Entry Name Cushing syndrome - Pteropus vampyrus (large flying fox)
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 Disease Organism Pteropus vampyrus (large flying fox) [GN:
pvp ]
Gene 105288866 CAMK2G; calcium/calmodulin-dependent protein kinase type II subunit gamma isoform X2 [KO:K04515 ] [EC:2.7.11.17 ]
105289200 ORAI1; calcium release-activated calcium channel protein 1 isoform X1 [KO:K16056 ]
105290070 CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 isoform X1 [KO:K09048 ]
105290195 ATF2; cyclic AMP-dependent transcription factor ATF-2 [KO:K04450 ]
105291624 CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048 ]
105291733 DVL2; segment polarity protein dishevelled homolog DVL-2 isoform X1 [KO:K02353 ]
105293715 KCNA4; potassium voltage-gated channel subfamily A member 4 [KO:K04877 ]
105295028 KCNK2; potassium channel subfamily K member 2 isoform X1 [KO:K04913 ]
105295155 GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630 ]
105295395 CACNA1G; voltage-dependent T-type calcium channel subunit alpha-1G isoform X7 [KO:K04854 ]
105295517 GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630 ]
105296460 CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048 ]
105296936 CACNA1S; voltage-dependent L-type calcium channel subunit alpha-1S [KO:K04857 ]
105297202 GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630 ]
105297298 CACNA1C; voltage-dependent L-type calcium channel subunit alpha-1C [KO:K04850 ]
105298070 ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374 ]
105298101 CACNA1I; voltage-dependent T-type calcium channel subunit alpha-1I [KO:K04856 ]
105298404 CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870 ]
105298440 CDKN2B; cyclin-dependent kinase 4 inhibitor B isoform X4 [KO:K04685 ]
105298737 PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858 ] [EC:3.1.4.11 ]
105300190 ASH2L; set1/Ash2 histone methyltransferase complex subunit ASH2 isoform X1 [KO:K14964 ]
105300196 STAR; steroidogenic acute regulatory protein, mitochondrial [KO:K16931 ]
105300436 GNA11; guanine nucleotide-binding protein subunit alpha-11 [KO:K04635 ]
105302190 PDE8B; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B [KO:K18437 ] [EC:3.1.4.53 ]
105302891 PDE8A; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A isoform X1 [KO:K18437 ] [EC:3.1.4.53 ]
105303376 CACNA1H; voltage-dependent T-type calcium channel subunit alpha-1H [KO:K04855 ]
105303599 DVL1; segment polarity protein dishevelled homolog DVL-1 [KO:K02353 ]
105304363 CACNA1D; LOW QUALITY PROTEIN: voltage-dependent L-type calcium channel subunit alpha-1D [KO:K04851 ]
105305286 ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049 ]
105305615 LDLR; LOW QUALITY PROTEIN: low-density lipoprotein receptor [KO:K12473 ]
105305713 NCEH1; neutral cholesterol ester hydrolase 1 isoform X1 [KO:K14349 ] [EC:3.1.1.-]
105306027 PBX1; pre-B-cell leukemia transcription factor 1 isoform X1 [KO:K09355 ]
105306466 CREB3; cyclic AMP-responsive element-binding protein 3 isoform X1 [KO:K09048 ]
105306745 CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048 ]
105307126 DVL3; segment polarity protein dishevelled homolog DVL-3 isoform X1 [KO:K02353 ]
105309056 CACNA1F; voltage-dependent L-type calcium channel subunit alpha-1F isoform X1 [KO:K04853 ]
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 pvp04927 Cortisol synthesis and secretion
pvp04960 Aldosterone-regulated sodium reabsorption
KO pathway
