Entry Name Cushing syndrome - Piliocolobus tephrosceles (Ugandan red Colobus)
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 Ortholog table Organism Piliocolobus tephrosceles (Ugandan red Colobus) [GN:
pteh ]
Gene 111529275 CRHR1; corticotropin-releasing factor receptor 1 isoform X1 [KO:K04578 ]
111523626 CRHR2; corticotropin-releasing factor receptor 2 isoform X1 [KO:K04579 ]
111555637 GNAS; guanine nucleotide-binding protein G(s) subunit alpha isoform X6 [KO:K04632 ]
111547676 CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870 ]
111542753 ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450 ]
111548991 ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374 ]
111521981 CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048 ]
111543707 CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048 ]
111544982 CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048 ]
111536760 CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048 ]
111524755 CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048 ]
111551841 CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047 ]
111528965 ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049 ]
111544130 ASH2L; set1/Ash2 histone methyltransferase complex subunit ASH2 isoform X1 [KO:K14964 ]
111526168 RASD1; dexamethasone-induced Ras-related protein 1 isoform X1 [KO:K07843 ]
111552452 GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630 ]
111555442 GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630 ]
111556065 GNAI3; guanine nucleotide-binding protein G(i) subunit alpha [KO:K04630 ]
111527932 LOW QUALITY PROTEIN: uncharacterized protein LOC111527932 [KO:K09093 ]
111521362 AIPL1; aryl-hydrocarbon-interacting protein-like 1 isoform X1 [KO:K17767 ]
111552085 CDKN1B; cyclin-dependent kinase inhibitor 1B isoform X1 [KO:K06624 ]
111520328 CACNA1C; voltage-dependent L-type calcium channel subunit alpha-1C [KO:K04850 ]
111524370 CACNA1D; voltage-dependent L-type calcium channel subunit alpha-1D isoform X1 [KO:K04851 ]
111550963 CACNA1S; voltage-dependent L-type calcium channel subunit alpha-1S [KO:K04857 ]
111552236 CAMK2B; calcium/calmodulin-dependent protein kinase type II subunit beta isoform X1 [KO:K04515 ] [EC:2.7.11.17 ]
111552636 CAMK2A; calcium/calmodulin-dependent protein kinase type II subunit alpha isoform X1 [KO:K04515 ] [EC:2.7.11.17 ]
111537843 CAMK2G; calcium/calmodulin-dependent protein kinase type II subunit gamma isoform X1 [KO:K04515 ] [EC:2.7.11.17 ]
111547908 CAMK2D; calcium/calmodulin-dependent protein kinase type II subunit delta isoform X1 [KO:K04515 ] [EC:2.7.11.17 ]
111525089 MRAP; melanocortin-2 receptor accessory protein isoform X1 [KO:K22398 ]
111544409 PDE8B; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B [KO:K18437 ] [EC:3.1.4.53 ]
111522891 PDE8A; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A isoform X1 [KO:K18437 ] [EC:3.1.4.53 ]
111539276 PBX1; pre-B-cell leukemia transcription factor 1 isoform X1 [KO:K09355 ]
111544129 STAR; steroidogenic acute regulatory protein, mitochondrial [KO:K16931 ]
111543474 NCEH1; neutral cholesterol ester hydrolase 1 [KO:K14349 ] [EC:3.1.1.-]
111525632 ARMC5; armadillo repeat-containing protein 5 isoform X1 [KO:K22499 ]
111543374 guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634 ]
111520693 GNA11; guanine nucleotide-binding protein subunit alpha-11 [KO:K04635 ]
111524236 PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X1 [KO:K05858 ] [EC:3.1.4.11 ]
111546452 PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858 ] [EC:3.1.4.11 ]
111546970 ITPR1; inositol 1,4,5-trisphosphate receptor type 1 isoform X1 [KO:K04958 ]
111540617 ITPR2; inositol 1,4,5-trisphosphate receptor type 2 isoform X1 [KO:K04959 ]
111537013 KCNK2; potassium channel subfamily K member 2 isoform X1 [KO:K04913 ]
111537578 CACNA1G; voltage-dependent T-type calcium channel subunit alpha-1G isoform X1 [KO:K04854 ]
111524152 CACNA1H; voltage-dependent T-type calcium channel subunit alpha-1H [KO:K04855 ]
111549100 CACNA1I; voltage-dependent T-type calcium channel subunit alpha-1I [KO:K04856 ]
111538017 ORAI1; calcium release-activated calcium channel protein 1 [KO:K16056 ]
111554702 KCNA4; potassium voltage-gated channel subfamily A member 4 [KO:K04877 ]
111552064 SCARB1; scavenger receptor class B member 1 isoform X1 [KO:K13885 ]
111523166 DVL3; segment polarity protein dishevelled homolog DVL-3 [KO:K02353 ]
111521282 DVL2; segment polarity protein dishevelled homolog DVL-2 [KO:K02353 ]
111526841 DVL1; segment polarity protein dishevelled homolog DVL-1 isoform X1 [KO:K02353 ]
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 pteh04960 Aldosterone-regulated sodium reabsorption
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