Somatic and Inherited Mutations in Primary Aldosteronism

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f l fernandes-rosa, s boulkroun Genetic basis of 59: 1 R47–R63 Review and others primary aldosteronism

Somatic and inherited mutations in primary aldosteronism

Fabio Luiz Fernandes-Rosa1,2,3,*, Sheerazed Boulkroun1,2,* and Maria-Christina Zennaro1,2,3 Correspondence should be addressed 1 INSERM, UMRS_970, Paris Cardiovascular Research Center, Paris, France to F L Fernandes-Rosa or 2 University Paris Descartes, Sorbonne Paris Cité, Paris, France S Boulkroun 3 Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique, Email Paris, France fabio.fernandes-rosa@ *(F L Fernandes-Rosa and S Boulkroun contributed equally to this work) inserm.fr or sheerazed. [email protected]

Abstract

Primary aldosteronism (PA), the most common form of secondary hypertension, is caused Key Words in the majority of cases by unilateral aldosterone-producing adenoma (APA) or bilateral ff primary aldosteronism adrenal hyperplasia. Over the past few years, somatic mutations in KCNJ5, CACNA1D, ff aldosterone-producing ATP1A1 and ATP2B3 have been proven to be associated with APA development, adenoma representing more than 50% of sporadic APA. The identification of these mutations has ff familial allowed the development of a model for APA involving modification on the intracellular hyperaldosteronism ionic equilibrium and regulation of cell membrane potential, leading to autonomous ff somatic mutations aldosterone overproduction. Furthermore, somatic CTNNB1 mutations have also been ff germline mutations identified in APA, but the link between these mutations and APA development remains ff potassium channels unknown. The sequence of events responsible for APA formation is not completely ff calcium channels understood, in particular, whether a single hit or a double hit is responsible for both ff ATPase Journal of Molecular Endocrinology aldosterone overproduction and cell proliferation. Germline mutations identified in ff Wnt/β-catenin pathway patients with early-onset PA have expanded the classification of familial forms (FH) of PA. The description of germline KCNJ5 and CACNA1H mutations has identified FH-III and FH-IV based on genetic findings; germlineCACNA1D mutations have been identified in patients with very early-onset PA and severe neurological abnormalities. This review summarizes current knowledge on the genetic basis of PA, the association of driver gene mutations and clinical findings and in the contribution to patient care, plus the current Journal of Molecular understanding on the mechanisms of APA development. Endocrinology (2017) 59, R47–R63

Background

Arterial hypertension is a major cardiovascular risk an estimated prevalence of 5–10% in hypertensive factor with an estimated global age-standardized patients (Mulatero et al. 2004, Plouin et al. 2004, prevalence of 24.1% in adult males and 20.1% in adult Rossi et al. 2006, Douma et al. 2008, Hannemann & females (NCD-RisC 2017). Detection of secondary Wallaschofski 2012, Hannemann et al. 2012). PA is hypertension is crucial for targeted management of the due to autonomous aldosterone production from underlying disease and prevention of cardiovascular the adrenal gland, leading to hypertension with an complications. Primary aldosteronism (PA) is the increased aldosterone-to-renin ratio and on occasion most common form of secondary hypertension with hypokalemia (Funder et al. 2016).

10.1530/JME-17-0035 Journal of Molecular Endocrinology CYP11B2 concentration leadstoactivationof theCa inhibit potassiumchannelsandNa depolarization leadingtoopeningof voltagegatedCa triphosphate inositol(IP3)increase, to thereleaseofstoredCa pathway, themajortriggerforaldosterone biosynthesis.ThebindingofangiotensinII(AngII)totheAngIItype 1receptor(AT1R) leads,through depolarization ofcellmembrane,openingvoltagegatedCa increase orintracellulardecreaseofK intracellular andextracellularspacesrequiredtomaintainthismembrane potentialisgeneratedbytheNa hyperpolarized duetothepresenceofahighnumberpotassiumchannels atthecellsurface.ThegradientofK Regulation ofaldosteronebiosynthesisinzonaglomerulosaunderphysiological conditions.(A)Inbasalcondition,zonaglomerulosacellsare Figure 1 determining end-organdamage.Giventhemajor recently, aldosteronehasemergedasakeyhormone thus regulationofbloodpressure( a majorroleinpromotingsodiumreabsorptionand particularly intherenalcollectingduct,whereitplays by thekidney. Aldosterone acts on epithelial cells, controlled tomaintainelectrolyteandfluidhomeostasis 2004 release fromtheendoplasmicreticulum( AngII type1receptors,thehormonealsoinducesCa intracellular Ca calcium (Ca the ZGcellmembraneandopeningofvoltage-dependent angiotensin II(AngII)orK Lalli 2016 completely understood( pathway; however, thecompletemechanismsarenot the increaseofcAMPandactivationPKAsignaling to itsreceptor, themelanocortin2receptor, leadsto expression andaldosteronesecretion.BindingofACTH (K renin–angiotensin systemandextracellularpotassium Aldosterone biosynthesisismainlyregulatedbythe by thealdosteronesynthase(encoded (ZG) of theadrenal cortex. The finalsteps arecatalyzed of specificenzymaticreactionsinthezonaglomerulosa DOI: 10.1530/JME-17-0035 http://jme.endocrinology-journals.org Review + ) concentration. ACTH is also a regulator of Aldosterone issynthetizedfromcholesterolbyaseries ) ( mRNAexpressionandaldosteronebiosynthesis. i. 1 Fig. , MacKenzie 2+ ). Thus,aldosteroneproductionistightly ) channels,leadingtoanincreased 2+ concentration.Throughbindingto et al. Gallo-Payet 2016 + /K + results in depolarizationof + 2017 + -ATPase pumpactivity, leadingagaintocell membranedepolarization.ThefollowingriseinintracellularCa concentrationaswellinhibitionoftheNa and others f 2+

l signalingpathway, inducingactivation ofspecifictranscriptionfactors(NurrI,NGFIB)andthusincrease

bytheendoplasmicreticulum.AngII andK boulkroun ). More channel,increasedintracellularCa 2+ ). ).

gene codingfor and ATPases ( ( identification ofmutationsingenescodingforionchannels made inunderstandingthegeneticbasisofAPA, withthe up to10%ofhypertensive subjects. PA willimprovediagnosis,prognosisandtreatmentfor adrenal hyperplasia(BAH),themostcommonformsof of aldosterone-producingadenoma(APA) andbilateral the pathogenicmechanismsunderlyingdevelopment persist ( and treatmentofnon-surgicallycorrectableformsstill critical issuesrelatedtodiagnosis,subtypedifferentiation the publicationsofguidelinesformanagementPA, ( outcome andsurvival early detectionofPA hasenormousimpactonclinical cardiovascular adverseeffectsofaldosteroneexcess,the past few years using-omics approaches. These advances knowledge ofthegeneticbasesPA acquiredduringthe ( In addition,recurrentactivatingmutationsin signaling, themajortriggerforaldosteroneproduction. APA. Allthesemutationsleadtotheactivationofcalcium Scholl primary aldosteronism Genetic basisof KCNJ5 Tissier Published byBioscientifica Ltd. + /K In this review, we will summarize the current Over thepastfewyears,majoradvanceshavebeen ATP2B3 + et al -ATPase pumpactivityorofK et al ( Funder Choi ATP1A1 . 2013 . 2005 ( 2+ Beuschlein et al concentration.Inadditiontothiseffect, AngIIalso et al 2+ β ( concentrationandactivationofCa ) and -catenin havealsobeenidentifiedinAPA , Azizan . 2011 . 2008 Akerstrom + + /K induced,both,cellmembrane CACNA1H Rossi + -ATPase pumpactivity. (B)Extracellular Downloaded fromBioscientifica.com at09/24/202111:57:06PM , et al ), et al 2016 + CACNA1D concentrationbetweenthe et al . 2013 . 2013 + et al channelsleadtothe ). Abetterunderstandingof . 2008 ( . 2016 Daniil , )) inmorethan50%of Beuschlein ( 59 ). However, despite Azizan ). : et al 1 2+ . 2016 signal et al et al CTNN1B . 2013 . 2013 )) and 2+ R48 via freeaccess ) ,

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Review f l fernandes-rosa, s boulkroun Genetic basis of 59:1 R49 and others primary aldosteronism

have highlighted the major role of the ionic equilibrium (Choi et al. 2011). KCNJ5 codes for the G protein-activated and regulation of cell membrane potential in autonomous inward rectifier potassium channel 4 (GIRK4). The GIRK4 aldosterone overproduction. channel belongs to a large family of inwardly rectifying K+ channels. ‘Inward rectifiers’ are a class of K+ channels that conduct much larger inward currents at membrane Somatic mutations in APA voltages negative to the K+ equilibrium potential. The Zona glomerulosa cells from the adrenal cortex are GIRK channel family comprises four members (GIRK1 maintained in a hyperpolarized state, mainly due to to GIRK 4) that form heterotetramers or homotetramers. the high expression of potassium channels. The study They are composed of two membrane-spanning of mouse models in which the expression of specific domains (M1 and M2), one pore-forming region (H5) potassium channels was invalidated has highlighted their and cytoplasmic N- and C-termini that participate in crucial role in adrenal (Davies et al. 2008, Heitzmann et al. the pore structure. The first two mutations reported by 2008, Guagliardo et al. 2012, Penton et al. 2012). Hence, the Choi and coworkers, p.Gly151Arg and p.Leu168Arg, are deletion of TWIK-related acid-sensitive K+ channel (Task)-1 located near or within the selectivity filter of the channel (Task 1) and -3 (Task 3) leads to alteration in the membrane (Choi et al. 2011). Subsequently, many other studies have properties of ZG cells, inducing autonomous aldosterone reported additional somatic or germline mutations in or production with clinical features typical of glucocorticoid- surrounding the selectivity filter (from Thr149 to Gly153). remediable aldosteronism (Heitzmann et al. 2008) or All these mutations leads to a loss of K+ selectivity and an BAH (Davies et al. 2008). Task1−/− mice display severe increase of sodium (Na+) influx into the cells, producing hyperaldosteronism, hypokalemia and arterial low renin a chronic depolarization of cell membrane, opening hypertension. Interestingly, this hyperaldosteronism was of voltage-gated Ca2+ channels, activation of calcium remediable by glucocorticoids due to ectopic expression signaling, increase of aldosterone synthase expression and of AS in ZF before puberty in both male and female and autonomous aldosterone production by the cells (Fig. 2). then only in adult female (Heitzmann et al. 2008). In Overexpression of the GIRK4 p.Thr158Ala mutant in contrast, the phenotype of Task3−/− mice recapitulates low HAC cells resulted in increased aldosterone, cortisol and renin and salt-sensitive hypertension (Guagliardo et al. 18-oxocortisol levels, as observed in patients harboring 2012, Penton et al. 2012). Surprisingly, invalidation of this mutation, associated with increased expression both Task 1 and Task 3 in mice has no impact on cellular of CYP11B2 and CYP11B1 and decreased expression organization and zonation of the adrenal cortex, although of CYP17, but a decrease of cell proliferation (Oki et al. Journal of Molecular Endocrinology aldosterone production by ZG cells is inappropriate for 2012). Scholl and coworkers also reported a decrease of salt intake, recapitulating features of idiopathic primary cell viability in 293T cells overexpressing p.Gly151Glu aldosteronism (Davies et al. 2008). Invalidation of these or p.Gly151Arg (Scholl et al. 2012), due to increased different potassium channels leads to hyperaldosteronism Na+ influx into the cells via the mutated channels. due to abnormal depolarization of ZG cell membrane resulting in increased intracellular Ca2+ concentration and stimulation of aldosterone biosynthesis; however, formation of adrenal tumors has never been observed in these models, indicating that other mechanisms are required to promote increased cell proliferation in APA.

Mutations affecting cell membrane potential

The emergence of high throughput sequencing techniques has allowed major advances in the understanding of the genetic basis of many diseases. Thus in 2011, Choi and coworkers identified two different somatic mutations in the KCNJ5 gene in 8 of 22 APA, as well as an inherited Figure 2 mutation in the same gene in a Mendelian form of severe Aldosterone biosynthesis in APA in presence of KCNJ5 mutations. Mutations affecting the GIRK4 potassium channel, encoded by KCNJ5, aldosteronism and massive bilateral adrenal hyper lead to increase of intracellular Na+ concentration, thus resulting in cell plasia (see below in the Familial forms of PA section) membrane depolarization and opening of voltage gated Ca2+ channel.

http://jme.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-17-0035 Printed in Great Britain Downloaded from Bioscientifica.com at 09/24/2021 11:57:06PM via free access Journal of Molecular Endocrinology Glu961del ( Glu961 del( 2013 (p.Phe100_Leu104del ( 2013 Beuschlein α the identification ofmutationsin of mutatedGIRK4channelsinAPA ( to someextentthepro-apoptoticeffectofoverexpression the overexpressionof protein thatmayprotectcellsfromapoptosisinducedby 2012 KCNJ5 short-chain familymember3( CYP11B2, have beenreported,suchasincreasedexpressionof 2013 nor specifictranscriptionalprofiles( associated neitherwithspecificadrenalcortexremodeling Fernandes-Rosa other mutations ( mutations comparedtonon-mutatedAPA orthosewith inAPAwith peritumoralZGwasobserved with level, decreasedGIRK4expressioninAPA compared is notaffectedbymutationalstatus,at the protein ( although thisisnotthecaseforothermutations and formationof adrenal adenoma( may leadtoinappropriatehypersecretionofaldosterone channels, suggestingthatreducedGIRK4incellsurface HEK cellsandalteredthemembraneabundanceof decreased GIRK4wtcurrentswhencoexpressedin KCNJ5 involved incellproliferation. but italsostronglysuggeststhatothermechanismsare be amechanismlimitingadrenocorticalcellmassgrowth, p.Leu103_Leu104del ( ( N- andC-tails.Differentsomaticvariants(p.Gly99Arg transmembrane domains (M1–M10) with intracellular electrogenic gradient.The exit ofthreeNa the plasmamembrane;hydrolysisofoneATP allowsthe generates electrochemicalgradientsforNa α the P-typeATPase familyandiscomposedoftwosubunits, additionaleffectof This Murthy Williams 1 subunitoftheNa and DOI: 10.1530/JME-17-0035 http://jme.endocrinology-journals.org Review More recently, exomesequencingapproachesallowed In additiontoaffectingK b ). Slightmodificationsofgeneexpressionpatterns ), p.Met102_Ile106del( ), p.Val332Gly ( , β expression ( mutations(p.Arg115Trp andp.Glu246Gly) . UsingtheenergyderivedfromATP hydrolysis,it Zhou et al t al et Visinin-like 1 ( et al Akerstrom t al et . 2012 . 2013 t al et . 2014 + Akerstrom and the entry oftwoK andtheentry Boulkroun . 2016 Monticone ). Although + /K Beuschlein ). TheNa . 2015 Akerstrom ), p.Leu104Arg( KCNJ5 Azizan + t al et -ATPase inAPA ( KCNJ5 ). VSNL-1isacalcium-sensor VSNL1 . 2015 et al α a t al et mutants,counterbalancing -subunit isformedoften et al ). et al + /K ACSS3 Akerstrom mutationsmaypossibly KCNJ5 + . 2013 et al ) or acyl-coA synthetase and others f KCNJ5 cellpermeability, two

+ t al et . 2013 l ), p.Glu960_Leu964del -ATPase isamemberof

ATP1A1 . 2015 © 2017SocietyforEndocrinology . 2012 fernandes Williams Boulkroun . 2013 Cheng ) inAPA harboring . 2015 , mRNAexpression mutationswere Cheng Azizan Beuschlein , + Beuschlein , Printed inGreatBritain , generatingan t al et + , encodingthe Williams ), p.Phe959_ )) ordeletions - andK rosa et al et al ), p.Phe956_ et al et al et al , , s . 2015 . 2012

. 2015 boulkroun + . 2015 . 2012 across . 2013 KCNJ5 et al t al et et al a ), ), ), ). , . . , . ,

membrane depolarizationanddecreaseofintracellularpH. to increaseofintracellularNa Mutations affecting theNa Aldosterone biosynthesisinAPA inpresenceof Figure 3 Residues mutated in M1 and M4 domains are essential 2013 ( potential, leadingtoincreased intracellularCa mutations in calcium concentrationinZG cells(seeabove).Although to increased plasma K The majortriggerofaldosteronebiosynthesisinresponse calcium equilibrium Mutations affecting directly intracellular with life. of functionthisproteinwouldnotbecompatible ATP1A1 Azizan Thr814) and M9 (Glu 960 and Glu961) ( specific residueslocatedinM5(Tyr778), M6(Gly813and for theNa mutated inM9,theseaminoacidsmaybeofimportance be established( aldosterone production,specificmechanismremainsto this acidificationmaycontributetotheautonomous acidification of thecellsduetoH there isnoincreaseinrestingCa ( binding affinity and thus a loss of pump function mutations leading to a major decrease in Na for K of thepH,incase concentration incaseof membrane depolarizationandimpairedK of p.Leu104Arg or the p.Val332Gly mutants leads to cell Remarkably, inH295R_S2cells,althoughtheexpression primary aldosteronism Genetic basisof Akerstrom i. 3 Fig. Published byBioscientifica Ltd. )) wereidentifiedinM1,M4andM9domains. + binding and gating of the binding pocket, their ) ( t al et haveneverbeenreported,suggestingthatloss Beuschlein + -specific siteIII,theNa et al . 2013 KCNJ5 . 2015 Stindl ). Untilnow, germlinemutationsin and + t al et + /K ), p.Glu960_Ala963del ( and angiotensin II is an increase of t al et + + andH -ATPase pump,encodedby Downloaded fromBioscientifica.com at09/24/202111:57:06PM KCNJ5 . 2013 ATP1A1 ATP1A1 . 2015 + concentration,thusresultingincell mutationsordisturbance 2+ , activitybutintracellular + mutations,mutations -binding siteinvolving affectcellmembrane Williams ). Whereresiduesare ATP1A1 59 + leak.Although : 1 mutations. Li + t al et t al et ATP1A1 sensitivity, Azizan + and K . 2014 . 2005 , lead R50 et al via freeaccess 2+ ). ). + , .

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Review f l fernandes-rosa, s boulkroun Genetic basis of 59:1 R51 and others primary aldosteronism

are associated to increased aldosterone production and CYP11B2 expression in adrenocortical cells (Tauber et al. 2016). CACNA1D encodes the L-type Ca2+ channel α-subunit

Cav1.3 (Azizan et al. 2013, Scholl et al. 2013). The channel contains four repeat domains (I–IV), each composed of six transmembrane segments (S1–S6), plus a membrane- associated loop between S5 and S6 (Catterall 2010). The S4 segment is involved in voltage sensing for activation, whereas S5, S6 and the loop between these two segments form the pore lining of the channel (Dutta et al. 2016). Figure 4 Cav1.3 is one of the most abundant calcium channels Aldosterone biosynthesis in APA in presence of mutations affecting intracellular calcium balance. Mutations in ATP2B3 coding for PMCA3, in normal human adrenal and in APA, predominantly CACNA1D, encoding the α subunit of the L-type Ca2+ channel Cav1.3, expressed in ZG (Scholl et al. 2013, Daniil et al. 2016). and CACNA1H, encoding the α subunit of the T-type Ca2+ channel Cav3.2 Although Cav3.2, encoded by CACNA1H, has been affect directly intracellular Ca2+ concentrations. shown necessary for membrane potential oscillations identified in ATP2B3, CACNA1D and CACNA1H (see in ZG cells, the role of Cav1.3 in adrenal is less clear below, in the Familial forms of PA and germline mutations (Hu et al. 2012). In 2013, exome sequencing approaches section) are directly involved in the control of intracellular identified somatic and germline mutations (see below) calcium equilibrium (Fig. 4). in CACNA1D (Azizan et al. 2013, Scholl et al. 2013). ATP2B3 codes for the plasma membrane calcium Nine different mutations were identified, all except two ATPase isoform 3 (PMCA3), a P-type ATPase family, like located specifically in S5, S6 or in the intracellular loop the Na+/K+-ATPase. PMCA3 is essential to extrude Ca2+ between the S5 and S6 segments. Electrophysiological from the cytoplasm and thereby has an essential role in studies showed different changes in channel properties regulating intracellular calcium homeostasis (Di Leva et al. depending on the mutations although all led to increased 2008). ATP2B3 is located on chromosome X, and germline Ca2+ influx and activation of calcium signaling stimulating mutations have been shown to be responsible for the aldosterone production (Azizan et al. 2013, Scholl et al. development of X-linked congenital cerebellar ataxia 2013). By sequencing the entire gene, we identified nine (Zanni et al. 2012). Similar to the α subunit of the Na+/ additional mutations located in segments S4, S5 and S6, Journal of Molecular Endocrinology K+-ATPase, PMCA3 is composed of 10 transmembrane cytoplasmic segments or repeated region III (Fernandes- domains, a large cytoplasmic loop and cytoplasmic N- Rosa et al. 2014). Although the prevalence of the different and C-tails. All the mutations identified in ATP2B3 are mutations was not the same, the identification of all located in the M4 domain, deletions of at least two amino these new mutations suggests the necessity of sequencing acids in a specific region between amino acids 425 and the entire CACNA1D gene when searching for causative 433 (Beuschlein et al. 2013, Dutta et al. 2014, Fernandes- mutations for APA (Fernandes-Rosa et al. 2014). Rosa et al. 2014, Akerstrom et al. 2015, Scholl et al. 2015a, Zheng et al. 2015), a region crucial for the binding of Ca2+ Mutations affecting β-catenin activation ions but also close to the catalytic core of the pump (Di Leva et al. 2008). Electrophysiological studies have shown Activation of Wnt/β-catenin pathway is one of the major that the ATP2B3 p.Leu425_Val426del mutation leads to features in APA, being found in at least two-thirds of increased intracellular Ca2+ concentration in transfected APA (Boulkroun et al. 2011, Berthon et al. 2012, Berthon human embryonic kidney (HEK-293) cells due to an & Stratakis 2014). The Wnt/β-catenin pathway plays increased Ca2+ influx and reduced capacity to export Ca2+, an important role in embryonic development, stem suggesting a loss of the physiological pump function cell maintenance and differentiation in many tissues, (Tauber et al. 2016). In addition to the alteration of Ca2+ especially normal adrenal development and tumorigenesis equilibrium, ATP2B3 mutations, like KCNJ5 but to a less (El Wakil & Lalli 2011). In the absence of ligand, β-catenin extent, lead to Na+ and possibly Ca2+ influx into the cells, is a part of the axin complex consisting of adenomatous contributing to increased intracellular Ca2+ concentration polyposis coli (APC), axin, glycogen synthase kinase-3β also through depolarization of the cell membrane and and casein kinase-1β. The phosphorylation of β-catenin in opening of voltage-gated Ca2+ channel. These alterations this complex results in its ubiquitination and degradation

http://jme.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-17-0035 Printed in Great Britain Downloaded from Bioscientifica.com at 09/24/2021 11:57:06PM via free access Journal of Molecular Endocrinology male patientsornon-pregnant females( have reportedsomatic CTNNB1 development, thepathophysiology ofAPA harboring the mechanismslinking provide asubstantialadditiontoourunderstanding of underlying PA ( receptor (GNRHR),suggestingthatpregnancymayreveal receptor (LHCGR)andgonadotropin-releasinghormone levels ofluteinizinghormone–chorionicgonadotropin menopause ( two diagnosedduringpregnancyandthethirdafter mutations (p.Ser33Cys,pSer45Pheandp.Gly34Arg), women withPA duetoanAPA withsomatic resulting inanearlyterminationoftheprotein. to previouslydescribedmutation( mutation hasalsobeenreported(A39Efs*3)locatedclose of the Wnt/ 2016 (p.Ser45Phe, p.Ser45Proandp.Thr41Ala)( in specific residues involved inthe stability ofthe protein studies havereportedknownmutationsin ( CTNN1B catenin wascommoninAPA, onlyraremutationsin ( inmiceexpressingadefectiveAPCallele that observed these micedevelophyperaldosteronism,similarto inhibition oforthotopicZFdifferentiation.With time, defects byectopicactivationofZGdifferentiationand in the adrenal cortex results in adrenocortical zonation Ward of aldosteroneproduction( the number of zona glomerulosa cells leading to adecrease of thedefinitivezoneadrenalcortexanddecrease production. Wnt4 this pathwayinadrenaldevelopmentandaldosterone (LEF) family. of theT-cell factor(TCF)/lymphocyteenhancer a transcriptionalcoactivatoroftranscriptionfactors as and translocationintothenucleus, where itserves from theaxincomplex,accumulationincytoplasm anditssubsequentdissociation of itsphosphorylation its specificreceptorfrizzledresultingintheinhibition catenin activationoccursviabindingofligandWntto nucleus and activatingspecific Wnttarget genes. Wnt/ in theproteasome,preventingitfromtranslocatingto Tissier Bhandaru DOI: 10.1530/JME-17-0035 http://jme.endocrinology-journals.org Review Teo andcoworkersreportedthecase ofthree Until recently, althoughtheactivationofWnt/ Different mouse models have highlighted the role of , et al Wu et al mutationsseemsmorecomplex. Previousstudies gene,codingfor et al . 2003 et al . 2005 Teo β . 2017 -catenin pathway. A novel frame-shift . 2009 ). The constitutive activation of t al et Teo −/− , micedisplayabnormaldifferentiation Tadjine , ), leadingtoconstitutiveactivation t al et . 2015 Berthon CTNNB1 . 2015 β CTNNB1 et al -catenin havebeendescribed ). Their APA expressed high Heikkila et al mutationsinAPA from . 2008 and others f ). Althoughthesedata

© 2017SocietyforEndocrinology . 2010 fernandes mutationandAPA Scholl t al et ). Different recent Scholl ). Akerstrom Printed inGreatBritain - . 2002 CTNNB1 t al et rosa et al , , β . 2015 s CTNN1B -catenin

. 2015 boulkroun , Jeays- gene et al a β β a ), - - , .

2012 2014 from a cohort from Paris have shown that patients with Genotype–phenotype analysis performedin199patients determine themutationalstatus ofAPA before surgery. phenotype correlations or to find biomarkers to different selectioncriteria. by ethnicbackground,environmentaldifferences or 2015 35% inEurope KCNJ5 with APA, reportedthattheoverallprevalenceofsomatic of somatic 2015 to 76%( appear tohaveahigherprevalence,rangingfrom59% Rosa rate washighestintheMunichcohort( was highestinthePariscohort, whereas European study:theprevalenceof the differentcentersparticipatinginmulticenter inthedistributionofmutationsacross were observed 2015 mutations in APA ranged from 2.1% to 5.1 % ( A firstmulticenterEuropeanstudyperformedon380APA Rosa correlates of somatic mutations in APA ( many studieshavereportedtheprevalenceandclinical Since theidentificationof in APA Prevalence andclinicalcorrelates ofsomaticmutations by toestablishthecomplexmechanismsaffected necessary thirds ofAPA ( evidence for ( than 40% of APA ( GNRHR andLHCGRoverexpressionisfoundinmore Akerstrom ( prevalence was reported in the American population ATP2B3 38% ofAPA, in 54.3% of tumors: study performed on 474 APA identified somatic mutations ( showed aprevalenceof34%somatic primary aldosteronism Genetic basisof Akerstrom Scholl Boulkroun Published byBioscientifica Ltd. CTNNB1 Various studieshavetriedtoestablishgenotype– , , ), ). Thiscontrastintheprevalencecouldbeexplained a et al et al Zheng Boulkroun , mutations was 43%, ranging from 63% in Asia to Akerstrom et al in1.7%( CTNNB1 Taguchi . 2014 . 2014 et al mutationsinAPA. . 2015 KCNJ5 et al t al et et al β CACNA1D -catenin activation observed inabouttwo- -catenin activationobserved . 2016 + , ). In Asian populations, Berthon . 2012 the UnitedStates mutationsareidentifiedonlyin5% et al . 2015 Kitamoto et al . 2016 a et al mutations,comprising1636patients Fernandes-Rosa ). Theprevalenceofsomatic Nakamura , . 2012 . 2012 Wu ). Morerecently, asecondEuropean . 2016 , KCNJ5 t al et Hong Downloaded fromBioscientifica.com at09/24/202111:57:06PM in9.3%, ), withimmunohistochemical et al et al , , Azizan , KCNJ5 . 2014 mutations were found in et al Wang . 2017 Wu t al et . 2014 + . 2016 et al Australia ( t al et . 2014 et al et al ATP1A1 mutationsin2011, ). Furtherstudiesare CACNA1D ). Moreover, although , 59 . 2017 Tauber KCNJ5 . 2013 . 2014 ATP2B3 ). Ameta-analysis KCNJ5 : . 2015 1 Akerstrom , in5.3%and Nicolini ). Differences Lenzini et al , ); asimilar Scholl mutations mutations mutations Fernandes- Fernandes- , mutation Wu CTNNB1 . 2014 t al et et al et al R52 et al et al via freeaccess )......

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Review f l fernandes-rosa, s boulkroun Genetic basis of 59:1 R53 and others primary aldosteronism

KCNJ5 mutations are more frequently female, diagnosed pointing to the complexity of genetic determinants younger and with higher minimal plasma potassium of APA. concentrations, and the presence of CACNA1D mutations associated with smaller adenomas (Fernandes-Rosa et al. 2014). No association was found between the mutation Familial forms of PA and germline mutations status and preoperative plasma aldosterone, renin levels, Familial forms are rare causes of PA that account for 1–5% aldosterone-to-renin ratio or number of medications of cases. Different forms displaying Mendelian inheritance taken before surgery. Replication analyses, performed have been described: familial hyperaldosteronism type I on APA from two other European cohorts, confirmed (FH-I) or glucocorticoid-remediable aldosteronism (GRA), the association of KCNJ5 mutations with female sex and familial hyperaldosteronism type II (FH-II), familial younger age of diagnosis (Fernandes-Rosa et al. 2014). hyperaldosteronism type III (FH-III) with KCNJ5 mutations The association of KCNJ5 mutations with female sex and familial hyperaldosteronism type IV (FH-IV) due to and younger age was also observed in a meta-analysis CACNA1H mutations. Germline KCNJ5, CACNA1D and study comprising 1636 APA patients from 13 studies CACNA1H mutations are also associated with sporadic PA (Lenzini et al. 2015), as were higher plasma levels of and/or early-onset hypertension due to PA (Scholl et al. aldosterone and larger tumors (Lenzini et al. 2015). 2013, Murthy et al. 2014, Daniil et al. 2016). Furthermore, Cardiovascular complications of aldosterone excess in germline ARMC5 variants have been identified in African APA in relation to the mutational status were evaluated American patients with PA (Zilbermint et al. 2015). in two studies (Kitamoto et al. 2014, Rossi et al. 2014). Left ventricular mass index (LVMI) was found to be higher Familial hyperaldosteronism type I in patients carrying KCNJ5 mutations (Rossi et al. 2014), and in both studies, LVMI was independently associated FH-I is characterized by clinical and biochemical with KCNJ5 mutations (Kitamoto et al. 2014, Rossi et al. findings of PA relieved by dexamethasone. The clinical 2014). Finally, steroid profiles performed on adrenal and characteristics comprise early and severe hypertension, peripheral venous plasma samples of 79 APA patients by biochemical abnormalities of PA, increased production liquid chromatography–tandem mass spectrometry (LC– of 18-hydroxycortisol and 18-oxocortisol, bilateral MS/MS) established that specific somatic mutations in adrenal hyperplasia or adrenal nodules (Sutherland et al. APAs can be defined by distinct steroid profiles in adrenal 1966, New 1980). FH-I has an autosomal dominant vein plasma. This approach may translate to identifying mode of inheritance, accounting for 0.5–1.0% of PA in Journal of Molecular Endocrinology specific steroid signatures in peripheral venous plasma, adult patients (Jackson et al. 2002, Pizzolo et al. 2005, and be potentially useful in determining the underlying Mulatero et al. 2011a) and for 3% in hypertensive APA genotype (Williams et al. 2016). children (Aglony et al. 2011). The genetic etiology is An unanswered question concerns the influence of a crossover of the homologous genes coding for AS somatic mutations on the management of PA. Higher (CYP11B2) and 11β-hydroxylase (CYP11B1), creating a lateralization indices on adrenal venous sampling (AVS) chimeric gene with the CYP11B1 promoter and CYP11B2 were found in patients carrying somatic KCNJ5 mutations coding sequences juxtaposed. This crossing over leads (Seccia et al. 2012). More recently, Osswald and coworkers to an ectopic expression of AS throughout the ZF, with observed no difference in steroid gradients during AVS as aldosterone being produced not only in isolated cells from a function of the mutation status (Osswald et al. 2013). ZG (Lifton et al. 1992, Stowasser & Gordon 2000). The Another difficulty in establishing genotype–phenotype description of different crossover patterns of the hybrid correlations or surrogate biomarkers of the mutational gene suggests that mutations arise independently (Dluhy status is APA heterogeneity. Different somatic mutations & Lifton 1995). The genetic diagnosis is usually made by have been identified in distinct nodules within the Southern blot or long PCR, both techniques with high same adrenal, including mutations in different genes sensitivity and specificity Funder ( et al. 2016). (Dekkers et al. 2014, Fernandes-Rosa et al. 2015b). The Endocrine Society Clinical Practice Guideline Moreover, APA mutations are reported to occur only suggests that in patients with an onset of confirmed in aldosterone synthase (AS)-positive regions with two PA earlier than 20 years of age and in those who different mutations identified in distinct AS-positive have a family history of PA or stroke at a young age regions within the same nodule (Nanba et al. 2016a), (<40 years), genetic testing for FH-I should be performed

http://jme.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-17-0035 Printed in Great Britain Downloaded from Bioscientifica.com at 09/24/2021 11:57:06PM via free access Journal of Molecular Endocrinology families ( chromosomal region7p22withFH-IIinsomeaffected evidence foranassociationofageneticlocusonthe On theotherhand,somestudieshaveestablished 1996 have been identified in FH-II patients ( CYP11B2 understood. No mutations in candidate genes including Mulatero family ( and differentsubtypesmaybepresentwithinthesame 2012 Medeau in adultpatientswithPA ( 2001 mode ofinheritance( transmission consistentwithanautosomaldominant and coworkersin1991( familial hyperaldosteronismfirstdescribedbyGordon FH-II isanon-glucocorticoid-remediableformof Familial hyperaldosteronism typeII over severalyears( of adrenocorticotropin is required to correct hypertension glucocorticoids are sufficient, as only partial suppression leading tothereductionofaldosteronelevels.Low-dose glucocorticoid hormones,whichsuppressACTHsecretion ( and thuschangethecurrent definitionofFH-II. ofgenesassociatedwithfamilialPAallow thediscovery exome andwhole-genome sequencingstudies,should mutations. Advancesingenetic techniques,withwhole- affected family members, without the diagnosisofFH-IIismadeonbasistwoormore years ofthe genetic basisof FH-III andFH-IV(see below), from sporadicformsofPA. With inthelast thediscovery Jeske were identified( I ( glucocorticoid-induced transcript1( protein A3( nucleotide-binding protein postmeiotic segregationincreased2( associated Kruppel-associatedboxgene( sequenced inFH-IIpatients,includingretinoblastoma- 2008 Funder FSCN1 DOI: 10.1530/JME-17-0035 http://jme.endocrinology-journals.org Review β -regulatory subunit( -regulatory FH-II isclinicallyandbiochemicallyindistinguishable The geneticbasesofFH-IIarenotcompletely a ). Candidategeneslocatedinthisregionwere et al ). FH-II patients display a familial history ofPA). FH-IIpatientsdisplayafamilialhistory ), andhisprevalencerangingfrom1.2%to6% , b ) andthecAMP-dependentproteinkinasetype , et al et al Stowasser &Gordon2001 , Davies Lafferty . 2008 et al AGTR1 . 2016 . 2005 RPA3 . 2011 ). et al et al Medeau andthep53tumor-suppressorgene Stowasser ). FH-Ipatientsshouldbetreatedwith ), zincfingerprotein12( , b Mulatero . 1997 ). . 2000 PRKAR1B Stowasser &Gordon2000 t al et , Gordon et al Stowasser &Gordon2001 , Stowasser &Gordon2001 α et al So -12 ( . 2005 et al and others f . 2000

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of steroidogenic enzyme expression and aldosterone by increasedintracellularCa Ca of theplasmamembraneandopeningvoltage-gated Na leading toalossinK region responsibleforGIRK4K ( FH-III isamutationinthe pressure ( with bilateraladrenalectomyrequiredtocontrolblood ( the hybridsteroids18-oxocortisoland18-hydroxycortisol highlevelsof with markedhyperaldosteronismandvery severe arterialhypertensionandhypokalemiaassociated described inafatherandtwodaughterswithearly-onset FH-III isanon-glucocorticoid-remediableformofFHfirst mutations Familial hyperaldosteronism typeIIIandgermlineKCNJ5 morphology, evenwithinthesamefamily( KCNJ5 In thesameway, thesamegermline patientscarrying 2012 Charmandari with drug-resistanthypertension( hyperaldosteronism tomassiveadrenalhyperplasia variability, rangingfromspironolactone-responsive mutations inFH-IIIfamilieswithaphenotypic production ( with of in FH-IIIcannotbedefined onlyonthebasisoftype 2014 a severephenotype(p.Gly151Arg)( germline with sporadicspironolactone-responsivePA witha 2012 the channelpreventingadrenalhyperplasia( lethality duetomuchhighersodiumconductance of p.Gly151Glu mutationmaybeexplainedbyrapidcell the the milderphenotypeinpatientscarrying p.Gly151Glu mutations. and amilderphenotypeassociatedwith p.Thr158Ala, p.Ile157Serandp.Tyr152Cys mutations, severe phenotypeassociatedwithGIRK4p.Gly151Arg, was attributedtothetypeof Adachi primary aldosteronism Genetic basisof Choi Geller Published byBioscientifica Ltd. KCNJ5 2+ + intothecytoplasm,resultingindepolarization Different studieshaveidentifiedgermline The complexity of the FH-III phenotype associated channels.Thecalciumsignalingpathwayisactivated ). Thesedifferencessuggest that theclinicalseverity ). Arecentstudy, however, describedapatient , KCNJ5 mutationmaydisplaydifferencesinadrenal Scholl t al et t al et t al et mutation. Geller KCNJ5 mutationshasbeenhighlighted bytworecent . 2011 . 2008 Oki . 2014 et al t al et t al et et al mutationpreviouslyassociatedwith . 2012 ). Thismutationislocatednearthe . 2012 ). ThepatientsshowedmassiveBAH , . 2012 . 2008 Tong + selectivityandincreasedinfluxof , Downloaded fromBioscientifica.com at09/24/202111:57:06PM , Mulatero t al et Monticone In vitro ). ). Thegeneticbackground of 2+ KCNJ5 , resultinginanincrease + KCNJ5 . 2016 selectivity(GYGmotif), et al studiesshowedthat gene(p.Thr158Ala) Adachi Choi t al et 59 mutation,witha . 2012 ). Thisvariability : 1 . 2013 t al et Adachi , t al et Scholl Mussa . 2014 . 2011 , 2015 KCNJ5 KCNJ5 KCNJ5 R54 et al et al et al via freeaccess ). ). . , . . ,

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Review f l fernandes-rosa, s boulkroun Genetic basis of 59:1 R55 and others primary aldosteronism

studies. Combined aldosterone and cortisol oversecretion pathogenesis of sporadic PA in Chinese patients. The associated with massive bilateral adrenal hyperplasia was same SNP was studied in 229 Chinese patients with described in a patient carrying a germline KCNJ5 mutation newly diagnosed essential hypertension (Wang et al. (p.Glu145Gln) (Tong et al. 2016). In primary cell culture 2017). KCNJ5 rs2604204 was related to increased plasma of the resected hyperplastic adrenal, calcium channel aldosterone, plasma renin, AngI and AngII levels in blockers inhibited the secretion of both aldosterone patients with essential hypertension (Wang et al. 2017). and cortisol and the mRNA expression of steroidogenic The mechanism underlying the association between a enzymes. The authors suggest that the hypersecretion KCNJ5 3′-UTR polymorphism and activation of the renin– of cortisol might be ascribed to overly large size of the angiotensin–aldosterone system remains unknown. hyperplastic adrenal (with low CYP11B1 expression) and, like aldosterone secretion, may be mediated by voltage- Germline CACNA1D mutations in sporadic PA gated Ca2+ channels (Tong et al. 2016). A second study reported that adrenals from patients carrying a germline De novo germline CACNA1D mutations have been described KCNJ5 mutation (p. p.Thr158Ala) were markedly enlarged in two children with PASNA (primary aldosteronism, with loss of zonation and cells expressing aldosterone seizures and neurological abnormalities), a syndrome of synthase and/or 11β-hydroxylase, with and without PA and neuromuscular abnormalities (Scholl et al. 2013). 17α-hydroxylase, and some expressing all three enzymes The first subject, without family history of early-onset (Gomez-Sanchez et al. 2017). GIRK4 was abundantly hypertension or seizures, showed hypertension with expressed in almost all cells, suggesting that the mutation biventricular hypertrophy as a newborn, with the diagnostic not only altered the potassium filter selectivity of the of aldosteronism (high plasma aldosterone, suppressed channel, but also a signal that designated specificity for renin and hypokalemia) at age 1 month. Neurological CYP11B2-expressing cells or the presence of a second abnormalities (cerebral palsy, cortical blindness and mutation that abolishes selectivity of steroidogenesis on complex neuromuscular abnormalities) were observed, the basis of adrenal zonation (Gomez-Sanchez et al. 2017). with seizures starting at age 7 months. Treatment with Germline KCNJ5 mutations have also been suggested a calcium channel blocker normalized blood pressure, to play a role in the common sporadic form of PA, although with cure of hypertension and PA on follow-up (Korah & the functional consequences of these germline mutations Scholl 2015). A germline mutation was identified in exon are not completely established. Sequencing germline DNA 8B of CACNA1D (p.Gly403Asp), in a residue also mutated from 251 subjects with sporadic PA, Murthy and coworkers in APA (p.Gly403Arg) (Azizan et al. 2013, Scholl et al.

Journal of Molecular Endocrinology identified three KCNJ5 missense mutations (p.Arg52His, 2013). The second patient, also without family history p.Glu246Lys and p.Gly247Arg), located outside the of early-onset hypertension or seizures, was diagnosed at selectivity filter of GIRK4, and a rare SNP (rs7102584, birth with cerebral palsy and complex seizures, arterial p.Glu282Gln) in 5% of patients (Murthy et al. 2014). The hypertension at the age of 5 years and hypokalemia at mutations p.Arg52His and p.Glu246Lys altered channel the age of 8 years due to hyperaldosteronism. No adrenal properties and the cells expressing GIRK4 channels abnormality was observed on CT scan. The patient carried carrying the SNP rs7102584 showed reduced viability, a germline CACNA1D mutation (p.Ile770Met) also found whereas channels carrying the p.Gly247Arg mutation in somatic DNA from APA patients. were functionally indistinguishable from the wild-type GIRK4 (Murthy et al. 2014). Familial hyperaldosteronism type IV (FH-IV) and germline The role of common KCNJ5 SNPs was also assessed CACNA1H mutations in cohorts of Asian patients with PA and essential hypertension (Li et al. 2013, Wang et al. 2017). Comparing To identify new genetic abnormalities associated to the 235 subjects with sporadic PA to 913 subjects with development of early-onset hypertension due to PA, essential hypertension, Li and coworkers showed that Scholl and coworkers performed whole-exome sequencing in Chinese population, the minor allele of the KCNJ5 analysis of 40 unrelated patients. A recurrent germline SNP rs2604204, located in the KCNJ5 3′-UTR, was more mutation in CACNA1H (encoding the pore-forming α1 frequent in males with PA (43.4%) than that in males subunit of the T-type voltage-dependent calcium channel with essential hypertension (33.3%, P = 0.001) (Li et al. Cav3.2) (p.Met1549Val) was identified in 5 children with 2013), suggesting that KCNJ5 may be involved in the PA before age 10 years (Scholl et al. 2015b). Familial analysis

http://jme.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-17-0035 Printed in Great Britain Downloaded from Bioscientifica.com at 09/24/2021 11:57:06PM via free access Journal of Molecular Endocrinology functional studiesinadrenocortical H295R-S2cells gain-of-function phenotype. Additionally, results from the Ca analysis ofthesefourmutant channelsdemonstratedthat implicated infastchannelactivation.Electrophysiological cytoplasmic domainofCav3.2,inaregionpossibly (p.Val1951Glu) wasfound,locatedintheC-terminal patient withAPA, agermline C-terminal cytoplasmicdomainofCav3.2.Finally, inone ofPAhistory andhisbrother. Thisvariantis located inthe (p.Pro2083Leu) wasidentifiedina PA subjectwithfamilial PA diagnosedat35 years ofage).Athird 36 (HT) and 51 years of age (PA), and in her sister (HT and ofHTandPA,family history diagnosedwithHTandPA at variation p.Ser196Leuwasidentifiedinapatientwith in FH-IV( acid asthe ( associated withmultiplexdevelopmentdisorders with early-onsethypertensionandhyperaldosteronism, mutation (p.Met1549Ile)wasidentifiedinapatient phenotypic presentations.A CACNA1H ( patients withCACNA1Hgain-of-functionmutations inhibitors maybeanusefultreatmentoptionfor untreated cells,suggestingthatT-type calciumchannel by transfectionofWTCav3.2and1549Val in aldosterone production and calcium channelblockerMibefradilreducedtheincreased cells transfectedwithWTCav3.2.Inaddition,theT-type in cellstransfected with Cav3.2 1549Val compared with production andincreased Functional studiesdemonstratedincreasedaldosterone reported intwomutationcarriers( However, developmentaldelayorattentiondeficitwere the carrying abnormalities or seizures were described in the patients CACNA1D inpatientscarrying neurological abnormalitiesobserved 2006 CACNA1H described associationbetweenepilepsyandautismwith or environmentalmodifiers.Despitethepreviously attributed toage-dependentvariabilityorgenetic withinfamilymembers, penetrance) wereobserved mutation. Differencesinclinicalpresentation(incomplete showed autosomaldominanttransmissionofthe Daniil Reimer DOI: 10.1530/JME-17-0035 http://jme.endocrinology-journals.org Review Using asimilarapproach,weidentifiedfourgermline , Heron 2+ et al et al currentpropertieswereaffected, suggestinga mutationsinPA patientswithdifferent mutations( mutations( Scholl . 2016 . 2016 t al et CACNA1H ). Thismutationmodifiesthesameamino CACNA1H t al et ). . 2007 . 2015 Scholl Chen p.Met1549Val variantreported ), andthepresenceofsevere p.Met1549Val mutation. CYP11B2 b t al et CYP11B2 de novo et al CACNA1H ). Thegermline and others f . 2013

l . 2003

© 2017SocietyforEndocrinology fernandes germline Scholl mRNAexpression expression caused CACNA1H ), noneurological missensevariant , Printed inGreatBritain Splawski - rosa t al et CACNA1H CACNA1H , , . 2015 s

boulkroun variant t al et b ). .

ARMC5 inactivation appears to affect steroidogenesis. to be a tumor-suppressor gene ( which thebest-knownmemberis family ofarmadillo(ARM)-repeat-containingproteins, (PBMAH) ( bilateralmacronodularadrenalhyperplasia in primary containing 5( Germline andsomaticmutationsinthearmadillorepeat ARMC5 variants CACNA1H broadens thephenotypicspectrumofPA associatedwith disorder orwithfamilialformsdiagnosedasFH-IIAPA, with early-onsetPA andmultiplexdevelopmental Identification ofnew genes coding for steroidogenic enzymes ( increased aldosteroneproductionand/orexpressionof directly linked electrophysiological abnormalities to cellular compositionandmolecular markersofadrenal 1985 the silencingof additional somaticmutationsin presence ofthegermline mutations butfailedtoidentify American. Tumor DNAsequencingconfirmedthe Interestingly, allcarriersofthesevariantswereAfrican that sixofthesevariantswerepredictedtobedamaging. (39%) ( identified in20unrelatedandtworelatedindividuals from 56PA patients,12different Upon sequencingthe of differentzonestheadrenal cortex( As APA maybecomposedofcellsexhibitingcharacteristics heterogeneity ofAPA Molecular andhistopathological mutations andPA isstilltobedetermined. function ( sequence variationsthatwerepredictedtoalterprotein In silico frequence reported 18ARMC5variants,including5rare(allele ( as seenwithhypercortisolism inpatientswithPBMAH capacityofindividualzonaglomerulosacells, secretory aldosterone secretion,despiteareductionofaldosterone- that theincreasedadrenocorticalmassleadstohigher expression ( primary aldosteronism Genetic basisof Zilbermint Published byBioscientifica Ltd. , Azizan analysisof these variants, however, did not detect Zilbermint Mulatero > mutations. Assie 1%) and2newvariants( Zilbermint et al t al et ARMC5 et al . 2015 ARMC5 . 2012 et al et al . 2013 ). Recently, Mulateroandcoworkers inH295Rcellsdecreased et al . 2015 ) genecauseshypercortisolism . 2016 CACNA1H ARMC5 Downloaded fromBioscientifica.com at09/24/202111:57:06PM ), theassociationbetween APA ). ARMC5 belongs to the large . 2015 ); ). Thelinkbetween Berthon & Stratakis 2014 geneingermlineDNA in silico ). Theauthorssuggested mutationsassociated β ARMC5 ARMC5 -catenin andislikely Mulatero 59 analysisrevealed Daniil : Neville &O’Hare 1 . Furthermore, variantswere et al et al CYP11B2 . 2016 ARMC5 . 2016 R56 via freeaccess ). ). ).

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Review f l fernandes-rosa, s boulkroun Genetic basis of 59:1 R57 and others primary aldosteronism

cortex with the mutation status was proposed, although of hypertension (Wolkersdorfer & Bornstein 1998), we conflictual results were observed among different studies. found an increase in nodulation of the cortex adjacent Some have described that APA harboring KCNJ5 mutations to APA compared with control adrenals (Boulkroun et al. are mainly composed by cells resembling cortisol- 2010). This raises the possibility that remodeling of the secreting cells of the adrenal zona fasciculate (ZF-like) adrenal cortex precedes the development of an APA, and and APA harboring CACNA1D and ATP1A1 mutations are thus, that somatic mutations could be a secondary event mainly composed by cells resembling the aldosterone- in the APA development. secreting cells of the adrenal zona glomerulosa (ZG-like) Different studies have provided strong arguments in (Azizan et al. 2012, 2013). Accordingly to these results, favor of the hypothesis of independent events leading to CYP17A1 expression was found to be higher in APA nodulation and aldosterone overproduction. Recently, harboring KCNJ5 mutations, suggesting that these we and others have reported different somatic mutations adenomas arise from the ZF (Azizan et al. 2012, 2013). in different CYP11B2-positive nodules within the same However, these results were not replicated in a large multinodular adrenal (Dekkers et al. 2014, Fernandes- cohort of APA with known somatic mutational status. Rosa et al. 2015b). Furthermore, a number of APA exhibited Analyzing histological characteristics of 78 APA, we found heterogeneity of expression of CYP11B2; among these that 72% of APA were composed of a majority of ZF-like APAs, recurrent somatic mutations were identified in 3 cells and no difference neither in the cellular composition nodules of the same adrenal, localized only in positive of APA nor in CYP11B2 expression according to the CYP11B2 regions. Interestingly, in one APA, two different mutation status was observed (Fernandes-Rosa et al. 2014). mutations were identified in two distinct CYP11B2- Furthermore, we have shown that APA, independently positive regions within the same APA (Nanba et al. 2016a). of the cellular composition phenotype, were composed Moreover, the co-existence of two different adrenocortical of cells expressing markers of ZG (CYP11B2, Dab2 and adenomas within the same adrenal causing the concurrent CD56), and that both APA and adjacent ZG exhibit diagnosis of PA and Cushing syndrome was recently histological characteristics of stem/progenitor cells, reported (Nanba et al. 2016b). Taken together, all these which may underlie excessive proliferation and APA results suggest that somatic mutations responsible for formation (Boulkroun et al. 2011). We have also shown aldosterone biosynthesis could be a secondary event in that Dab2 is coexpressed with CYP11B2 in APA, suggesting APA development. In agreement with this possibility, that APA is formed by ZG cells acquiring morphological we have described the concurrence of different germline characteristics of ZF cells due to the excess of steroid and somatic mutations leading to APA development

Journal of Molecular Endocrinology production (Boulkroun et al. 2010). (Vouillarmet et al. 2016). A young patient with severe PA Although the direct link between recurrent somatic aged 26 years, bilateral macronodular adrenal hyperplasia mutations and aldosterone production is well established, seen on CT, and lateralized aldosterone secretion, showed the effects of these mutations on nodulation and cell clinical improvement of PA after right adrenalectomy. The proliferation remain to be clarified.KCNJ5 germline resected adrenal contained three nodules, one expressing mutations originally described in FH-III were associated aldosterone synthase, with Weiss index of 3, and a somatic with massive bilateral hyperplasia, suggesting that KNCJ5 mutation. A FDG-PET performed after surgery the KCNJ5 mutation was responsible for increased cell revealed abnormal rectal activity despite the absence proliferation and autonomous aldosterone production of clinical symptoms, and gastrointestinal exploration (Choi et al. 2011). On the other hand, patients with revealed familial adenomatous polyposis. We identified the PASNA and germline CACNA1D mutations did not presence of a germline heterozygous APC gene mutation exhibit enlarged adrenals or adrenal nodules (Scholl et al. associated with nodular biallelic APC inactivation due to 2013), as also observed for some patients with germline loss of heterozygosity (Vouillarmet et al. 2016). This case KCNJ5 mutations (Mulatero et al. 2012, Adachi et al. supports a two-hit model for APA formation whereby 2014). Furthermore, in vitro studies demonstrated the first hit APC( germline mutation) drives the nodule that cells overexpressing a mutant GIRK4 exhibited development, whereas the second hit (KCNJ5 somatic lower proliferation, or even apoptosis, due to increased mutation) specifies the pattern of hormonal secretion. intracellular Na+ concentration (Oki et al. 2012, Scholl et al. On the other hand, some authors suggest that APA 2012). Although adrenal nodules can be observed in could be derived from aldosterone-producing cell clusters normal adrenals associated with older age and severity (APCCs) (Nishimoto et al. 2010). APCCs are composed

http://jme.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-17-0035 Printed in Great Britain Downloaded from Bioscientifica.com at 09/24/2021 11:57:06PM via free access Journal of Molecular Endocrinology in futurestudies. still unknownandconstitutes anewfieldfor PA research mechanisms involvedinAPA andBAHdevelopment, is determinants ofBAH,aswell asthepresenceofcommon to beverified.Finally, theexistenceofpossiblegenetic occurring inapreviouslyalteredadrenalcortexisyet are independenteventsleadingtoaldosteroneproduction proliferation andaldosteroneproductionorwhetherthey somatic mutationsinAPA areresponsibleforbothcellular open newoptionsinPA diagnosisandtreatment.Whether may identification ofsomaticmutationsbeforesurgery development ofbiomarkersortechniquesallowingthe of PA withoutgeneticdefectsidentifiedtodate.The 50% ofsporadicAPA, aswellthefamilialforms progressively explainthegeneticbasisofremaining which mayprovidepotentialtreatmentoptions. pharmacological characteristics of mutant channels, are yetlargelyunsuccessful; biomarkers associatedwithrecurrentsomaticmutations studies to establishgenotype–phenotype correlations and forms ofPA, nowbasedongeneticfindings.Clinical CACNA1H cases. Germlinemutationsidentifiedin APA development,explainingmorethan50%ofsporadic ATP2B3 mutations in five genes ( been doneinthefieldofgeneticcauses PA. Somatic and coworkers( In thepastfiveyears,sinceoriginalarticlefromChoi Conclusion ( KCNJ5 rapid progressof APA. Thelackof may representaprecursorpopulationofcellsthatleadto ATP1A1 2015 inAPA,alteration observed werefound( however, no CACNA1D adrenals showedknownaldosteronedrivermutationsin The sequencingofDNAfrom23APCCsnormal tissue ( CYP11B1 and found inbothnormaland PA adrenal sinusoids, stainingpositiveforbothCYP11B2and and innercolumnarZF-likecellsformingcordsalong of morphologicalZGcellsincontactwiththecapsule Nishimoto DOI: 10.1530/JME-17-0035 http://jme.endocrinology-journals.org Review In future studies, larger numbers of samples should ). TheauthorssuggestthatasAPCCssharethesame mutationsmayonlyberarelydetected in APCCs Nishimoto and , ATP2B3 have expanded the classification of familial , et al ATP1A1 CTNNB1 KCNJ5 . 2015 Choi and KCNJ5 KCNJ5 t al et and ) are proven to be associated with mutations,themostfrequent ). CACNA1D t al et . 2010 -mutated APCCstoAPA, sothat mutationsinAPCCmayreflect ATP2B3 . 2011 KCNJ5 in vitro , Boulkroun mutationsasAPA, they and others f in35%oftheAPCCs;

), largeadvanceshave l ,

. 2011 boulkroun et al and ). . ,

Adachi M,MuroyaK,AsakuraY, SugiyamaK,HommaK&HasegawaT References grant n°633983. Dr Maria-ChristinaZennaroisalsopartneroftheH2020projectENSAT-HT Délégué à la Recherche et des Nouvelles Technologies. The laboratory of (PHRC grantAOM06179),andbygrantsfromINSERMMinistère (DEQ20140329556), theProgrammeHospitalierdeRechercheClinique 005 03,ANR-13-ISV1-0006-01),theFondationpourlaRechercheMédicale the AgenceNationalepourlaRecherche(ANRBlanc2011,No.:11-BSV1 This workwasfundedthroughinstitutionalsupportfromINSERMandby Funding perceived asprejudicingtheimpartialityofthisreview The authorsdeclarethatthereisnoconflictofinterestcouldbe Declaration ofinterest Akerstrom T, CronaJ,DelgadoVerdugo A,StarkerLF, Cupisti K, CA,CampinoC,GarciaAglony M,Martinez-AguayoA,Carvajal H, Ballantine DM,KlemmSA,Tunny TJ,StowasserM&GordonRD1996 Ballantine DM,KlemmSA,Tunny TJ,StowasserM&GordonRD1996 Azizan EA,PoulsenH,Tuluc P, ZhouJ,ClausenMV, LiebA,Maniero C, Azizan EA,LamBY, NewhouseSJ,ZhouJ,KucRE,ClarkeHapperfield Assie G,LibeR,EspiardS,Rizk-RabinM,GuimierA,LuscapW, Barreau Akerstrom T, MaharjanR,SvenWillenberg H,CupistiK,IpJ,Moser A, Akerstrom T, Willenberg HS,CupistiK,IpJ,BackmanS,MoserA, primary aldosteronism Genetic basisof Published byBioscientifica Ltd. 138–142. report andreviewoftheliterature. hyperaldosteronism typeIIIwithKCNJ5genemutation:apatient 2014 Discordantgenotype-phenotypecorrelationinfamilial PCR-SSCP analysisofthepromoter region ofthereningenein (doi:10.1111/j.1440-1681.1996.tb02786.x) andPhysiology Clinical andExperimentalPharmacology PCR-SSCP analysisofthep53gene in tumoursoftheadrenalgland. hypertension. ATP1A1 andCACNA1Dunderlieacommonsubtypeofadrenal Garg S,BochukovaEG,ZhaoW, Metabolism and zonafasciculata-liketumors. differences ingenotypeandphenotypebetweenzonaglomerulosa- KCNJ5 sequencingofaldosterone-producingadenomasreveal L, MarkerA,HoffmanGJ&BrownMJ2012Microarray, qPCR,and NEJMoa1304603) ofMedicine England Journal macronodular adrenalhyperplasiawithCushing’s syndrome. O, LefevreL,SibonyM,GuignatL, adenomas. Activating mutationsinCTNNB1aldosteroneproducing Stalberg P, RobinsonB,AlexanderIwenK,DralleH, (doi:10.1530/ERC-15-0321) producing adenomas. somatic mutationsanddistinctmolecularsignatureinaldosterone- Maharjan R,RobinsonB,IwenKA,DralleH, pone.0041926) channel selectivityfilter. lesions revealthreesomaticmutationsneartheKCNJ5potassium Comprehensive re-sequencingofadrenalaldosteroneproducing Willenberg HS,KnoefelWT, SaegerW, FellerA,IpJ, 1117–1121. population: clinicalandbiochemicalpresentation. of familialhyperaldosteronismtype1inahypertensivepediatric Bancalari R,BolteL,Avalos C,Loureiro Trejo P, (doi:10.1159/000358197)

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et al . 2011 Frequency . 2011Frequency 23 582–583. . 2016 . 2012

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Received in final form 5 April 2017 Accepted 11 April 2017 Accepted Preprint published online 11 April 2017 Journal of Molecular Endocrinology