Entry
Name
Cushing syndrome - Hylobates moloch (silvery gibbon)
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 disease
BRITE hierarchy
Pathway map
Ortholog table
Organism
Hylobates moloch (silvery gibbon) [GN:
hmh ]
Gene
116475000 CRHR1; corticotropin-releasing factor receptor 1 isoform X1 [KO:K04578 ]
116812597 CRHR2; corticotropin-releasing factor receptor 2 isoform X2 [KO:K04579 ]
116812065 guanine nucleotide-binding protein G(s) subunit alpha [KO:K04632 ]
116463273 guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas isoform X1 [KO:K04632 ]
116463360 guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas isoform X1 [KO:K04632 ]
116810385 CREB1; cyclic AMP-responsive element-binding protein 1 isoform X3 [KO:K05870 ]
116810639 ATF2; cyclic AMP-dependent transcription factor ATF-2 [KO:K04450 ]
116458613 ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374 ]
116810327 LOW QUALITY PROTEIN: cyclic AMP-dependent transcription factor ATF-4-like [KO:K04374 ]
116476303 CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048 ]
116469376 CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048 ]
116814406 CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048 ]
116483538 CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048 ]
116475074 CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048 ]
116812715 CREB5; cyclic AMP-responsive element-binding protein 5 isoform X5 [KO:K09047 ]
116460313 cyclic AMP-dependent transcription factor ATF-6 beta-like [KO:K09049 ]
116462018 ASH2L; set1/Ash2 histone methyltransferase complex subunit ASH2 isoform X1 [KO:K14964 ]
116483042 RASD1; dexamethasone-induced Ras-related protein 1 isoform X1 [KO:K07843 ]
116469652 GNAI3; guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630 ]
116464223 guanine nucleotide-binding protein G(i) subunit alpha-2 isoform X1 [KO:K04630 ]
116464225 guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630 ]
116814165 GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630 ]
116458833 AIPL1; aryl-hydrocarbon-interacting protein-like 1 isoform X3 [KO:K17767 ]
116469474 ARNT; aryl hydrocarbon receptor nuclear translocator isoform X1 [KO:K09097 ]
116460475 CDKN1A; cyclin-dependent kinase inhibitor 1 isoform X1 [KO:K06625 ]
116472525 CACNA1C; voltage-dependent L-type calcium channel subunit alpha-1C isoform X1 [KO:K04850 ]
116473372 CACNA1D; voltage-dependent L-type calcium channel subunit alpha-1D isoform X9 [KO:K04851 ]
116811686 CACNA1F; voltage-dependent L-type calcium channel subunit alpha-1F isoform X1 [KO:K04853 ]
116457338 CACNA1S; voltage-dependent L-type calcium channel subunit alpha-1S [KO:K04857 ]
116459675 CAMK2G; calcium/calmodulin-dependent protein kinase type II subunit gamma isoform X1 [KO:K04515 ] [EC:2.7.11.17 ]
116471714 CAMK2A; calcium/calmodulin-dependent protein kinase type II subunit alpha isoform X1 [KO:K04515 ] [EC:2.7.11.17 ]
116812488 CAMK2B; calcium/calmodulin-dependent protein kinase type II subunit beta isoform X1 [KO:K04515 ] [EC:2.7.11.17 ]
116463099 CAMK2D; calcium/calmodulin-dependent protein kinase type II subunit delta isoform X2 [KO:K04515 ] [EC:2.7.11.17 ]
116461658 NR4A1; nuclear receptor subfamily 4 group A member 1 isoform X1 [KO:K04465 ]
116481794 MRAP; melanocortin-2 receptor accessory protein isoform X1 [KO:K22398 ]
116471082 PDE8B; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B isoform X7 [KO:K18437 ] [EC:3.1.4.53 ]
116481464 PDE8A; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A isoform X1 [KO:K18437 ] [EC:3.1.4.53 ]
116473306 PBX1; pre-B-cell leukemia transcription factor 1 isoform X1 [KO:K09355 ]
116462019 STAR; steroidogenic acute regulatory protein, mitochondrial [KO:K16931 ]
116481249 NCEH1; neutral cholesterol ester hydrolase 1 [KO:K14349 ] [EC:3.1.1.-]
116471197 ARMC5; armadillo repeat-containing protein 5 isoform X1 [KO:K22499 ]
116475178 GNAQ; guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634 ]
116483096 GNA11; guanine nucleotide-binding protein subunit alpha-11 [KO:K04635 ]
116461202 PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858 ] [EC:3.1.4.11 ]
116461370 PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X2 [KO:K05858 ] [EC:3.1.4.11 ]
116481969 PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X6 [KO:K05858 ] [EC:3.1.4.11 ]
116466681 ITPR1; inositol 1,4,5-trisphosphate receptor type 1 isoform X1 [KO:K04958 ]
116459671 ITPR3; inositol 1,4,5-trisphosphate receptor type 3 isoform X1 [KO:K04960 ]
116474359 CACNA1G; voltage-dependent T-type calcium channel subunit alpha-1G isoform X5 [KO:K04854 ]
116462356 CACNA1H; voltage-dependent T-type calcium channel subunit alpha-1H isoform X1 [KO:K04855 ]
116458615 CACNA1I; voltage-dependent T-type calcium channel subunit alpha-1I isoform X1 [KO:K04856 ]
116477786 ORAI1; calcium release-activated calcium channel protein 1 [KO:K16056 ]
116476402 KCNA4; potassium voltage-gated channel subfamily A member 4 [KO:K04877 ]
116477710 SCARB1; scavenger receptor class B member 1 isoform X4 [KO:K13885 ]
116479887 DVL3; segment polarity protein dishevelled homolog DVL-3 [KO:K02353 ]
116459316 DVL2; segment polarity protein dishevelled homolog DVL-2 isoform X1 [KO:K02353 ]
116812776 DVL1; segment polarity protein dishevelled homolog DVL-1 isoform X1 [KO:K02353 ]
116483925 APC2; adenomatous polyposis coli protein 2 isoform X1 [KO:K02085 ]
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 pathway
hmh04927 Cortisol synthesis and secretion
hmh04960 Aldosterone-regulated sodium reabsorption
KO pathway
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