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====Gain of function mutations(KCNJ5, CACNA1D, CTNNB1 mutations)====
====Gain of function mutations(KCNJ5, CACNA1D, CTNNB1 mutations)====
* Inherited and acquired mutations in  potassium inwardly rectifying channel, subfamily J, member 5 (''KCNJ5)'' gene, which codes for a K ion channel has been associated with autonomous cell proliferation in the adrenal cortex. <ref name="pmid21311022">{{cite journal |vauthors=Choi M, Scholl UI, Yue P, Björklund P, Zhao B, Nelson-Williams C, Ji W, Cho Y, Patel A, Men CJ, Lolis E, Wisgerhof MV, Geller DS, Mane S, Hellman P, Westin G, Åkerström G, Wang W, Carling T, Lifton RP |title=K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension |journal=Science |volume=331 |issue=6018 |pages=768–72 |year=2011 |pmid=21311022 |pmc=3371087 |doi=10.1126/science.1198785 |url=}}</ref> Two somatic mutations in the K+ channel KCNJ5 (G151R and L168R) cause ~40% of APA. <ref name="pmid262526182">{{cite journal |vauthors=Scholl UI, Healy JM, Thiel A, Fonseca AL, Brown TC, Kunstman JW, Horne MJ, Dietrich D, Riemer J, Kücükköylü S, Reimer EN, Reis AC, Goh G, Kristiansen G, Mahajan A, Korah R, Lifton RP, Prasad ML, Carling T |title=Novel somatic mutations in primary hyperaldosteronism are related to the clinical, radiological and pathological phenotype |journal=Clin. Endocrinol. (Oxf) |volume=83 |issue=6 |pages=779–89 |year=2015 |pmid=26252618 |pmc=4995792 |doi=10.1111/cen.12873 |url=}}</ref>  These mutations affect K ion selectivity leading to increased Na+ conductance and membrane depolarization resulting in activation of voltage-gated Ca2+channels. Increased intracellular Ca results in CYP11B2 expression and release of aldosterone from the adrenal gland. Patients with KCNJ5 mutations are more frequently female, diagnosed younger, and with higher minimal plasma potassium concentrations. <ref name="pmid24866132">{{cite journal |vauthors=Fernandes-Rosa FL, Williams TA, Riester A, Steichen O, Beuschlein F, Boulkroun S, Strom TM, Monticone S, Amar L, Meatchi T, Mantero F, Cicala MV, Quinkler M, Fallo F, Allolio B, Bernini G, Maccario M, Giacchetti G, Jeunemaitre X, Mulatero P, Reincke M, Zennaro MC |title=Genetic spectrum and clinical correlates of somatic mutations in aldosterone-producing adenoma |journal=Hypertension |volume=64 |issue=2 |pages=354–61 |year=2014 |pmid=24866132 |doi=10.1161/HYPERTENSIONAHA.114.03419 |url=}}</ref>
* Inherited and acquired mutations in  potassium inwardly rectifying channel, subfamily J, member 5 (''KCNJ5)'' gene, which codes for a K ion channel has been associated with autonomous cell proliferation in the adrenal cortex. <ref name="pmid21311022">{{cite journal |vauthors=Choi M, Scholl UI, Yue P, Björklund P, Zhao B, Nelson-Williams C, Ji W, Cho Y, Patel A, Men CJ, Lolis E, Wisgerhof MV, Geller DS, Mane S, Hellman P, Westin G, Åkerström G, Wang W, Carling T, Lifton RP |title=K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension |journal=Science |volume=331 |issue=6018 |pages=768–72 |year=2011 |pmid=21311022 |pmc=3371087 |doi=10.1126/science.1198785 |url=}}</ref> Two somatic mutations in the K+ channel KCNJ5 (G151R and L168R) cause ~40% of APA. <ref name="pmid262526182">{{cite journal |vauthors=Scholl UI, Healy JM, Thiel A, Fonseca AL, Brown TC, Kunstman JW, Horne MJ, Dietrich D, Riemer J, Kücükköylü S, Reimer EN, Reis AC, Goh G, Kristiansen G, Mahajan A, Korah R, Lifton RP, Prasad ML, Carling T |title=Novel somatic mutations in primary hyperaldosteronism are related to the clinical, radiological and pathological phenotype |journal=Clin. Endocrinol. (Oxf) |volume=83 |issue=6 |pages=779–89 |year=2015 |pmid=26252618 |pmc=4995792 |doi=10.1111/cen.12873 |url=}}</ref>  These mutations affect K ion selectivity leading to increased Na+ conductance and membrane depolarization resulting in activation of voltage-gated Ca2+channels. Increased intracellular Ca results in CYP11B2 expression and release of aldosterone from the adrenal gland. Patients with KCNJ5 mutations are more frequently female, diagnosed younger, and with higher minimal plasma potassium concentrations. <ref name="pmid24866132">{{cite journal |vauthors=Fernandes-Rosa FL, Williams TA, Riester A, Steichen O, Beuschlein F, Boulkroun S, Strom TM, Monticone S, Amar L, Meatchi T, Mantero F, Cicala MV, Quinkler M, Fallo F, Allolio B, Bernini G, Maccario M, Giacchetti G, Jeunemaitre X, Mulatero P, Reincke M, Zennaro MC |title=Genetic spectrum and clinical correlates of somatic mutations in aldosterone-producing adenoma |journal=Hypertension |volume=64 |issue=2 |pages=354–61 |year=2014 |pmid=24866132 |doi=10.1161/HYPERTENSIONAHA.114.03419 |url=}}</ref><ref name="pmid22628608">{{cite journal |vauthors=Monticone S, Hattangady NG, Nishimoto K, Mantero F, Rubin B, Cicala MV, Pezzani R, Auchus RJ, Ghayee HK, Shibata H, Kurihara I, Williams TA, Giri JG, Bollag RJ, Edwards MA, Isales CM, Rainey WE |title=Effect of KCNJ5 mutations on gene expression in aldosterone-producing adenomas and adrenocortical cells |journal=J. Clin. Endocrinol. Metab. |volume=97 |issue=8 |pages=E1567–72 |year=2012 |pmid=22628608 |pmc=3410264 |doi=10.1210/jc.2011-3132 |url=}}</ref><ref name="pmid24037882">{{cite journal |vauthors=Monticone S, Hattangady NG, Penton D, Isales CM, Edwards MA, Williams TA, Sterner C, Warth R, Mulatero P, Rainey WE |title=a Novel Y152C KCNJ5 mutation responsible for familial hyperaldosteronism type III |journal=J. Clin. Endocrinol. Metab. |volume=98 |issue=11 |pages=E1861–5 |year=2013 |pmid=24037882 |pmc=3816265 |doi=10.1210/jc.2013-2428 |url=}}</ref><ref name="pmid22315453">{{cite journal |vauthors=Oki K, Plonczynski MW, Luis Lam M, Gomez-Sanchez EP, Gomez-Sanchez CE |title=Potassium channel mutant KCNJ5 T158A expression in HAC-15 cells increases aldosterone synthesis |journal=Endocrinology |volume=153 |issue=4 |pages=1774–82 |year=2012 |pmid=22315453 |pmc=3320257 |doi=10.1210/en.2011-1733 |url=}}</ref>
* A germline mutation in the KCNJ5 gene produces familial hyperaldosteronism type III.
* A germline mutation in the KCNJ5 gene produces familial hyperaldosteronism type III.
*Gain-of-function mutation in the ''CACNA1D gene.'' CACNA1D mutation leads to increased calcium influx through the mutant channel by shifting the voltage dependence of activation to less depolarized potentials and, in some cases, impairing inactivation.
*Gain-of-function mutation in the ''CACNA1D gene.'' CACNA1D mutation leads to increased calcium influx through the mutant channel by shifting the voltage dependence of activation to less depolarized potentials and, in some cases, impairing inactivation.
*Activating somatic CTNNB1 mutations, which mediate their effects through WnT signalling pathyway have also been known to cause APA.
*Activating somatic CTNNB1 mutations, which mediate their effects through WnT signalling pathyway have also been known to cause APA.<ref name="pmid26815163">{{cite journal |vauthors=Åkerström T, Maharjan R, Sven Willenberg H, Cupisti K, Ip J, Moser A, Stålberg P, Robinson B, Alexander Iwen K, Dralle H, Walz MK, Lehnert H, Sidhu S, Gomez-Sanchez C, Hellman P, Björklund P |title=Activating mutations in CTNNB1 in aldosterone producing adenomas |journal=Sci Rep |volume=6 |issue= |pages=19546 |year=2016 |pmid=26815163 |pmc=4728393 |doi=10.1038/srep19546 |url=}}</ref>
*CTNNB1 mutations cause adrenocortical cells to de-differentiate into their the precursor adrenal gonadal cell.
*CTNNB1 mutations cause adrenocortical cells to de-differentiate into their the precursor adrenal gonadal cell.


Revision as of 15:11, 7 July 2017

Overview

Pathophysiology

Basic physiology of aldosterone

Circulating aldosterone is principally made in the zona glomerulosa of the adrenal cortex (outer layer of the cortex) by a cascade of enzyme steps leading to the conversion of cholesterol to aldosterone.  

  • Aldosterone's production is regulated at two critical enzyme steps:
    • (1) early in its biosynthetic pathway (the conversion of cholesterol to pregnenolone cholesterol side chain cleavage enzyme) and
    • (2) late (the conversion of corticosterone to aldosterone by aldosterone synthase).
  • A variety of factors modify aldosterone secretion--the most important are angiotensin II (AngII), the end-product of the renin-angiotensin system (RAS), and potassium. However ACTH, neural mediators and natriuretic factors also play part in the feedback mechanism. 
  • Aldosterone's classical epithelial effect is to increase the transport of sodium across the cell in exchange for potassium and hydrogen ions. [1]

Pathogenesis

Conn's syndrome (primary hyperaldoseronism-PH) features overproduction of aldosterone despite suppressed plasma renin activity (PRA). The resulting Na+ retention produces hypertension, and elevated K+ excretion may cause hypokalemia.

  • Patients with Conn's syndrome due to primary hyperaldosertonism may have:
    • Aldosterone producing adrenocortical adenoma (APA)- Classically referred to as Conn's syndrome.[2]
    • Unilateral hyperplasia
    • Idiopathic hyperaldosteronism (IHA, also known as bilateral adrenal hyperplasia).[3] Familial forms (familial hyperaldosteronism types I, II, and III) have also been described.
    • Ectopic secretion of aldosterone (The ovaries and kidneys are the 2 organs described in the literature that, in the setting of neoplastic disease, can be ectopic sources of aldosterone, but this is a rare occurrence.)

Genetics Of Aldosterone producing adenoma(APA)

APAs are typically solitary, well circumscribed, and diagnosed between ages 30 and 70.

Somatic mutations

  • Conn's syndrome producing aldosterone-producing adenomas (APAs) have mutations in genes encoding ion channels/pumps that change the intracellular calcium homeostasis and cause renin-independent aldosterone production through enhanced CYP11B2 expression. Subcapsular aldosterone-producing cell clusters (APCCs) are CYP11B2-expressing clusters of cells that are found beneath the adrenal capsule but protrude into cortisol-producing cells that are negative for CYP11B2 expression.
  • APCCs are also frequently found in adrenal tissue in close proximity to APA.
  • The renin-angiotensin axis is supressed in patients with APAs, pointing towards an autonomous, renin-independent production of aldosterone by APCCs.
  • Somatic mutations in KCNJ5, ATP1A1, ATP2B3, and CACNA1D are found in approximately 50 percent of APAs .

Gain of function mutations(KCNJ5, CACNA1D, CTNNB1 mutations)

  • Inherited and acquired mutations in  potassium inwardly rectifying channel, subfamily J, member 5 (KCNJ5) gene, which codes for a K ion channel has been associated with autonomous cell proliferation in the adrenal cortex. [4] Two somatic mutations in the K+ channel KCNJ5 (G151R and L168R) cause ~40% of APA. [5] These mutations affect K ion selectivity leading to increased Na+ conductance and membrane depolarization resulting in activation of voltage-gated Ca2+channels. Increased intracellular Ca results in CYP11B2 expression and release of aldosterone from the adrenal gland. Patients with KCNJ5 mutations are more frequently female, diagnosed younger, and with higher minimal plasma potassium concentrations. [6][7][8][9]
  • A germline mutation in the KCNJ5 gene produces familial hyperaldosteronism type III.
  • Gain-of-function mutation in the CACNA1D gene. CACNA1D mutation leads to increased calcium influx through the mutant channel by shifting the voltage dependence of activation to less depolarized potentials and, in some cases, impairing inactivation.
  • Activating somatic CTNNB1 mutations, which mediate their effects through WnT signalling pathyway have also been known to cause APA.[10]
  • CTNNB1 mutations cause adrenocortical cells to de-differentiate into their the precursor adrenal gonadal cell.

Loss of function mutations(ATP1A1 and ATP2A3)

  • Other genes implicated in development of APAs are loss-of-function mutations in ATP1A1 and ATP2A3 genes.
  • ATP1A1 mutations lead to permeability of the pump for Na+ or H+ ions in a channel-like mode, again causing depolarization and release of aldosterone.[11]


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References

  1. ↑ Williams GH (2005). "Aldosterone biosynthesis, regulation, and classical mechanism of action". Heart Fail Rev. 10 (1): 7–13. doi:10.1007/s10741-005-2343-3. PMID 15947886.
  2. ↑ Young WF (2007). "Primary aldosteronism: renaissance of a syndrome". Clin. Endocrinol. (Oxf). 66 (5): 607–18. doi:10.1111/j.1365-2265.2007.02775.x. PMID 17492946.
  3. ↑ Scholl UI, Healy JM, Thiel A, Fonseca AL, Brown TC, Kunstman JW, Horne MJ, Dietrich D, Riemer J, Kücükköylü S, Reimer EN, Reis AC, Goh G, Kristiansen G, Mahajan A, Korah R, Lifton RP, Prasad ML, Carling T (2015). "Novel somatic mutations in primary hyperaldosteronism are related to the clinical, radiological and pathological phenotype". Clin. Endocrinol. (Oxf). 83 (6): 779–89. doi:10.1111/cen.12873. PMC 4995792. PMID 26252618.
  4. ↑ Choi M, Scholl UI, Yue P, Björklund P, Zhao B, Nelson-Williams C, Ji W, Cho Y, Patel A, Men CJ, Lolis E, Wisgerhof MV, Geller DS, Mane S, Hellman P, Westin G, Åkerström G, Wang W, Carling T, Lifton RP (2011). "K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension". Science. 331 (6018): 768–72. doi:10.1126/science.1198785. PMC 3371087. PMID 21311022.
  5. ↑ Scholl UI, Healy JM, Thiel A, Fonseca AL, Brown TC, Kunstman JW, Horne MJ, Dietrich D, Riemer J, Kücükköylü S, Reimer EN, Reis AC, Goh G, Kristiansen G, Mahajan A, Korah R, Lifton RP, Prasad ML, Carling T (2015). "Novel somatic mutations in primary hyperaldosteronism are related to the clinical, radiological and pathological phenotype". Clin. Endocrinol. (Oxf). 83 (6): 779–89. doi:10.1111/cen.12873. PMC 4995792. PMID 26252618.
  6. ↑ Fernandes-Rosa FL, Williams TA, Riester A, Steichen O, Beuschlein F, Boulkroun S, Strom TM, Monticone S, Amar L, Meatchi T, Mantero F, Cicala MV, Quinkler M, Fallo F, Allolio B, Bernini G, Maccario M, Giacchetti G, Jeunemaitre X, Mulatero P, Reincke M, Zennaro MC (2014). "Genetic spectrum and clinical correlates of somatic mutations in aldosterone-producing adenoma". Hypertension. 64 (2): 354–61. doi:10.1161/HYPERTENSIONAHA.114.03419. PMID 24866132.
  7. ↑ Monticone S, Hattangady NG, Nishimoto K, Mantero F, Rubin B, Cicala MV, Pezzani R, Auchus RJ, Ghayee HK, Shibata H, Kurihara I, Williams TA, Giri JG, Bollag RJ, Edwards MA, Isales CM, Rainey WE (2012). "Effect of KCNJ5 mutations on gene expression in aldosterone-producing adenomas and adrenocortical cells". J. Clin. Endocrinol. Metab. 97 (8): E1567–72. doi:10.1210/jc.2011-3132. PMC 3410264. PMID 22628608.
  8. ↑ Monticone S, Hattangady NG, Penton D, Isales CM, Edwards MA, Williams TA, Sterner C, Warth R, Mulatero P, Rainey WE (2013). "a Novel Y152C KCNJ5 mutation responsible for familial hyperaldosteronism type III". J. Clin. Endocrinol. Metab. 98 (11): E1861–5. doi:10.1210/jc.2013-2428. PMC 3816265. PMID 24037882.
  9. ↑ Oki K, Plonczynski MW, Luis Lam M, Gomez-Sanchez EP, Gomez-Sanchez CE (2012). "Potassium channel mutant KCNJ5 T158A expression in HAC-15 cells increases aldosterone synthesis". Endocrinology. 153 (4): 1774–82. doi:10.1210/en.2011-1733. PMC 3320257. PMID 22315453.
  10. ↑ Åkerström T, Maharjan R, Sven Willenberg H, Cupisti K, Ip J, Moser A, Stålberg P, Robinson B, Alexander Iwen K, Dralle H, Walz MK, Lehnert H, Sidhu S, Gomez-Sanchez C, Hellman P, Björklund P (2016). "Activating mutations in CTNNB1 in aldosterone producing adenomas". Sci Rep. 6: 19546. doi:10.1038/srep19546. PMC 4728393. PMID 26815163.
  11. ↑ Scholl UI, Healy JM, Thiel A, Fonseca AL, Brown TC, Kunstman JW, Horne MJ, Dietrich D, Riemer J, Kücükköylü S, Reimer EN, Reis AC, Goh G, Kristiansen G, Mahajan A, Korah R, Lifton RP, Prasad ML, Carling T (2015). "Novel somatic mutations in primary hyperaldosteronism are related to the clinical, radiological and pathological phenotype". Clin. Endocrinol. (Oxf). 83 (6): 779–89. doi:10.1111/cen.12873. PMC 4995792. PMID 26252618.

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