PATHWAY: mmu04934 Help
Entry
Name
Cushing syndrome - Mus musculus (house mouse)
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
Mus musculus (house mouse) [GN:
mmu ]
Gene
12921 Crhr1; corticotropin releasing hormone receptor 1 [KO:K04578 ]
12922 Crhr2; corticotropin releasing hormone receptor 2 [KO:K04579 ]
12912 Creb1; cAMP responsive element binding protein 1 [KO:K05870 ]
11909 Atf2; activating transcription factor 2 [KO:K04450 ]
11911 Atf4; activating transcription factor 4 [KO:K04374 ]
12913 Creb3; cAMP responsive element binding protein 3 [KO:K09048 ]
26427 Creb3l1; cAMP responsive element binding protein 3-like 1 [KO:K09048 ]
208647 Creb3l2; cAMP responsive element binding protein 3-like 2 [KO:K09048 ]
208677 Creb3l3; cAMP responsive element binding protein 3-like 3 [KO:K09048 ]
78284 Creb3l4; cAMP responsive element binding protein 3-like 4 [KO:K09048 ]
231991 Creb5; cAMP responsive element binding protein 5 [KO:K09047 ]
12915 Atf6b; activating transcription factor 6 beta [KO:K09049 ]
23808 Ash2l; ASH2 like histone lysine methyltransferase complex subunit [KO:K14964 ]
213464 Rbbp5; retinoblastoma binding protein 5, histone lysine methyltransferase complex subunit [KO:K14961 ]
12580 Cdkn2c; cyclin dependent kinase inhibitor 2C [KO:K06622 ]
12579 Cdkn2b; cyclin dependent kinase inhibitor 2B [KO:K04685 ]
12578 Cdkn2a; cyclin dependent kinase inhibitor 2A [KO:K06621 ]
19645 Rb1; RB transcriptional corepressor 1 [KO:K06618 ]
114230 Aipl1; aryl hydrocarbon receptor-interacting protein-like 1 [KO:K17767 ]
11632 Aip; aryl-hydrocarbon receptor-interacting protein [KO:K17767 ]
11863 Arnt; aryl hydrocarbon receptor nuclear translocator [KO:K09097 ]
12576 Cdkn1b; cyclin dependent kinase inhibitor 1B [KO:K06624 ]
12575 Cdkn1a; cyclin dependent kinase inhibitor 1A [KO:K06625 ]
12288 Cacna1c; calcium channel, voltage-dependent, L type, alpha 1C subunit [KO:K04850 ]
12289 Cacna1d; calcium channel, voltage-dependent, L type, alpha 1D subunit [KO:K04851 ]
54652 Cacna1f; calcium channel, voltage-dependent, alpha 1F subunit [KO:K04853 ]
12292 Cacna1s; calcium channel, voltage-dependent, L type, alpha 1S subunit [KO:K04857 ]
15370 Nr4a1; nuclear receptor subfamily 4, group A, member 1 [KO:K04465 ]
77037 Mrap; melanocortin 2 receptor accessory protein [KO:K22398 ]
26423 Nr5a1; nuclear receptor subfamily 5, group A, member 1 [KO:K08560 ]
20683 Sp1; trans-acting transcription factor 1 [KO:K04684 ]
20845 Star; steroidogenic acute regulatory protein [KO:K16931 ]
320024 Nceh1; neutral cholesterol ester hydrolase 1 [KO:K14349 ] [EC:3.1.1.-]
11607 Agtr1a; angiotensin II receptor, type 1a [KO:K04166 ]
11608 Agtr1b; angiotensin II receptor, type 1b [KO:K04166 ]
14682 Gnaq; guanine nucleotide binding protein, alpha q polypeptide [KO:K04634 ]
14672 Gna11; guanine nucleotide binding protein, alpha 11 [KO:K04635 ]
16438 Itpr1; inositol 1,4,5-trisphosphate receptor 1 [KO:K04958 ]
16439 Itpr2; inositol 1,4,5-triphosphate receptor 2 [KO:K04959 ]
16440 Itpr3; inositol 1,4,5-triphosphate receptor 3 [KO:K04960 ]
16526 Kcnk2; potassium channel, subfamily K, member 2 [KO:K04913 ]
12291 Cacna1g; calcium channel, voltage-dependent, T type, alpha 1G subunit [KO:K04854 ]
58226 Cacna1h; calcium channel, voltage-dependent, T type, alpha 1H subunit [KO:K04855 ]
239556 Cacna1i; calcium channel, voltage-dependent, alpha 1I subunit [KO:K04856 ]
109305 Orai1; ORAI calcium release-activated calcium modulator 1 [KO:K16056 ]
16492 Kcna4; potassium voltage-gated channel, shaker-related subfamily, member 4 [KO:K04877 ]
16527 Kcnk3; potassium channel, subfamily K, member 3 [KO:K04914 ]
16835 Ldlr; low density lipoprotein receptor [KO:K12473 ]
20778 Scarb1; scavenger receptor class B, member 1 [KO:K13885 ]
22408 Wnt1; wingless-type MMTV integration site family, member 1 [KO:K03209 ]
22413 Wnt2; wingless-type MMTV integration site family, member 2 [KO:K00182 ]
22414 Wnt2b; wingless-type MMTV integration site family, member 2B [KO:K00182 ]
22415 Wnt3; wingless-type MMTV integration site family, member 3 [KO:K00312 ]
22416 Wnt3a; wingless-type MMTV integration site family, member 3A [KO:K00312 ]
22417 Wnt4; wingless-type MMTV integration site family, member 4 [KO:K00408 ]
22418 Wnt5a; wingless-type MMTV integration site family, member 5A [KO:K00444 ]
22419 Wnt5b; wingless-type MMTV integration site family, member 5B [KO:K00444 ]
22420 Wnt6; wingless-type MMTV integration site family, member 6 [KO:K00445 ]
22421 Wnt7a; wingless-type MMTV integration site family, member 7A [KO:K00572 ]
22422 Wnt7b; wingless-type MMTV integration site family, member 7B [KO:K00572 ]
20890 Wnt8a; wingless-type MMTV integration site family, member 8A [KO:K00714 ]
22423 Wnt8b; wingless-type MMTV integration site family, member 8B [KO:K00714 ]
216795 Wnt9a; wingless-type MMTV integration site family, member 9A [KO:K01064 ]
22412 Wnt9b; wingless-type MMTV integration site family, member 9B [KO:K01064 ]
22410 Wnt10b; wingless-type MMTV integration site family, member 10B [KO:K01357 ]
22409 Wnt10a; wingless-type MMTV integration site family, member 10A [KO:K01357 ]
22411 Wnt11; wingless-type MMTV integration site family, member 11 [KO:K01384 ]
93735 Wnt16; wingless-type MMTV integration site family, member 16 [KO:K01558 ]
13544 Dvl3; dishevelled segment polarity protein 3 [KO:K02353 ]
13542 Dvl1; dishevelled segment polarity protein 1 [KO:K02353 ]
13543 Dvl2; dishevelled segment polarity protein 2 [KO:K02353 ]
11789 Apc; APC, WNT signaling pathway regulator [KO:K02085 ]
23805 Apc2; APC regulator of WNT signaling pathway 2 [KO:K02085 ]
21414 Tcf7; transcription factor 7, T cell specific [KO:K02620 ]
21415 Tcf7l1; transcription factor 7 like 1 (T cell specific, HMG box) [KO:K04490 ]
21416 Tcf7l2; transcription factor 7 like 2, T cell specific, HMG box [KO:K04491 ]
16842 Lef1; lymphoid enhancer binding factor 1 [KO:K04492 ]
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
mmu04927 Cortisol synthesis and secretion
mmu04960 Aldosterone-regulated sodium reabsorption
KO pathway
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