Entry Name Cushing syndrome - Homo sapiens (human)
Description Cushing syndrome (CS) is a rare disorder resulting from prolonged exposure to excess glucocorticoids via exogenous and endogenous sources. The typical clinical features of CS are related to hypercortisolism and include accumulation of central fat, moon facies, neuromuscular weakness, osteoporosis or bone fractures, metabolic complications, and mood changes. Traditionally, endogenous CS is classified as adrenocorticotropic hormone (ACTH)-dependent (about 80%) or ACTH- independent (about 20%). Among ACTH-dependent forms, pituitary corticotroph adenoma (Cushing's disease) is most common. Most pituitary tumors are sporadic, resulting from monoclonal expansion of a single mutated cell. Recently recurrent activating somatic driver mutations in the ubiquitin-specific protease 8 gene (USP8) were identified in almost half of corticotroph adenoma. Germline mutations in MEN1 (encoding menin), AIP (encoding aryl-hydrocarbon receptor-interacting protein), PRKAR1A (encoding cAMP-dependent protein kinase type I alpha regulatory subunit) and CDKN1B (encoding cyclin-dependent kinase inhibitor 1B; also known as p27 Kip1) have been identified in familial forms of pituitary adenomas. However, the frequency of familial pituitary adenomas is less than 5% in patients with pituitary adenomas. Among ACTH-independent CS, adrenal adenoma is most common. Rare adrenal causes of CS include primary bilateral macronodular adrenal hyperplasia (BMAH) or primary pigmented nodular adrenocortical disease (PPNAD).
Class Human Diseases; Endocrine and metabolic diseaseBRITE hierarchy
Pathway map Network Element N00290 Mutation-inactivated MEN1 to transcription
N00315 Mutation-inactivated AIP to AhR-mediated transcription
N00316 Mutation-inactivated CDKN1B to p27-cell cycle G1/S
N00319 Mutation-activated USP8 to EGFR-ERK-ACTH signaling pathway
N00320 Mutation-activated PRKACA to ACTH-cortisol signaling pathway
N00321 Mutation-activated GNAS to ACTH-cortisol signaling pathway
N00322 Mutation-inactivated PRKAR1A to ACTH-cortisol signaling pathway
N00323 Mutation-inactivated PDE11A/PDE8B to ACTH-cortisol signaling pathway
N00325 Mutation-inactivated RASD1 to CRHR-PKA-ACTH signaling pathway
N00326 Mutation-activated GNAS to CRHR-PKA-ACTH signaling pathway
N00327 Mutation-inactivated PRKAR1A to CRHR-PKA-ACTH signaling pathway
Disease Drug D10950 Levoketoconazole (USAN/INN)
Organism Homo sapiens (human) [GN:
hsa ]
Gene 1026 CDKN1A; cyclin dependent kinase inhibitor 1A [KO:K06625 ]
1027 CDKN1B; cyclin dependent kinase inhibitor 1B [KO:K06624 ]
1029 CDKN2A; cyclin dependent kinase inhibitor 2A [KO:K06621 ]
10297 APC2; APC regulator of WNT signaling pathway 2 [KO:K02085 ]
1030 CDKN2B; cyclin dependent kinase inhibitor 2B [KO:K04685 ]
1031 CDKN2C; cyclin dependent kinase inhibitor 2C [KO:K06622 ]
10488 CREB3; cAMP responsive element binding protein 3 [KO:K09048 ]
1385 CREB1; cAMP responsive element binding protein 1 [KO:K05870 ]
1386 ATF2; activating transcription factor 2 [KO:K04450 ]
1388 ATF6B; activating transcription factor 6 beta [KO:K09049 ]
1392 CRH; corticotropin releasing hormone [KO:K05256 ]
1394 CRHR1; corticotropin releasing hormone receptor 1 [KO:K04578 ]
1395 CRHR2; corticotropin releasing hormone receptor 2 [KO:K04579 ]
148327 CREB3L4; cAMP responsive element binding protein 3 like 4 [KO:K09048 ]
185 AGTR1; angiotensin II receptor type 1 [KO:K04166 ]
1855 DVL1; dishevelled segment polarity protein 1 [KO:K02353 ]
1856 DVL2; dishevelled segment polarity protein 2 [KO:K02353 ]
1857 DVL3; dishevelled segment polarity protein 3 [KO:K02353 ]
196 AHR; aryl hydrocarbon receptor [KO:K09093 ]
23746 AIPL1; aryl hydrocarbon receptor interacting protein like 1 [KO:K17767 ]
2516 NR5A1; nuclear receptor subfamily 5 group A member 1 [KO:K08560 ]
2767 GNA11; G protein subunit alpha 11 [KO:K04635 ]
2770 GNAI1; G protein subunit alpha i1 [KO:K04630 ]
2771 GNAI2; G protein subunit alpha i2 [KO:K04630 ]
2773 GNAI3; G protein subunit alpha i3 [KO:K04630 ]
3164 NR4A1; nuclear receptor subfamily 4 group A member 1 [KO:K04465 ]
324 APC; APC regulator of WNT signaling pathway [KO:K02085 ]
3708 ITPR1; inositol 1,4,5-trisphosphate receptor type 1 [KO:K04958 ]
3709 ITPR2; inositol 1,4,5-trisphosphate receptor type 2 [KO:K04959 ]
3710 ITPR3; inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960 ]
3739 KCNA4; potassium voltage-gated channel subfamily A member 4 [KO:K04877 ]
3776 KCNK2; potassium two pore domain channel subfamily K member 2 [KO:K04913 ]
3777 KCNK3; potassium two pore domain channel subfamily K member 3 [KO:K04914 ]
3949 LDLR; low density lipoprotein receptor [KO:K12473 ]
405 ARNT; aryl hydrocarbon receptor nuclear translocator [KO:K09097 ]
468 ATF4; activating transcription factor 4 [KO:K04374 ]
51176 LEF1; lymphoid enhancer binding factor 1 [KO:K04492 ]
51655 RASD1; ras related dexamethasone induced 1 [KO:K07843 ]
56246 MRAP; melanocortin 2 receptor accessory protein [KO:K22398 ]
57552 NCEH1; neutral cholesterol ester hydrolase 1 [KO:K14349 ] [EC:3.1.1.-]
5906 RAP1A; RAP1A, member of RAS oncogene family [KO:K04353 ]
5908 RAP1B; RAP1B, member of RAS oncogene family [KO:K07836 ]
5925 RB1; RB transcriptional corepressor 1 [KO:K06618 ]
5929 RBBP5; RB binding protein 5, histone lysine methyltransferase complex subunit [KO:K14961 ]
64764 CREB3L2; cAMP responsive element binding protein 3 like 2 [KO:K09048 ]
6770 STAR; steroidogenic acute regulatory protein [KO:K16931 ]
6934 TCF7L2; transcription factor 7 like 2 [KO:K04491 ]
775 CACNA1C; calcium voltage-gated channel subunit alpha1 C [KO:K04850 ]
776 CACNA1D; calcium voltage-gated channel subunit alpha1 D [KO:K04851 ]
778 CACNA1F; calcium voltage-gated channel subunit alpha1 F [KO:K04853 ]
779 CACNA1S; calcium voltage-gated channel subunit alpha1 S [KO:K04857 ]
815 CAMK2A; calcium/calmodulin dependent protein kinase II alpha [KO:K04515 ] [EC:2.7.11.17 ]
816 CAMK2B; calcium/calmodulin dependent protein kinase II beta [KO:K04515 ] [EC:2.7.11.17 ]
817 CAMK2D; calcium/calmodulin dependent protein kinase II delta [KO:K04515 ] [EC:2.7.11.17 ]
818 CAMK2G; calcium/calmodulin dependent protein kinase II gamma [KO:K04515 ] [EC:2.7.11.17 ]
83439 TCF7L1; transcription factor 7 like 1 [KO:K04490 ]
84699 CREB3L3; cAMP responsive element binding protein 3 like 3 [KO:K09048 ]
84876 ORAI1; ORAI calcium release-activated calcium modulator 1 [KO:K16056 ]
8911 CACNA1I; calcium voltage-gated channel subunit alpha1 I [KO:K04856 ]
8912 CACNA1H; calcium voltage-gated channel subunit alpha1 H [KO:K04855 ]
8913 CACNA1G; calcium voltage-gated channel subunit alpha1 G [KO:K04854 ]
9049 AIP; aryl hydrocarbon receptor interacting protein [KO:K17767 ]
9070 ASH2L; ASH2 like, histone lysine methyltransferase complex subunit [KO:K14964 ]
90993 CREB3L1; cAMP responsive element binding protein 3 like 1 [KO:K09048 ]
949 SCARB1; scavenger receptor class B member 1 [KO:K13885 ]
9586 CREB5; cAMP responsive element binding protein 5 [KO:K09047 ]
Compound C01176 17alpha-Hydroxyprogesterone
C01245 D-myo-Inositol 1,4,5-trisphosphate
C05138 17alpha-Hydroxypregnenolone
C07557 2,3,7,8-Tetrachlorodibenzodioxin
Reference Authors Lacroix A, Feelders RA, Stratakis CA, Nieman LK
Title Cushing's syndrome.
Journal Reference Authors Xiong Q, Ge W
Title Gene mutations in Cushing's disease.
Journal Reference Authors Fukuoka H, Takahashi Y
Title The role of genetic and epigenetic changes in pituitary tumorigenesis.
Journal Reference Authors Quereda V, Malumbres M
Title Cell cycle control of pituitary development and disease.
Journal Reference Authors Caimari F, Korbonits M
Title Novel Genetic Causes of Pituitary Adenomas.
Journal Reference Authors Lecoq AL, Kamenicky P, Guiochon-Mantel A, Chanson P
Title Genetic mutations in sporadic pituitary adenomas--what to screen for?
Journal Reference Authors Hannah-Shmouni F, Faucz FR, Stratakis CA
Title Alterations of Phosphodiesterases in Adrenocortical Tumors.
Journal Reference Authors Melmed S
Title Pathogenesis of pituitary tumors.
Journal Reference Authors Daly AF, Tichomirowa MA, Beckers A
Title Genetic, molecular and clinical features of familial isolated pituitary adenomas.
Journal Reference Authors Albani A, Theodoropoulou M, Reincke M
Title Genetics of Cushing's disease.
Journal Reference Authors Duan K, Hernandez KG, Mete O
Title Clinicopathological correlates of adrenal Cushing's syndrome.
Journal Reference Authors Drougat L, Espiard S, Bertherat J
Title Genetics of primary bilateral macronodular adrenal hyperplasia: a model for early diagnosis of Cushing's syndrome?
Journal Reference Authors Stratakis CA, Boikos SA
Title Genetics of adrenal tumors associated with Cushing's syndrome: a new classification for bilateral adrenocortical hyperplasias.
Journal Reference Authors Refojo D, Holsboer F
Title CRH signaling. Molecular specificity for drug targeting in the CNS.
Journal Reference Authors Kovalovsky D, Refojo D, Liberman AC, Hochbaum D, Pereda MP, Coso OA, Stalla GK, Holsboer F, Arzt E
Title Activation and induction of NUR77/NURR1 in corticotrophs by CRH/cAMP: involvement of calcium, protein kinase A, and MAPK pathways.
Journal Reference Authors Lacroix A, Baldacchino V, Bourdeau I, Hamet P, Tremblay J
Title Cushing's syndrome variants secondary to aberrant hormone receptors.
Journal Reference Authors Reincke M, Sbiera S, Hayakawa A, Theodoropoulou M, Osswald A, Beuschlein F, Meitinger T, Mizuno-Yamasaki E, Kawaguchi K, Saeki Y, Tanaka K, Wieland T, Graf E, Saeger W, Ronchi CL, Allolio B, Buchfelder M, Strom TM, Fassnacht M, Komada M
Title Mutations in the deubiquitinase gene USP8 cause Cushing's disease.
Journal Reference Authors Kaiser UB
Title Cushing's disease: towards precision medicine.
Journal Reference Authors Uzilov AV, Cheesman KC, Fink MY, Newman LC, Pandya C, Lalazar Y, Hefti M, Fowkes M, Deikus G, Lau CY, Moe AS, Kinoshita Y, Kasai Y, Zweig M, Gupta A, Starcevic D, Mahajan M, Schadt EE, Post KD, Donovan MJ, Sebra R, Chen R, Geer EB
Title Identification of a novel RASD1 somatic mutation in a USP8-mutated corticotroph adenoma.
Journal Reference Authors Huang C, Shi Y, Zhao Y
Title USP8 mutation in Cushing's disease.
Journal Reference Authors Theodoropoulou M, Reincke M, Fassnacht M, Komada M
Title Decoding the genetic basis of Cushing's disease: USP8 in the spotlight.
Journal Reference Authors Yu L, Zhang J, Guo X, Chen X, He Z, He Q
Title ARMC5 mutations in familial and sporadic primary bilateral macronodular adrenal hyperplasia.
Journal Reference Authors Wu X, Hua X
Title Menin, histone h3 methyltransferases, and regulation of cell proliferation: current knowledge and perspective.
Journal Reference Authors Ozfirat Z, Korbonits M
Title AIP gene and familial isolated pituitary adenomas.
Journal Related hsa04927 Cortisol synthesis and secretion
hsa04960 Aldosterone-regulated sodium reabsorption
KO pathway
