Entry Name Cushing syndrome - Loxodonta africana (African savanna elephant)
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 Loxodonta africana (African savanna elephant) [GN:
lav ]
Gene 100653565 CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048 ]
100653927 CAMK2G; calcium/calmodulin-dependent protein kinase type II subunit gamma isoform X1 [KO:K04515 ] [EC:2.7.11.17 ]
100654542 KCNK2; potassium channel subfamily K member 2 isoform X1 [KO:K04913 ]
100656672 GNAQ; guanine nucleotide-binding protein G(q) subunit alpha isoform X1 [KO:K04634 ]
100657649 DVL1; segment polarity protein dishevelled homolog DVL-1 isoform X1 [KO:K02353 ]
100657749 DVL2; segment polarity protein dishevelled homolog DVL-2 isoform X1 [KO:K02353 ]
100657989 ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450 ]
100658312 PBX1; pre-B-cell leukemia transcription factor 1 isoform X1 [KO:K09355 ]
100658501 PDE8A; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A isoform X3 [KO:K18437 ] [EC:3.1.4.53 ]
100659551 CRHR1; corticotropin-releasing factor receptor 1 isoform X3 [KO:K04578 ]
100659666 ITPR3; LOW QUALITY PROTEIN: inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960 ]
100659992 CACNA1D; LOW QUALITY PROTEIN: voltage-dependent L-type calcium channel subunit alpha-1D [KO:K04851 ]
100660332 CACNA1I; LOW QUALITY PROTEIN: voltage-dependent T-type calcium channel subunit alpha-1I [KO:K04856 ]
100662521 ATF4; cyclic AMP-dependent transcription factor ATF-4 isoform X2 [KO:K04374 ]
100663321 CAMK2D; calcium/calmodulin-dependent protein kinase type II subunit delta isoform X2 [KO:K04515 ] [EC:2.7.11.17 ]
100663645 ARMC5; LOW QUALITY PROTEIN: armadillo repeat-containing protein 5 [KO:K22499 ]
100663829 PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 isoform X1 [KO:K05858 ] [EC:3.1.4.11 ]
100664947 STAR; steroidogenic acute regulatory protein, mitochondrial [KO:K16931 ]
100665028 ITPR1; LOW QUALITY PROTEIN: inositol 1,4,5-trisphosphate receptor type 1 [KO:K04958 ]
100665231 ASH2L; set1/Ash2 histone methyltransferase complex subunit ASH2 isoform X2 [KO:K14964 ]
100666211 CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048 ]
100666344 GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630 ]
100666554 CACNA1G; voltage-dependent T-type calcium channel subunit alpha-1G isoform X1 [KO:K04854 ]
100666885 ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X2 [KO:K09049 ]
100667029 KCNA4; potassium voltage-gated channel subfamily A member 4 [KO:K04877 ]
100667957 GNAI3; LOW QUALITY PROTEIN: guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630 ]
100668092 NCEH1; neutral cholesterol ester hydrolase 1 isoform X1 [KO:K14349 ] [EC:3.1.1.-]
100668575 PLCB2; LOW QUALITY PROTEIN: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858 ] [EC:3.1.4.11 ]
100669326 ORAI1; calcium release-activated calcium channel protein 1 [KO:K16056 ]
100670234 GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630 ]
100670574 CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048 ]
100670617 PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X3 [KO:K05858 ] [EC:3.1.4.11 ]
100670699 PDE8B; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B [KO:K18437 ] [EC:3.1.4.53 ]
100672435 PLCB1; LOW QUALITY PROTEIN: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858 ] [EC:3.1.4.11 ]
100673089 CACNA1S; LOW QUALITY PROTEIN: voltage-dependent L-type calcium channel subunit alpha-1S [KO:K04857 ]
100673586 DVL3; segment polarity protein dishevelled homolog DVL-3 isoform X1 [KO:K02353 ]
100673667 ARNT; aryl hydrocarbon receptor nuclear translocator isoform X6 [KO:K09097 ]
100673694 CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048 ]
100674649 CACNA1F; LOW QUALITY PROTEIN: voltage-dependent L-type calcium channel subunit alpha-1F [KO:K04853 ]
100675079 CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047 ]
100675162 CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870 ]
100675598 CACNA1H; LOW QUALITY PROTEIN: voltage-dependent T-type calcium channel subunit alpha-1H [KO:K04855 ]
100677344 CREB3; cyclic AMP-responsive element-binding protein 3 isoform X1 [KO:K09048 ]
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 lav04927 Cortisol synthesis and secretion
lav04960 Aldosterone-regulated sodium reabsorption
KO pathway
