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Kuppusamy, Maniselvan (2014) Prevalence of KCNJ5 mutations and functional impact of a novel KCNJ5-insT149 mutation in aldosterone producing adenoma causing resistant hypertension. [Tesi di dottorato]

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Abstract (inglese)

Primary aldosteronism (PA), a common form of secondary hypertension, is characterized by an excess autonomous aldosterone secretion. In a percentage ranging from a half to two thirds of the cases it is due to a surgically curable aldosterone-producing adenoma (APA) and in the rest to bilateral adrenal hyperplasia. The molecular mechanisms underlying aldosterone hypersecretion are unknown.
Recent evidences suggest that amino acid residue substitutions in the selectivity filter of the Kir3.4 (KCNJ5) potassium channel may cause a constitutive aldosterone secretion from aldosterone-producing adenomas (APA). Such somatic mutations were also found to be associated with higher plasma aldosterone concentrations in the patients with an APA, thereby suggesting a causative role of the mutations in the development of APA and hyperaldosteronism. Hence, we performed a study with the aims to search for KCNJ5 mutations in APA patients referred to two Italian referral centers. Through this search we could also identify a novel KCNJ5-insT149 mutation out of the selectivity filter that was a fully characterized from the electrophysiological and phenotypic standpoint.
APA samples (n=195) from consecutive patients with a conclusive diagnosis of APA were screened by high melting resolution curve for KCNJ5 mutations. We found that the mutations occurred in 24.6% of patients. These findings were confirmed by Sanger sequencing. The mRNA content of CYP11B2, but not of CYP11B1, and plasma aldosterone and, accordingly, the lateralization index were higher (P < 0.02) in the APA with the mutation than in the APA without such mutations.
A novel c.446insAAC insertion resulting in the mutant protein KCNJ5-insT149 was identified In a patient presenting with severe drug-resistant hypertension. To functionally characterize this novel KCNJ5 channel mutation a mutated cDNA harbouring c.446insAAC insertion was generated by site-directed mutagenesis and transfected in mammalian cells. KCNJ3 cDNA was also transfected into the same cells to reproduce the tetrameric structure of the KCNJ3/KCNJ5 channel.
CYP11B1, CYP11B2 and 17α-hydroxylase were localized in the adrenal gland of the mutated APA patient with immunohistochemistry and immunofluorescence.
CYP11B2 mRNA levels and aldosterone concentrations were also measured to investigate the impact of the mutation on the secreting activity. By using a whole-cell patch clamp technique and molecular modeling we explored membrane Na+ and Ca2+ currents and created a 3D image of the insT149 KCNJ5 channel. Compared to wild type and mock-transfected HAC15 adrenocortical cells, those expressing the mutant KCNJ5 showed increased CYP11B2 expression and aldosterone secretion. Likewise HEK293 expressing the mutated KCNJ5-insT149 channel exhibited a 2-fold increase in intracellular Na+ and a substantial rise in intracellular Ca2+ caused by activation of voltage-gated Ca2+ channels. Hence, the novel KCNJ5 K+ channel mutation induces abnormal Na+ permeability, membrane depolarization, a rise in cytosolic Ca2+ and increased aldosterone synthesis.
Thus, our findings support the concept that channelopathies involving the KCNJ5 K+ channel mechanistically account for constitutive secretion of aldosterone in human APA.

Abstract (italiano)

L’ iperaldosteronismo primario (PA) è la causa più frequente di ipertensione secondaria ed è caratterizzato da una secrezione elevata ed autonoma di aldosterone. Le due forme principali sono l’iperplasia surrenalica bilaterale e l’adenoma secernente aldosterone. I meccanismi molecolari alla base dell’ipersecrezione di aldosterone sono tuttora sconosciuti.
Tuttavia recenti studi hanno dimostrato che sostituzioni amminoacidiche all’interno del filtro di selettività del canale del potassio Kir3.4 (KCNJ5 possono provocare una secrezione autonoma di aldosterone in adenomi producenti aldosterone (APA). Tali mutazioni somatiche sono associate ad alti livelli plasmatici di aldosterone nei pazienti con APA, suggerendo un ruolo causale di tali mutazioni nello sviluppo di APA e iperaldosteronismo. Pertanto abbiamo condotto uno studio in pazienti affetti da APA afferenti a due centri di riferimento italiani, effettuando lo screening per le mutazioni somatiche di KCNJ5, ed abbiamo individuato e caratterizzato la mutazione KCNJ5-insT149, mai descritta in precedenza.
Mediante analisi ad alta risoluzione delle curve di melting per le mutazioni in KCNJ5 sono stati studiati 195 pazienti consecutive con una diagnosi conclusiva di APA. Il 24,6% dei pazienti presentava una mutazione nel filtro di selettività del KCNJ5, tale prevalenza è stata confermata mediante sequenziamento Sanger.
Nei pazienti affetti da mutazione di KCNJ5 l’espressione genica di CYP11B2 (29,9 ± 7,4 vs 10,3 ± 3,6, P <0,02), ma non quella di CYP11B1, risultava superiore rispetto ai pazienti non affetti da mutazioni, lo stesso valeva per l’indice di lateralizzazione.
In un paziente con ipertensione farmaco-resistente grave è stata identificata l’ inserzione c.446insAAC, che codifica per la proteina mutante KCNJ5-insT149. Per caratterizzare funzionalmente questa nuova mutazione, attaverso mutagenesi sito-diretta, è stato generato un cDNA codificante per il canale KCNJ5 mutato e trasfettato in cellule di mammifero. Il cDNA codificante KCNJ3 è stato transfettato insieme a quello per KCNJ5 in modo da riprodurre la struttura tetramerica del canale KCNJ3/KCNJ5.
CYP11B1, CYP11B2 e 17α-idrossilasi sono stati rilevati attraverso tecniche di immunoistochimica e immunofluorescenza nella ghiandola surrenale del paziente. L’espressione genica di CYP11B2 e le concentrazioni di aldosterone sono stati misurati per studiare l'impatto della mutazione sull'attività secernente. Utilizzando la tecnica di “whole-cell patch clamp e modeling molecolare” abbiamo studiato le correnti trans-membrana di Na+ e Ca2+ e generato una immagine 3D del canale insT149 KCNJ5. Rispetto al wild type e alle cellule adrenocorticali HAC15, le cellule transfettate con KCNJ5-insT149 esprimevano alti livelli del gene CYP11B2 e mostravano un’aumentata produzione di aldosterone.
Allo stesso modo cellule HEK293 che esprimono il canale KCNJ5-insT149 mutato mostravano un aumento pari a due volte di Na+ intracellulare e un aumento sostanziale di Ca2+ intracellulare in seguito all’ attivazione dei canali del Ca2+ voltaggio-dipendenti. Quindi, la nuova mutazione del canale del K+ KCNJ5 induce un’anomala permeabilità della membrana al Na+, depolarizzazione della membrana, un aumento di Ca2+ intracellulare e aumento della sintesi di aldosterone.
I nostri risultati nel complesso supportano il concetto che le canalopatie che coinvolgono il canale del K+ KCNJ5 sono alla base della secrezione costitutiva di aldosterone in pazienti affetti da APA.

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Tipo di EPrint:Tesi di dottorato
Relatore:Seccia, Teresa Maria
Dottorato (corsi e scuole):Ciclo 26 > Corsi 26 > Ipertensione Arteriosa e Biologia Vascolare
Data di deposito della tesi:29 Gennaio 2014
Anno di Pubblicazione:30 Gennaio 2014
Parole chiave (italiano / inglese):Aldosterone, Aldosterone Producing Adenoma, Hyperaldosteronism, Primary aldosteronism, Hypertension, Potassium Channel
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/09 Medicina interna
Struttura di riferimento:Dipartimenti > Dipartimento di Medicina
Codice ID:6501
Depositato il:14 Nov 2014 13:15
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