AKAP proteins is more
intricate than had been appreciated.

Using a combination of in vitro explant assays, mutant analysis, and
gene delivery into mouse embryos cultured ex vivo, Chen et al. (2005)
demonstrated that adenylyl cyclase (see 103072) signaling through PKA
and its target transcription factor CREB are required for Wnt (see
164820)-directed myogenic gene expression. Wnt proteins can also
stimulate CREB-mediated transcription, providing evidence for a Wnt
signaling pathway involving PKA and CREB.

Basu et al. (2005) showed that activation-induced cytidine deaminase
(AID; 605257) from B cells is phosphorylated on a consensus PKA site and
that PKA is the physiologic AID kinase. Basu et al. (2005) showed that
AID from nonlymphoid cells can be functionally phosphorylated by
recombinant PKA to allow interaction with replication protein A (RPA;
see 179835) and promote deamination of transcribed double-stranded DNA
(dsDNA) substrates. Moreover, mutation of the major PKA phosphorylation
site of AID preserves single-stranded DNA (ssDNA) deamination activity,
but markedly reduces RPA-dependent dsDNA deamination activity and
severely impairs the ability of AID to effect class switch recombination
in vivo. Basu et al. (2005) concluded that PKA has a critical role in
posttranslation al regulation of AID activity in B cells.

BIOCHEMICAL FEATURES

Kim et al. (2005) determined the crystal structure of the cAMP-dependent
protein kinase catalytic subunit bound to a deletion mutant of the
regulatory subunit (RI-alpha) at 2.0-angstrom resolution. This structure
defines a previously unidentified extended interface in which the large
lobe of the catalytic subunit is like a stable scaffold where tyr247 in
the G helix and trp196 in the phosphorylated activation loop serve as
anchor points for binding the RI-alpha subunit. These residues compete
with cAMP for the phosphate-binding cassette in RI-alpha. In contrast to
this catalytic subunit, RI-alpha undergoes major conformational changes
when the complex is compared with cAMP-bound RI-alpha. Kim et al. (2005)
concluded that the complex provides a molecular mechanism for inhibition
of PKA and suggests how cAMP binding leads to activation.

CYTOGENETICS

Papillary thyroid carcinoma (188550) can be caused by chimeric oncogenes
formed by fusion of the tyrosine kinase domain of the RET protooncogene
(164761) to the 5-prime terminal region of another gene. See, for
example, PTC1 (601985). Bongarzone et al. (1993) isolated and sequenced
a type of RET oncogenic rearrangement involving the TSE1 gene. Analysis
of the nucleotide sequence indicated that the transforming activity was
created by the fusion of the RET tyrosine kinase domain with part of the
RI-alpha regulatory subunit of PKA. The authors stated that this was the
first example of an oncogenic activity involving a PKA gene. The
chimeric oncogene formed by the fusion of the RET and TSE1 genes is
known as PTC2.

Catalano et al. (2007) reported a 66-year-old man with acute
promyelocytic leukemia (APL) who was found to have a PRKAR1A/RARA
(180240) fusion gene, possibly resulting from an insertion of RARA
distal to PRKAR1A, followed by a deletion of 3-prime PRKAR1A, 5-prime
RARA, and any intervening sequences. The fusion transcript resulted from
cryptic splicing of the first 100 bases of PRKAR1A exon 3 to the 5-prime
end of RARA exon 3, and predicted a 495-amino acid fusion protein. The
C-terminal end of RARA involved is that shared by all RARA
rearrangements in APL. The patient had a good response to chemotherapy
with complete remission of the disease by 11 months. Catalano et al.
(2007) postulated that fusion of the R1-alpha dimerization domain to
RARA may be involved in deregulation of PKA.

MOLECULAR GENETICS

Carney complex (see CNC1, 160980) is a multiple neoplasia syndrome
characterized by spotty skin pigmentation, cardiac and other myxomas,
endocrine tumors, and psammomatous melanotic schwannomas. Because of its
similarities to the McCune-Albright syndrome (MAS; 174800) and other
features, such as paradoxical responses to endocrine signals, genes
implicated in cyclic nucleotide-dependent signaling were thought to be
candidates for the site of mutation(s) in Carney complex (DeMarco et
al., 1996). In tumor tissue from Carney complex families mapping to 17q,
Kirschner et al. (2000) detected loss of heterozygosity (LOH) in the
vicinity of the PRKAR1A gene, including a polymorphic site within its
5-prime region. In affected members of 3 unrelated kindreds, they
identified a germline mutation in the PRKAR1A gene (188830.0001).
Analysis of additional cases demonstrated the same mutation in a
sporadic case of Carney complex, and different mutations in 3 other
families, including 1 with isolated inherited cardiac myxomas
(188830.0002-188830.0004). Analysis of protein kinase A (PKA) activity
in Carney complex tumors demonstrated a decreased basal activity, but an
increase in cAMP-stimulated activity compared with non-Carney complex
tumors. Kirschner et al. (2000) concluded that germline mutations in
PRKAR1A, an apparent tumor-suppressor gene, are responsible for the
Carney complex phenotype in a subset of patients with that disorder.

Independently, Casey et al. (2000) had noted from a search of the Human
Genome Project databases that the PRKAR1A gene is included within the
minimal interval for the Carney complex locus on 17q. Furthermore, they
noted that a human genomic BAC clone contained sequences corresponding
to both PRKAR1A and an anonymous marker that exhibited no recombination
with the Carney complex gene in families they had studied. Therefore,
the PRKAR1A chromosomal location, the known role of PKA in signal
transduction and cell growth, and the ubiquitous expression pattern of
the R1-alpha subunit all suggested this gene as a candidate for Carney
complex. In affected members of 3 unrelated families, they demonstrated
PRKAR1A frameshift mutations resulting in haploinsufficiency of R1-alpha
(188830.0005-188830.0007).

Kirschner et al. (2000) identified the PRKAR1A genomic structure,
screened for mutations in 34 CNC families and 20 patients with sporadic
disease, and confirmed the genetic heterogeneity of CNC. Altogether, 15
distinct PRKAR1A mutations were identified in 22 (41%) of 54 kindreds.
In 14 mutations, the sequence change was predicted to lead to a
premature stop codon; one altered the initiator ATG codon. Mutant mRNAs
containing a premature stop codon were unstable, as a result of
nonsense-mediated mRNA decay (NMD). Accordingly, the predicted truncated
PRKAR1A protein products were absent in these cells. The authors
concluded that all of the CNC alleles on 17q are functionally null
mutations of PRKAR1A. Six families mapped to the CNC2 locus (605244) on
2p16.

Groussin et al. (2002) studied 11 new kindreds with primary pigmented
nodular adrenocortical disease or Carney complex and found that 9 of
them had PRKAR1A gene defects (including 7 novel inactivating
mutations), most of which led to nonsense mRNA and, thus, were not
expressed in patients' cells. However, in 1 kindred, a splice site
mutation, ivs6+1G-T (188830.0011), led to exon 6 skipping and an
expressed shorter PRKAR1A protein. The mutant protein was present in
patients' leukocytes and tumors, and in vitro studies indicated that the
mutant PRKAR1A activated cAMP-dependent PKA signaling at the nuclear
level. The authors stated that this was the first demonstration of an
inactivating PRKAR1A mutation expressed at the protein level and leading
to stimulation of the PKA pathway in patients with Carney complex. Along
with the lack of allelic loss at the PRKAR1A locus in most of the tumors
from this kindred, these data suggested that alteration of PRKAR1A
function, not only its complete loss, is sufficient for augmenting PKA
activity leading to tumorigenesis in tissues in patients with Carney
complex.

Robinson-White et al. (2003) determined that PKA activity both at
baseline and after stimulation with cAMP was augmented in cells carrying
PRKAR1A mutations. Quantitative message analysis showed that the main
PKA subunits expressed were type I (RI-alpha and RI-beta), but RI-alpha
was decreased in mutant cells. Immunoblot assays of ERK1/2 (601795,
176948) phosphorylation by the cell- and pathway-specific stimulant
lysophosphatidic acid (LPA) showed activation of this pathway in a time-
and concentration-dependent manner that was prevented by a specific
inhibitor. There was a greater rate of growth in mutant cells; forskolin
and isoproterenol inhibited LPA-induced ERK1/2 phosphorylation in normal
but not in mutant cells. Forskolin inhibited LPA-induced cell
proliferation and metabolism in normal cells, but stimulated these
parameters in mutant cells. These data were also replicated in a
pituitary tumor cell line carrying the most common PRKAR1A mutation,
578delTG (188830.0001), and an in vitro construct of mutant PRKAR1A that
was shown to lead to augmented PKA-mediated phosphorylation.
Robinson-White et al. (2003) concluded that PKA activity in CNC cells is
increased and that its stimulation by forskolin or isoproterenol
increases LPA-induced ERK1/2 phosphorylation, cell metabolism, and
proliferation. They speculated that reversal of PKA-mediated inhibition
of this MAPK pathway in CNC cells may contribute to tumorigenesis in
this condition.

Robinson-White et al. (2006) investigated how PKA and its subunits and
ERK1/2 and their molecular partners change in the presence of PRKAR1A
mutations in adrenocortical tissue. Mutations in PRKAR1A caused
increased total cAMP-stimulated kinase activity, likely the result of
upregulation of other PKA subunits caused by downregulation of RI-alpha,
as seen in human lymphocytes and mouse animal models. The authors
concluded that these changes, associated with enhanced MAPK activity,
may be, in part, responsible for the proliferative signals that result
in primary pigmented nodular adrenocortical disease.

Veugelers et al. (2004) performed mutation analysis of the PRKAR1A gene
in 51 unrelated probands with Carney complex and identified mutations in
33 (65%). All mutations, except for 1 missense mutation (188830.0013),
led to PRKAR1A haploinsufficiency.

Greene et al. (2008) identified 7 pathogenic PRKAR1A mutations (see,
e.g., 188830.0013) that resulted in expressed mutant proteins and not
premature stop codons that lead to subsequent NMD. In vitro functional
expression studies showed that the mutant proteins all resulted in
increased PKA activity, most likely caused by decreased binding of the
mutant PRKAR1A to cAMP and/or the catalytic subunit. The findings
suggested that altered PRKAR1A activity, not only haploinsufficiency, is
sufficient enough to increase PKA activity, which likely results in
tumorigenesis.

Systemic lupus erythematosus (SLE; 152700) is an autoimmune disorder
characterized by diverse dysfunctions of immune effector cells,
including proliferation and cytotoxicity. In T cells from patients with
SLE, activity of type 1 protein kinase A isozymes is greatly reduced
because of decreased expression of the alpha and beta regulatory
subunits. Laxminarayana et al. (2002) cloned and sequenced cDNA of
PRKAR1A and corresponding genomic DNA of the coding region to detect
sequence changes from 8 patients with SLE and 6 healthy controls.
Various transcript mutations, including deletions, transitions, and
transversions, were found at a frequency 7.5 times higher than that in
control T cells. By contrast, no genomic mutations were identified.
Because transcript editing is regulated by adenosine deaminases that act
on RNA (ADAR; 146920), they quantified expression of ADAR1 transcripts
in SLE and control cells, finding that ADAR1 mRNA content was 3.5 times
higher in SLE cells than in control T cells.

In 3 unrelated patients with acrodysostosis with hormone resistance
(ACRDYS1; 101800), Linglart et al. (2011) identified a de novo
truncating mutation in the PRKAR1A gene (R368X; 188830.0015). The
mutation resulted in decreased protein kinase A sensitivity to cAMP,
causing multiple hormone resistance and skeletal anomalies.

ANIMAL MODEL

Because they had identified 24 mutations in the PRKAR1A gene in 33 of 51
(65%) unrelated probands with Carney complex, all but 1 of which
resulted in haploinsufficiency, Veugelers et al. (2004) studied the
consequences of Prkar1a haploinsufficiency in mice. Although they did
not observe cardiac myxomas or altered pigmentation in Prkar1a +/- mice,
they did observe some phenotypes similar to Carney complex, including
altered heart rate variability. Moreover, Prkar1a +/- mice exhibited a
marked propensity for extracardiac tumorigenesis. They developed
sarcomas and hepatocellular carcinomas. Sarcomas were frequently
associated with myxomatous differentiation. Tumors from Prkar1a +/- mice
did not exhibit Prkar1a loss of heterozygosity. Veugelers et al. (2004)
concluded that although PRKAR1A haploinsufficiency does predispose to
tumorigenesis, distinct secondary genetic events are required for tumor
formation.

Griffin et al. (2004) created a transgenic mouse model carrying an
antisense transgene for Prkar1a, resulting in an approximately 50%
decrease in protein levels similar to haploinsufficiency. The transgenic
mice developed thyroid follicular hyperplasia and adenomas,
adrenocortical hyperplasia, hypercorticosteronemia, late-onset weight
gain, visceral adiposity, and mesenchymal tumors. The thyroid and
adrenocortical tumors showed loss of heterozygosity at the Prkar1a
locus. Griffin et al. (2004) suggested that the transgenic mice
displayed several findings seen in patients with Carney complex,
supporting the role of PRKAR1A as a tumor suppressor gene.

Almeida et al. (2010) investigated Prkar1a +/- mice when bred within the
Rb1 +/- (614041) or Trp53 +/- (191170) backgrounds, or treated with a
2-step skin carcinogenesis protocol. Prkar1a +/- Trp53 +/- mice
developed more sarcomas than Trp53 +/- mice (p less than 0.05), and
Prkar1a +/- Rb1 +/- mice grew more (and larger) pituitary and thyroid
tumors than Rb1 +/- mice. All mice with double heterozygosity had
significantly reduced life spans compared with their single-heterozygous
counterparts. Prkar1a +/- mice also developed more papillomas than
wildtype animals. A whole-genome transcriptome profiling of tumors
produced by all 3 models identified Wnt signaling as the main pathway
activated by abnormal cAMP signaling, along with cell cycle
abnormalities. siRNA downregulation of Ctnnb1 (116806), E2f1 (189971),
or Cdk4 (123829) inhibited proliferation of human adrenal cells bearing
a PRKAR1A-inactivating mutation and Prkar1a +/- mouse embryonic
fibroblasts and arrested both cell lines at the G0/G1 phase of the cell
cycle. Almeida et al. (2010) concluded that Prkar1a haploinsufficiency
is a relatively weak tumorigenic signal that can act synergistically
with other tumor suppressor gene defects or chemicals to induce tumors,
mostly through Wnt-signaling activation and cell cycle dysregulation.

*FIELD* AV
.0001
CARNEY COMPLEX, TYPE 1
PRKAR1A, 2-BP DEL, 578TG

In affected members of 2 unrelated families with Carney complex
(160980), Kirschner et al. (2000) identified a heterozygous 2-bp
deletion (578delTG) in exon 4B of the PRKAR1A gene, resulting in a
frameshift and premature termination of the protein before the cAMP
binding domain. The families did not share the same chromosome 17
haplotype on the disease-bearing allele. The 2-bp deletion was also
found in a third family and in a sporadic case.

.0002
CARNEY COMPLEX, TYPE 1
PRKAR1A, 889GG-CT

In affected members of a family with Carney complex (160980), Kirschner
et al. (2000) identified a heterozygous 889GG-CT change in exon 8 of the
PRKAR1A gene, leading to premature termination after residue 204 and
truncation of the N terminus at the second cAMP binding domain.

.0003
CARNEY COMPLEX, TYPE 1
PRKAR1A, IVS8DS, A-G, +3

In affected members of a family with Carney complex (160980), Kirschner
et al. (2000) identified a heterozygous A-to-G transition at position +3
of intron 8 of the PRKAR1A gene, presumably resulting in a defect in
splicing of the protein product.

.0004
MYXOMA, INTRACARDIAC
PRKAR1A, 4-BP DEL, 617TTAT

In affected members of a family segregating cardiac myxomas (255960) and
no other features of Carney complex (160980), originally reported by
Liebler et al. (1976), Kirschner et al. (2000) identified a heterozygous
4-bp deletion, 617TTAT, in exon 5 of the PRKAR1A gene. The deletion
resulted in a frameshift after residue 204 and a stop codon after 26
missense residues. The mutation would abolish the second cAMP-binding
domain.

.0005
CARNEY COMPLEX, TYPE 1
PRKAR1A, 1-BP DEL, 710G

In affected members of a family with Carney complex (160980), Casey et
al. (2000) demonstrated a 1-bp deletion (G) at nucleotide 710 of the
PRKAR1A gene (gly208 of the protein), with a consequent frameshift and
premature stop 13 codons later.

.0006
CARNEY COMPLEX, TYPE 1
PRKAR1A, 2-BP DEL, 845TC

In affected members of a family with Carney complex (160980), Casey et
al. (2000) found a 2-bp deletion (TC) of nucleotides 845-846 at val253
of the PRKAR1A gene, with a consequent frameshift and a premature stop
15 codons later.

.0007
CARNEY COMPLEX, TYPE 1
PRKAR1A, 2-BP DEL, 576TG

In affected members of a family with Carney complex (160980), Casey et
al. (2000) found a 2-bp deletion (TG) of nucleotides 576-577 at thr163
of the PRKAR1A gene, resulting in a frameshift and a premature stop 6
codons later.

.0008
CARNEY COMPLEX, TYPE 1
PRKAR1A, 88AG

In affected members of a family with Carney complex (160980), Kirschner
et al. (2000) found an A-to-G transition at nucleotide 88 of the PRKAR1A
gene, abolishing the ATG translation start codon in exon 2.

.0009
PIGMENTED NODULAR ADRENOCORTICAL DISEASE, PRIMARY, 1
PRKAR1A, 102G-A

Groussin et al. (2002) investigated the genetics of patients with
sporadic and isolated primary pigmented nodular adrenocortical disease
(PPNAD1; 610489) by sequencing the PRKAR1A gene in 5 patients. Different
inactivating germline mutations were found in all 5 patients. In an
18-year-old woman of African origin with ACTH-independent Cushing
syndrome, who presented with a 2.5-cm macronodule of the right adrenal
mimicking an adrenal adenoma, the authors found 2 mutations in the
PRKAR1A gene. One was a germline point mutation in the splice donor site
of exon 1B, 102G-A, that resulted in partial exon skipping. An
abnormally short mRNA was predicted to impede translation into PRKAR1A
protein. The second mutation was a 16-bp deletion of the acceptor splice
site of exon 4B (-17 to -2) was found only in the macronodule of the
right adrenal. Groussin et al. (2002) concluded that inactivating
germline mutations of PRKAR1A are frequent in sporadic and isolated
cases of PPNAD. The wildtype allele can be inactivated by somatic
mutations, consistent with the hypothesis of the gene being a tumor
suppressor gene.

.0010
PIGMENTED NODULAR ADRENOCORTICAL DISEASE, PRIMARY, 1
PRKAR1A, 16-BP DEL

See 188830.0009 and Groussin et al. (2002).

.0011
CARNEY COMPLEX, TYPE 1
PRKAR1A, IVS6DS, G-T, +1

In a mother and son with Carney complex (160980), Groussin et al. (2002)
demonstrated heterozygosity for a splice site mutation in the PRKAR1A
gene, IVS6+1G-T, which led to exon 6 skipping and an expressed shorter
PRKAR1A protein. The mother had the disorder in severe form and died of
a pancreatic adenocarcinoma with rapidly growing liver metastasis. She
had lentigines, heart myxoma, primary pigmented nodular adrenocortical
disease, toxic multinodular goiter, and ovarian cyst. The mutant protein
was present in patients' leukocytes and tumors, and in vitro studies
indicated that it activated PKA signaling at the nuclear level. Along
with a lack of allelic loss at the PRKAR1A locus in most of the tumors
from this kindred, these data suggested that alteration of PRKAR1A
function, not only its complete loss, is sufficient for augmenting PKA
activity leading to tumorigenesis.

.0012
ADRENOCORTICAL TUMOR, SOMATIC
PRKAR1A, IVS9AS, G-A, -1

In 3 cases of sporadic adrenocortical tumor, Bertherat et al. (2003)
identified somatic mutations in the PRKAR1A gene, 1 of which was a
splicing mutation (IVS9AS-1G-A). All 3 mutations predicted premature
termination of the protein. Somatic alterations in PRKAR1A had
previously been described only in thyroid tumors (Sandrini et al.,
2002).

.0013
CARNEY COMPLEX, TYPE 1
PRKAR1A, ARG74CYS

In affected members of an English family with Carney complex (160980),
Veugelers et al. (2004) identified a 307C-T transition in the PRKAR1A
gene, resulting in an arg74-to-cys (R74C) substitution. The mutation did
not result in haploinsufficiency, and lymphoblasts from the proband
showed no alteration in R1-alpha protein levels. The phenotypes in
affected individuals were typical of Carney complex and included spotty
pigmentation, cardiac myxoma, thyroid adenoma, breast myxofibroma, and
pulmonic stenosis. One affected member had congenital unilateral
deafness.

By in vitro functional expression studies, Greene et al. (2008) found
that the R74C mutant protein was expressed and resulted in increased PKA
activity, most likely caused by decreased binding of the mutant PRKAR1A
to cAMP and/or the catalytic subunit. The R74C substitution is located
in the linker region of the protein. The findings indicated that altered
PRKAR1A activity, not only haploinsufficiency, is sufficient enough to
increase PKA activity, which likely results in tumorigenesis.

.0014
PIGMENTED NODULAR ADRENOCORTICAL DISEASE, PRIMARY, 1
CARNEY COMPLEX, INCLUDED
PRKAR1A, IVS6, 6-BP DEL

In 12 unrelated kindreds referred for Cushing syndrome due to primary
pigmented nodular adrenocortical disease (PPNAD1; 610489), Groussin et
al. (2006) reported a 6-bp polypyrimidine tract deletion extending from
positions -7 to -2 in intron 6 of the PRKAR1A gene. Nine of the patients
had no family history; in 2, there was a family history of isolated
PPNAD. Only 1 patient met the criteria for Carney complex (160980). Some
relatives carrying the same mutation had no manifestations of Carney
complex or PPNAD, suggesting a low penetrance of this PRKAR1A defect.
Groussin et al. (2002) originally described this mutation in 1 of 5
patients with PPNAD.

.0015
ACRODYSOSTOSIS 1, WITH HORMONE RESISTANCE
PRKAR1A, ARG368TER

In 3 unrelated patients with acrodysostosis-1 with hormone resistance
(ACRDYS1; 101800), Linglart et al. (2011) identified a de novo
heterozygous 1101C-T transition in exon 11 of the PRKAR1A gene,
resulting in an arg368-to-ter (R368X) substitution predicted to result
in absence of the cAMP-binding domain B. The mutation was not found in
200 control samples. Patient cells showed decreased protein kinase A
activity compared to controls. In vitro functional expression studies
showed that the mutant protein had decreased cAMP-induced activation of
protein kinase A compared to wildtype. Bioluminescent studies showed
that the mutant regulatory PRKAR1A subunits were able to bind protein
kinase A catalytic subunits, but were insensitive to dissociation in
response to cAMP. Finally, 3-dimensional models indicated that the R368X
mutation would lead to abnormalities in the domain B pocket that would
preclude high-affinity binding of cAMP. Linglart et al. (2011) concluded
that this was a gain-of-function mutation that decreased protein kinase
A sensitivity to cAMP. The 3 patients had short stature, peripheral
dysostosis, nasal and maxillary hypoplasia, severe brachydactyly,
epiphyseal stippling, and advanced bone age. Serum parathyroid hormone
was markedly increased, but calcium was normal. All had evidence of
multiple hormone resistance, including thyrotropin, calcitonin, growth
hormone-releasing hormone, and gonadotropin. Linglart et al. (2011)
stated that the mutation resulted in an impairment of protein kinase A
activity, not total absence, which may have resulted in variation in the
extent to hormone resistance depending on cell-specific expression of
alternative protein kinase A isoforms.

Michot et al. (2012) identified a heterozygous de novo R368X mutation in
4 unrelated patients with acrodysostosis with hormone resistance. The
patients had short stature, severe brachydactyly, short metatarsals,
metacarpals, and phalanges, and cone-shaped epiphyses in childhood. Only
2 had mild facial dysostosis and all had normal intellect. All had
evidence of hormone resistance, with increased PTH and TSH and clinical
hypothyroidism.

.0016
ACRODYSOSTOSIS 1, WITH HORMONE RESISTANCE
PRKAR1A, TYR373HIS

In a 22-year-old woman with acrodysostosis-1 with hormone resistance
(101800), Michot et al. (2012) identified a de novo heterozygous 1117T-C
transition in the PRKAR1A gene, resulting in a tyr373-to-his (Y373H)
substitution in a highly conserved residue in the catalytic domain. The
mutation was not found in 200 controls and was predicted to be damaging
by PolyPhen. She had intrauterine growth retardation, short stature,
severe brachydactyly, short metatarsals, metacarpals, and phalanges, and
cone-shaped epiphyses in childhood. There was evidence of multiple
hormone resistance, with increased PTH and TSH and clinical
hypothyroidism. She did not have facial dysostosis or intellectual
disability.

.0017
ACRODYSOSTOSIS 1, WITHOUT HORMONE RESISTANCE
PRKAR1A, ARG335PRO

In a patient with acrodysostosis-1 (101800), Lee et al. (2012)
identified a de novo heterozygous 1004G-C transversion in exon 11 of the
PRKAR1A gene, resulting in an arg335-to-pro (R335P) substitution in the
highly conserved cAMP-binding domain B. The mutation was identified by
exome sequencing and confirmed by Sanger sequencing. Lee et al. (2012)
suggested that the mutation would cause reduced cAMP binding, reduced
PKA activation, and decreased downstream signaling. The patient had mild
short stature, small hands, midface hypoplasia, lumbar stenosis, and
mild developmental disability. There was no evidence of endocrine
dysfunction.

.0018
ACRODYSOSTOSIS 1, WITH HORMONE RESISTANCE
PRKAR1A, ILE327THR

In a patient with acrodysostosis-1 (101800), Lee et al. (2012)
identified a de novo heterozygous 980T-C transition in exon 11 of the
PRKAR1A gene, resulting in an ile327-to-thr (I327T) substitution in the
highly conserved cAMP-binding domain B. The mutation was identified by
exome sequencing and confirmed by Sanger sequencing. Lee et al. (2012)
suggested that the mutation would cause reduced cAMP binding, reduced
PKA activation, and decreased downstream signaling. The patient,
previously reported by Graham et al. (2001) (case 1), had mild short
stature, small hands, midface hypoplasia, lumbar stenosis, and mild
developmental disability. He had congenital hypothyroidism, unilateral
undescended testes, and moderate mixed hearing loss. Other features
included dextrocardia, Kartagener syndrome (244400), and multiple
orthopedic problems.

*FIELD* RF
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14. Graham, J. M., Jr.; Krakow, D.; Tolo, V. T.; Smith, A. K.; Lachman,
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15. Greene, E. L.; Horvath, A. D.; Nesterova, M.; Giatzakis, C.; Bossis,
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17. Groussin, L.; Horvath, A.; Jullian, E.; Boikos, S.; Rene-Corail,
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P.; Conte-Devolx, B.; Lucas, M.; Gentil, A.; Malchoff, C. D.; Tissier,
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18. Groussin, L.; Jullian, E.; Perlemoine, K.; Louvel, A.; Leheup,
B.; Luton, J. P.; Bertagna, X.; Bertherat, J.: Mutations of the PRKAR1A
gene in Cushing's syndrome due to sporadic primary pigmented nodular
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19. Groussin, L.; Kirschner, L. S.; Vincent-Dejean, C.; Perlemoine,
K.; Jullian, E.; Delemer, B.; Zacharieva, S.; Pignatelli, D.; Carney,
J. A.; Luton, J. P.; Bertagna, X.; Stratakis, C. A.; Bertherat, J.
: Molecular analysis of the cyclic AMP-dependent protein kinase A
(PKA) regulatory subunit 1A (PRKAR1A) gene in patients with Carney
complex and primary pigmented nodular adrenocortical disease (PPNAD)
reveals novel mutations and clues for pathophysiology: augmented PKA
signaling is associated with adrenal tumorigenesis in PPNAD. Am.
J. Hum. Genet. 71: 1433-1442, 2002.

20. Jia, J.; Tong, C.; Wang, B.; Luo, L.; Jiang, J.: Hedgehog signalling
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A and casein kinase I. Nature 432: 1045-1050, 2004.

21. Jones, K. W.; Shapero, M. H.; Chevrette, M.; Fournier, R. E. K.
: Subtractive hybridization cloning of a tissue-specific extinguisher:
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22. Killary, A. M.; Fournier, R. E. K.: A genetic analysis of extinction:
trans-dominant loci regulate expression of liver-specific traits in
hepatoma hybrid cells. Cell 38: 523-534, 1984.

23. Kim, C.; Xuong, N.-H.; Taylor, S. S.: Crystal structure of a
complex between the catalytic and regulatory (RI-alpha) subunits of
PKA. Science 307: 690-696, 2005.

24. Kirschner, L. S.; Carney, J. A.; Pack, S. D.; Taymans, S. E.;
Giatzakis, C.; Cho, Y. S.; Cho-Chung, Y. S.; Stratakis, C. A.: Mutations
of the gene encoding the protein kinase A type I-alpha regulatory
subunit in patients with the Carney complex. Nature Genet. 26: 89-92,
2000.

25. Kirschner, L. S.; Sandrini, F.; Monbo, J.; Lin, J.-P.; Carney,
J. A.; Stratakis, C. A.: Genetic heterogeneity and spectrum of mutations
of the PRKAR1A gene in patients with the Carney complex. Hum. Molec.
Genet. 9: 3037-3046, 2000.

26. Laxminarayana, D.; Khan, I. U.; Kammer, G. M.: Transcript mutations
of the alpha regulatory subunit of protein kinase A and up-regulation
of the RNA-editing gene transcript in lupus T lymphocytes. Lancet 360:
842-849, 2002.

27. Lee, H.; Graham, J. M., Jr.; Rimoin, D. L.; Lachman, R. S.; Krejci,
P.; Tompson, S. W.; Nelson, S. F.; Krakow, D.; Cohn, D. H.: Exome
sequencing identifies PDE4D mutations in acrodysostosis. Am. J. Hum.
Genet. 90: 746-751, 2012.

28. Lem, J.; Chin, A. C.; Thayer, M. J.; Leach, R. J.; Fournier, R.
E. K.: Coordinate regulation of two genes encoding gluconeogenic
enzymes by the trans-dominant locus Tse-1. Proc. Nat. Acad. Sci. 85:
7302-7306, 1988.

29. Liebler, G. A.; Magovern, G. J.; Park, S. B.; Cushing, W. J.;
Begg, F. R.; Joyner, C. R.: Familial myxomas in four siblings. J.
Thorac. Cardiovasc. Surg. 71: 605-608, 1976.

30. Linglart, A.; Menguy, C.; Couvineau, A.; Auzan, C.; Gunes, Y.;
Cancel, M.; Motte, E.; Pinto, G.; Chanson, P.; Bougneres, P.; Clauser,
E.; Silve, C.: Recurrent PRKAR1A mutation in acrodysostosis with
hormone resistance. New Eng. J. Med. 364: 2218-2226, 2011.

31. Michot, C.; Le Goff, C.; Goldenberg, A.; Abhyankar, A.; Klein,
C.; Kinning, E.; Guerrot, A.-M.; Flahaut, P.; Duncombe, A.; Baujat,
G.; Lyonnet, S.; Thalassinos, C.; Nitschke, P.; Casanova, J.-L.; Le
Merrer, M.; Munnich, A.; Cormier-Daire, V.: Exome sequencing identifies
PDE4D mutations as another cause of acrodysostosis. Am. J. Hum. Genet. 90:
740-745, 2012.

32. Robinson-White, A.; Hundley, T. R.; Shiferaw, M.; Bertherat, J.;
Sandrini, F.; Stratakis, C. A.: Protein kinase-A activity in PRKAR1A-mutant
cells, and regulation of mitogen-activated protein kinases ERK1/2. Hum.
Molec. Genet. 12: 1475-1484, 2003.

33. Robinson-White, A.; Meoli, E.; Stergiopoulos, S.; Horvath, A.;
Boikos, S.; Bossis, I.; Stratakis, C. A.: PRKAR1A mutations and protein
kinase A interactions with other signaling pathways in the adrenal
cortex. J. Clin. Endocr. Metab. 91: 2380-2388, 2006.

34. Sandberg, M.; Tasken, K.; Oyen, O.; Hansson, V.; Jahnsen, T.:
Molecular cloning, cDNA structure and deduced amino acid sequence
for a type I regulatory subunit of cAMP-dependent protein kinase from
human testis. Biochem. Biophys. Res. Commun. 149: 939-945, 1987.

35. Sandrini, F.; Matyakhina, L.; Sarlis, N. J.; Kirschner, L. S.;
Farmakidis, C.; Gimm, O.; Stratakis, C. A.: Regulatory subunit type
1-alpha of protein kinase A (PRKAR1A): a tumor-suppressor gene for
sporadic thyroid cancer. Genes Chromosomes Cancer 35: 182-192, 2002.

36. Veugelers, M.; Wilkes, D.; Burton, K.; McDermott, D. A.; Song,
Y.; Goldstein, M. M.; La Perle, K.; Vaughan, C. J.; O'Hagan, A.; Bennett,
K. R.; Meyer, B. J.; Legius, E.; and 27 others: Comparative PRKAR1A
genotype-phenotype analyses in humans with Carney complex and prkar1a
haploinsufficient mice. Proc. Nat. Acad. Sci. 101: 14222-14227,
2004.

37. Zhang, J.; Hupfeld, C. J.; Taylor, S. S.; Olefsky, J. M.; Tsien,
R. Y.: Insulin disrupts beta-adrenergic signalling to protein kinase
A in adipocytes. Nature 437: 569-573, 2005.

*FIELD* CN
Cassandra L. Kniffin - updated: 5/1/2012
George E. Tiller - updated: 11/17/2011
Cassandra L. Kniffin - updated: 7/11/2011
Carol A. Bocchini - updated: 6/3/2009
Cassandra L. Kniffin - updated: 8/25/2008
Cassandra L. Kniffin - updated: 4/21/2008
John A. Phillips, III - updated: 7/18/2007
John A. Phillips, III - updated: 7/16/2007
Ada Hamosh - updated: 1/30/2006
Ada Hamosh - updated: 11/3/2005
George E. Tiller - updated: 4/22/2005
Ada Hamosh - updated: 3/3/2005
Ada Hamosh - updated: 2/25/2005
Cassandra L. Kniffin - updated: 1/24/2005
Victor A. McKusick - updated: 12/2/2004
Victor A. McKusick - updated: 11/26/2003
Victor A. McKusick - updated: 1/8/2003
John A. Phillips, III - updated: 12/16/2002
Victor A. McKusick - updated: 11/11/2002
Paul J. Converse - updated: 5/4/2001
George E. Tiller - updated: 3/5/2001
Anne M. Stumpf - updated: 2/14/2001
Victor A. McKusick - updated: 8/29/2000
Victor A. McKusick - updated: 8/28/2000

*FIELD* CD
Victor A. McKusick: 10/16/1986

*FIELD* ED
alopez: 01/29/2014
carol: 9/17/2013
terry: 9/14/2012
terry: 5/4/2012
carol: 5/4/2012
ckniffin: 5/1/2012
terry: 2/16/2012
terry: 1/17/2012
carol: 11/22/2011
terry: 11/17/2011
wwang: 7/13/2011
ckniffin: 7/11/2011
carol: 9/17/2009
terry: 6/4/2009
carol: 6/3/2009
carol: 10/9/2008
wwang: 9/18/2008
ckniffin: 8/25/2008
wwang: 4/23/2008
ckniffin: 4/21/2008
alopez: 3/25/2008
carol: 2/15/2008
carol: 1/31/2008
carol: 1/2/2008
alopez: 7/18/2007
alopez: 7/16/2007
carol: 10/18/2006
ckniffin: 10/17/2006
carol: 4/17/2006
alopez: 1/31/2006
terry: 1/30/2006
alopez: 11/7/2005
terry: 11/3/2005
tkritzer: 4/22/2005
alopez: 3/4/2005
terry: 3/3/2005
wwang: 3/3/2005
wwang: 2/28/2005
terry: 2/25/2005
tkritzer: 1/27/2005
ckniffin: 1/24/2005
tkritzer: 12/9/2004
terry: 12/2/2004
terry: 2/23/2004
tkritzer: 12/8/2003
tkritzer: 12/4/2003
terry: 11/26/2003
tkritzer: 1/16/2003
tkritzer: 1/9/2003
terry: 1/8/2003
alopez: 12/16/2002
alopez: 11/12/2002
terry: 11/11/2002
mgross: 5/4/2001
cwells: 3/6/2001
cwells: 3/5/2001
cwells: 3/2/2001
carol: 2/14/2001
alopez: 2/14/2001
alopez: 8/30/2000
terry: 8/29/2000
terry: 8/28/2000
alopez: 10/19/1998
dkim: 9/22/1998
mark: 3/24/1997
terry: 9/6/1996
terry: 9/5/1996
carol: 3/18/1993
carol: 10/12/1992
carol: 7/7/1992
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989

MIM 255960
*RECORD*
*FIELD* NO
255960
*FIELD* TI
#255960 MYXOMA, INTRACARDIAC
;;ATRIAL MYXOMA, FAMILIAL
*FIELD* TX
A number sign (#) is used with this entry because in some instances
read moreintracardiac myxoma is a solitary manifestation of heterozygous mutation
in the PRKAR1A gene on chromosome 17q24.

Atrial myxoma is a component of the Carney complex (160980), which is
also caused by mutation in the PRKAR1A gene.

CLINICAL FEATURES

Krause et al. (1971) treated a 34-year-old patient with a pulmonic valve
myxoma complicated by bacterial endocarditis. A brother of the patient
had died at age 25 years of left atrial myxoma. Two other sibs had had
rheumatic heart disease.

Heydorn et al. (1973) reported the occurrence of atrial myxoma in 2
teenaged brothers. Kleid et al. (1973) described left atrial myxoma in a
14-year-old boy and a right atrial myxoma in his 16-year-old brother.
Farah (1975) reported affected brother and sister. Siltanen et al.
(1976) reported myxoma in a mother and all 3 of her sons.

Powers et al. (1979) described myxoma in father and daughter. The
daughter had an infected right ventricular myxoma that was mistaken for
valvular bacterial endocarditis. The father had a right atrial myxoma
associated with atrial septal defect and mitral valve prolapse, and
findings suggestive of paradoxical emboli. Grauer and Grauer (1983)
reported affected father and daughter.

Farah (1994) used 2-dimensional echocardiography to study relatives of
14 patients with cardiac myxoma. Four family members from 2 different
families were found to have cardiac myxoma. The first family included a
brother and a sister, both with acromegaly, suggesting a syndromal form
of myxoma. Farah (1994) stated that 'none of the family members had skin
tumors, abnormal pigmentation, other tumors or evidence of endocrine
disease.' In the family in which a brother and sister had atrial myxoma
and acromegaly, he also stated that 'a complete study of all members of
this family was not possible because some members refused the
echocardiographic studies provided free.' It should be noted that the
association of acromegaly with familial myxoma was reported by Carney et
al. (1985). Thus, it seems likely that the sibs in fact had Carney
syndrome. Indeed, the sister would appear to have been case 14 of Carney
et al. (1985). In that report, the brother was in fact said to have
pigmented spots of the face and lips and had had nodular and
pedunculated myxomas of the skin removed. The mother and 3 out of 7
children had cardiac myxoma. Farah (1994) concluded that cardiac myxoma
was more frequently found in family members when the proband had
right-sided or bilateral myxoma; that patients with familial cardiac
myxoma are younger than the nonfamilial cases; and that long-term
recurrence is more frequent. Cardiac myxomas of Carney complex are
histologically indistinguishable from more common sporadic cardiac
myxomas and, like the latter, most often arise in the left atrium at the
fossa ovalis (Carney, 1985). However, unlike sporadic cardiac myxomas,
which most often occur as isolated single lesions in middle-aged women
and which are usually amenable to surgical resection, syndromic cardiac
myxomas exhibit no age or sex preference and may present as multiple
concurrent lesions in any cardiac chamber. Affected individuals may have
multiple recurrences at any cardiac location despite adequate surgical
margins.

In a review of the literature, van Gelder et al. (1992) noted 15
families with myxoma of the heart, to which they added 2 more. The
patients were young (mean age 27 years) with multicenteric lesions in
22% of the cases. In 61%, the tumors occurred in the left atrium, with a
recurrence rate of 10% after removal.

Dandolu et al. (1995) described a family in which the mother had
biatrial myxoma with stalks growing from either side of the interatrial
septum. A son and a daughter of hers had atrial myxoma and a 12-year-old
son had died suddenly after having cardiac symptoms consistent with
myxoma. No signs indicative of Carney syndrome were found. Dandolu et
al. (1995) suggested autosomal dominant inheritance.

INHERITANCE

From a review of the literature, van Gelder et al. (1992) concluded that
the mode of inheritance of myxoma of the heart appears to be autosomal
dominant.

MOLECULAR GENETICS

Liebler et al. (1976) described a family in which 4 sibs had
intracardiac myxomas. Kirschner et al. (2000), who stated that this
family had no other manifestations of the Carney myxoma-endocrine
complex (160980), demonstrated a specific mutation in the PRKAR1A gene
(188830.0004).

*FIELD* SA
Dewald et al. (1987)
*FIELD* RF
1. Carney, J. A.: Differences between nonfamilial and familial cardiac
myxoma. Am. J. Surg. Path. 9: 53-55, 1985.

2. Carney, J. A.; Gordon, H.; Carpenter, P. C.; Shenoy, B. V.; Go,
V. L. W.: The complex of myxomas, spotty pigmentation, and endocrine
overactivity. Medicine 64: 270-283, 1985.

3. Dandolu, B. R.; Iyer, K. S.; Das, B.; Venugopal, P.: Nonsyndrome
familial atrial myxoma in two generations. J. Thorac. Cardiovasc.
Surg. 110: 872-874, 1995.

4. Dewald, G. W.; Dahl, R. J.; Spurbeck, J. L.; Carney, J. A.; Gordon,
H.: Chromosomally abnormal clones and nonrandom telomeric translocations
in cardiac myxomas. Mayo Clin. Proc. 62: 558-567, 1987.

5. Farah, M. G.: Familial atrial myxoma. Ann. Intern. Med. 83:
358-360, 1975.

6. Farah, M. G.: Familial cardiac myxoma: a study of relatives of
patients with myxoma. Chest 105: 65-68, 1994.

7. Grauer, K.; Grauer, M. C.: Familial atrial myxoma with bilateral
recurrence. Heart Lung 12: 600-602, 1983.

8. Heydorn, W. H.; Gomez, A. C.; Kleid, J. J.; Haas, J. J.: Atrial
myxoma in siblings. J. Thorac. Cardiovasc. Surg. 65: 484-486, 1973.

9. Kirschner, L. S.; Carney, J. A.; Pack, S. D.; Taymans, S. E.; Giatzakis,
C.; Cho, Y. S.; Cho-Chung, Y. S.; Stratakis, C. A.: Mutations of
the gene encoding the protein kinase A type I-alpha regulatory subunit
in patients with the Carney complex. Nature Genet. 26: 89-92, 2000.

10. Kleid, J. J.; Klugman, J.; Haas, J. M.; Battock, D.: Familial
atrial myxoma. Am. J. Cardiol. 32: 361-364, 1973.

11. Krause, S.; Adler, L. N.; Reddy, P. S.; Magovern, G. J.: Intracardiac
myxoma in siblings. Chest 60: 404-406, 1971.

12. Liebler, G. A.; Magovern, G. J.; Park, S. B.; Cushing, W. J.;
Begg, F. R.; Joyner, C. R.: Familial myxomas in four siblings. J.
Thorac. Cardiovasc. Surg. 71: 605-608, 1976.

13. Powers, J. C.; Falkoff, M.; Heinle, R. A.; Nanda, N. C.; Ong,
L. S.; Weiner, R. S.; Barold, S. S.: Familial cardiac myxoma: emphasis
on unusual clinical manifestations. J. Thorac. Cardiovasc. Surg. 77:
782-788, 1979.

14. Siltanen, P.; Tuuteri, L.; Norio, R.; Tala, P.; Ahrenberg, P.;
Halonen, P. I.: Atrial myxoma in a family. Am. J. Cardiol. 38:
252-256, 1976.

15. van Gelder, H. M.; O'Brien, D. J.; Staples, E. D.; Alexander,
J. A.: Familial cardiac myxoma. Ann. Thorac. Surg. 53: 419-424,
1992.

*FIELD* CS

Cardiac:
Left atrial myxoma;
Right atrial myxoma;
Pulmonic valve myxoma;
Bacterial endocarditis susceptible

Inheritance:
Autosomal recessive

*FIELD* CN
Victor A. McKusick - updated: 8/29/2000
Victor A. McKusick - updated: 8/28/2000

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

*FIELD* ED
carol: 11/22/2011
alopez: 8/30/2000
terry: 8/29/2000
terry: 8/28/2000
dkim: 7/24/1998
terry: 2/6/1996
mark: 11/13/1995
terry: 5/10/1994
mimadm: 3/28/1994
carol: 3/14/1994
supermim: 3/17/1992
supermim: 3/20/1990

MIM 610489
*RECORD*
*FIELD* NO
610489
*FIELD* TI
#610489 PIGMENTED NODULAR ADRENOCORTICAL DISEASE, PRIMARY, 1; PPNAD1
;;PIGMENTED MICRONODULAR ADRENOCORTICAL DISEASE, PRIMARY, 1;;
read moreCUSHING SYNDROME, ADRENAL, DUE TO PPNAD1;;
ADRENOCORTICAL NODULAR DYSPLASIA, PRIMARY
*FIELD* TX
A number sign (#) is used with this entry because primary pigmented
nodular adrenocortical disease-1 (PPNAD1) is caused by heterozygous
mutation in the protein kinase A regulatory subunit 1-alpha gene
(PRKAR1A; 188830) on chromosome 17q.

DESCRIPTION

Primary pigmented micronodular adrenocortical disease is a form of
ACTH-independent adrenal hyperplasia resulting in Cushing syndrome. It
is usually seen as a manifestation of the Carney complex (CNC1; 160980),
a multiple neoplasia syndrome. However, PPNAD can also occur in
isolation (Groussin et al., 2002).

- Genetic Heterogeneity of Primary Pigmented Micronodular
Adrenocortical Disease

See also PPNAD2 (610475), caused by mutation in the PDE11A gene (604961)
on chromosome 2q31, and PPNAD3 (614190), caused by mutation in the PDE8B
gene (603390) on chromosome 5q13.

CLINICAL FEATURES

Arce et al. (1978) reported 4 sibs with 'familial Cushing syndrome.'
Three sibs had onset around adolescence of moon facies, obesity,
hypertrichosis, purple striae, and osteoporosis. Skull radiographs
showed no enlargement of the sella turcica, and dexamethasone
suppression resulted in no change of circulating steroid levels.
Measurement of serum ACTH was not available. Functional studies showed
adrenal autonomy. Adrenalectomy resulted in complete remission in 3
sibs; the fourth died from a presumed virilizing adrenal carcinoma.
Histology of the 3 sibs demonstrated enlarged adrenal glands containing
numerous yellow cortical nodules ranging in size from 0.3 to 1.5 cm.
Lipochromic pigment was reported. Although data were lacking, this
family may have had PPNAD.

Donaldson et al. (1981) described a brother and sister with bilateral
micronodular adrenal hyperplasia manifesting at birth. Both had clinical
features of adrenal Cushing syndrome, including hypertension, increased
serum cortisol, and decreased serum ACTH.

Shenoy et al. (1984) reported 4 patients, aged 12 to 21 years, with
Cushing syndrome due to autonomously functioning bilateral
adrenocortical neoplasms. All underwent curative adrenalectomy.
Pathologic findings included decreased, normal, or slightly increased
total gland weight, multiple small (less than 4 mm) black, brown,
dark-green, red, or yellow nodules, and cortical atrophy and
disorganization of the normal zonation between the nodules. Lipofuscin
was present within most of the enlarged cortical cells. Shenoy et al.
(1984) suggested the term 'primary pigmented nodular adrenocortical
disease' to describe the disease entity.

Hodge and Froesch (1988) described 2 sisters with primary micronodular
adrenocortical dysplasia leading to Cushing syndrome. Bilateral
adrenalectomy was performed at ages 14 and 30 years, respectively. The
disease appeared to be characterized by autonomous overactivity of nests
of abnormal adrenal cells with suppression of endogenous corticotropin.

Teding van Berkhout et al. (1989) described Cushing syndrome due to
pigmented nodular adrenocortical dysplasia in 2 sisters. The disorder
was successfully treated by complete adrenalectomy. No evidence of
associated disorders suggesting Carney syndrome was found in the 2
sisters or their first-degree relatives. However, the serum of both
girls and their mother contained immunoglobulins capable of stimulating
adrenal cortisol production in vitro. The results were interpreted as
indicating that the disorder is an inherited disease of immunologic
origin (Wulffraat et al., 1988).

DIAGNOSIS

Stratakis et al. (1999) found that 9 (70%) of 13 patients with PPNAD
demonstrated a paradoxical increase in urinary free cortisol on day 6 of
the dexamethasone suppression test, a finding that distinguished
patients with PPNAD from those with ACTH-independent macronodular
adrenocortical hyperplasia (AIMAH; 219080).

MOLECULAR GENETICS

Groussin et al. (2002) identified mutations in the PRKAR1A gene (see,
e.g., 188830.0009) in 5 unrelated patients with isolated PPNAD who had
no clinical signs or symptoms of Carney complex. All of the mutations
were predicted to result in truncation of the protein. The authors
concluded that mutations in the PRKAR1A gene can result in isolated
cases of PPNAD.

*FIELD* RF
1. Arce, B.; Licea, M.; Hung, S.; Padron, R.: Familial Cushing's
syndrome. Acta Endocr. 87: 139-147, 1978.

2. Donaldson, M. D. C.; Grant, D. B.; O'Hare, M. J.; Shackleton, C.
H. L.: Familial congenital Cushing's syndrome due to bilateral nodular
adrenal hyperplasia. Clin. Endocr. 14: 519-526, 1981.

3. Groussin, L.; Jullian, E.; Perlemoine, K.; Louvel, A.; Leheup,
B.; Luton, J. P.; Bertagna, X.; Bertherat, J.: Mutations of the PRKAR1A
gene in Cushing's syndrome due to sporadic primary pigmented nodular
adrenocortical disease. J. Clin. Endocr. Metab. 87: 4324-4329, 2002.

4. Hodge, B. O.; Froesch, T. A.: Familial Cushing's syndrome: micronodular
adrenocortical dysplasia. Arch. Intern. Med. 148: 1133-1136, 1988.

5. Shenoy, B. V.; Carpenter, P. C.; Carney, J. A.: Bilateral primary
pigmented nodular adrenocortical disease: rare cause of the Cushing
syndrome. Am. J. Surg. Path. 8: 335-344, 1984.

6. Stratakis, C. A.; Sarlis, N.; Kirschner, L. S.; Carney, J. A.;
Doppman, J. L.; Nieman, L. K.; Chrousos, G. P.; Papanicolaou, D. A.
: Paradoxical response to dexamethasone in the diagnosis of primary
pigmented nodular adrenocortical disease. Ann. Intern. Med. 131:
585-591, 1999.

7. Teding van Berkhout, F.; Croughs, R. J. M.; Wulffraat, N. M.; Drexhage,
H. A.: Familial Cushing's syndrome due to nodular adrenocortical
dysplasia is an inherited disease of immunological origin. Clin.
Endocr. 31: 185-191, 1989.

8. Wulffraat, N. M.; Drexhage, H. A.; Wiersinga, W. M.; van der Gaag,
R. D.; Jencken, P.; Mol, J. A.: Immunoglobulins of patients with
Cushing's syndrome due to pigmented adrenocortical micronodular dysplasia
stimulate in-vitro steroidogenesis. J. Clin. Endocr. Metab. 66:
301-307, 1988.

*FIELD* CS
INHERITANCE:
Autosomal dominant

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

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

ENDOCRINE FEATURES:
Cushing syndrome;
Pigmented micronodular adrenocortical disease;
ACTH-independent hypercortisolemia;
Adrenal glands may be normal, atrophic, or slightly enlarged

LABORATORY ABNORMALITIES:
Increased serum cortisol;
Paradoxical increased cortisol secretion on dexamethasone suppression
test;
Decreased serum ACTH

MISCELLANEOUS:
Onset in childhood or young adulthood;
Manifestations of Cushing syndrome may be mild;
Genetic heterogeneity, see PPNAD2 (610475);
Usually a manifestation of the Carney complex (CNC1, 1609890)

MOLECULAR BASIS:
Caused by mutation in the cAMP-dependent protein kinase, regulatory,
type I, alpha gene (PRKAR1A, 188830.0009)

*FIELD* CD
Cassandra L. Kniffin: 10/16/2006

*FIELD* ED
joanna: 12/05/2008
joanna: 5/22/2007
ckniffin: 10/17/2006

*FIELD* CD
Cassandra L. Kniffin: 10/13/2006

*FIELD* ED
carol: 08/25/2011
alopez: 3/25/2008
carol: 10/18/2006
ckniffin: 10/17/2006

RBCC Red Blood Cell Collection

Full text data of PRKAR1A