Entry |
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Name |
Cushing syndrome - Loxodonta africana (African savanna elephant)
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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).
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Class |
Human Diseases; Endocrine and metabolic disease
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Pathway map |

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Organism |
Loxodonta africana (African savanna elephant) [GN: lav]
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Gene |
100659551 | CRHR1; corticotropin-releasing factor receptor 1 isoform X3 [KO:K04578] |
100655206 | guanine nucleotide-binding protein G(s) subunit alpha isoform X1 [KO:K04632] |
100675162 | CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870] |
100657989 | ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450] |
100662521 | ATF4; cyclic AMP-dependent transcription factor ATF-4 isoform X2 [KO:K04374] |
100653565 | CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048] |
100673694 | CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048] |
100666211 | CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048] |
100670574 | CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048] |
100677344 | CREB3; cyclic AMP-responsive element-binding protein 3 isoform X1 [KO:K09048] |
100675079 | CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047] |
100666885 | ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X2 [KO:K09049] |
100665231 | ASH2L; set1/Ash2 histone methyltransferase complex subunit ASH2 isoform X2 [KO:K14964] |
100666344 | GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630] |
100670234 | GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630] |
100667957 | GNAI3; LOW QUALITY PROTEIN: guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630] |
100673667 | ARNT; aryl hydrocarbon receptor nuclear translocator isoform X6 [KO:K09097] |
100659992 | CACNA1D; LOW QUALITY PROTEIN: voltage-dependent L-type calcium channel subunit alpha-1D [KO:K04851] |
100674649 | CACNA1F; LOW QUALITY PROTEIN: voltage-dependent L-type calcium channel subunit alpha-1F [KO:K04853] |
100673089 | CACNA1S; LOW QUALITY PROTEIN: voltage-dependent L-type calcium channel subunit alpha-1S [KO:K04857] |
100653927 | CAMK2G; calcium/calmodulin-dependent protein kinase type II subunit gamma isoform X1 [KO:K04515] [EC:2.7.11.17] |
100663321 | CAMK2D; calcium/calmodulin-dependent protein kinase type II subunit delta isoform X2 [KO:K04515] [EC:2.7.11.17] |
100670699 | PDE8B; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B [KO:K18437] [EC:3.1.4.53] |
100658501 | PDE8A; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A isoform X3 [KO:K18437] [EC:3.1.4.53] |
100658312 | PBX1; pre-B-cell leukemia transcription factor 1 isoform X1 [KO:K09355] |
100664947 | STAR; steroidogenic acute regulatory protein, mitochondrial [KO:K16931] |
100668092 | NCEH1; neutral cholesterol ester hydrolase 1 isoform X1 [KO:K14349] [EC:3.1.1.-] |
100663645 | ARMC5; LOW QUALITY PROTEIN: armadillo repeat-containing protein 5 [KO:K22499] |
100656672 | GNAQ; guanine nucleotide-binding protein G(q) subunit alpha isoform X1 [KO:K04634] |
100670617 | PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X3 [KO:K05858] [EC:3.1.4.11] |
100672435 | PLCB1; LOW QUALITY PROTEIN: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858] [EC:3.1.4.11] |
100668575 | PLCB2; LOW QUALITY PROTEIN: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11] |
100663829 | PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 isoform X1 [KO:K05858] [EC:3.1.4.11] |
100665028 | ITPR1; LOW QUALITY PROTEIN: inositol 1,4,5-trisphosphate receptor type 1 [KO:K04958] |
100659666 | ITPR3; LOW QUALITY PROTEIN: inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960] |
100654542 | KCNK2; potassium channel subfamily K member 2 isoform X1 [KO:K04913] |
100666554 | CACNA1G; voltage-dependent T-type calcium channel subunit alpha-1G isoform X1 [KO:K04854] |
100675598 | CACNA1H; LOW QUALITY PROTEIN: voltage-dependent T-type calcium channel subunit alpha-1H [KO:K04855] |
100660332 | CACNA1I; LOW QUALITY PROTEIN: voltage-dependent T-type calcium channel subunit alpha-1I [KO:K04856] |
100669326 | ORAI1; calcium release-activated calcium channel protein 1 [KO:K16056] |
100667029 | KCNA4; potassium voltage-gated channel subfamily A member 4 [KO:K04877] |
100673586 | DVL3; segment polarity protein dishevelled homolog DVL-3 isoform X1 [KO:K02353] |
100657749 | DVL2; segment polarity protein dishevelled homolog DVL-2 isoform X1 [KO:K02353] |
100657649 | DVL1; segment polarity protein dishevelled homolog DVL-1 isoform X1 [KO:K02353] |
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Compound |
C01176 | 17alpha-Hydroxyprogesterone |
C01245 | D-myo-Inositol 1,4,5-trisphosphate |
C05138 | 17alpha-Hydroxypregnenolone |
C07557 | 2,3,7,8-Tetrachlorodibenzodioxin |
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Reference |
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Authors |
Lacroix A, Feelders RA, Stratakis CA, Nieman LK |
Title |
Cushing's syndrome. |
Journal |
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Reference |
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Authors |
Xiong Q, Ge W |
Title |
Gene mutations in Cushing's disease. |
Journal |
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Reference |
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Authors |
Fukuoka H, Takahashi Y |
Title |
The role of genetic and epigenetic changes in pituitary tumorigenesis. |
Journal |
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Reference |
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Authors |
Quereda V, Malumbres M |
Title |
Cell cycle control of pituitary development and disease. |
Journal |
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Reference |
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Authors |
Caimari F, Korbonits M |
Title |
Novel Genetic Causes of Pituitary Adenomas. |
Journal |
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Reference |
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Authors |
Lecoq AL, Kamenicky P, Guiochon-Mantel A, Chanson P |
Title |
Genetic mutations in sporadic pituitary adenomas--what to screen for? |
Journal |
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Reference |
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Authors |
Hannah-Shmouni F, Faucz FR, Stratakis CA |
Title |
Alterations of Phosphodiesterases in Adrenocortical Tumors. |
Journal |
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Reference |
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Authors |
Melmed S |
Title |
Pathogenesis of pituitary tumors. |
Journal |
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Reference |
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Authors |
Daly AF, Tichomirowa MA, Beckers A |
Title |
Genetic, molecular and clinical features of familial isolated pituitary adenomas. |
Journal |
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Reference |
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Authors |
Albani A, Theodoropoulou M, Reincke M |
Title |
Genetics of Cushing's disease. |
Journal |
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Reference |
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Authors |
Duan K, Hernandez KG, Mete O |
Title |
Clinicopathological correlates of adrenal Cushing's syndrome. |
Journal |
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Reference |
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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 |
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Reference |
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Authors |
Stratakis CA, Boikos SA |
Title |
Genetics of adrenal tumors associated with Cushing's syndrome: a new classification for bilateral adrenocortical hyperplasias. |
Journal |
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Reference |
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Authors |
Refojo D, Holsboer F |
Title |
CRH signaling. Molecular specificity for drug targeting in the CNS. |
Journal |
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Reference |
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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 |
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Reference |
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Authors |
Lacroix A, Baldacchino V, Bourdeau I, Hamet P, Tremblay J |
Title |
Cushing's syndrome variants secondary to aberrant hormone receptors. |
Journal |
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Reference |
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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 |
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Reference |
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Authors |
Kaiser UB |
Title |
Cushing's disease: towards precision medicine. |
Journal |
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Reference |
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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 |
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Reference |
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Authors |
Huang C, Shi Y, Zhao Y |
Title |
USP8 mutation in Cushing's disease. |
Journal |
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Reference |
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Authors |
Theodoropoulou M, Reincke M, Fassnacht M, Komada M |
Title |
Decoding the genetic basis of Cushing's disease: USP8 in the spotlight. |
Journal |
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Reference |
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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 |
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Reference |
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Authors |
Wu X, Hua X |
Title |
Menin, histone h3 methyltransferases, and regulation of cell proliferation: current knowledge and perspective. |
Journal |
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Reference |
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Authors |
Ozfirat Z, Korbonits M |
Title |
AIP gene and familial isolated pituitary adenomas. |
Journal |
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Related pathway |
lav04927 | Cortisol synthesis and secretion |
lav04960 | Aldosterone-regulated sodium reabsorption |
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KO pathway |
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LinkDB |
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