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European Journal of 10.1530/EJE-17-0946 , where it promotes retention and (ACTH) ( extracellular potassiumandadrenocorticotrophin its secretionistightlyregulatedbyangiotensinII, in humansand,underphysiologicalconditions, isthemainmineralocorticoidhormone Introduction molecular basisisyettobeuncovered. the molecularmechanismsunderlyingBAHandFH-II,mostcommonformsofsporadicfamilialPA whose featuring primaryaldosteronismseizuresandneurologicalabnormalities.Furtherstudiesarewarrantedtoidentify cause FH-IIIandFH-IV, respectively, whilegermlinemutations in homeostasis, havebeenidentifiedinnearly60%ofthesporadicAPAs. Germlinemutationsin Somatic mutationsinfourgenes( molecular mechanismsresponsibleforautonomousaldosteroneoverproductioninbothsporadicandfamilialPA. six years,theintroductionofnext-generationsequencinghassignificantlyimprovedourunderstanding of sporadicPA and4formsoffamilialhyperaldosteronism(FH-ItoFH-IV)havebeenidentified.Overthelast Aldosterone-producing (APA) andbilateraladrenalhyperplasia(BAH)arethetwomostfrequentsubtypes by theadrenalglands,affects 6%ofthegeneralhypertensivepopulationandcanbeeithersporadicorfamilial. electrolyte homeostasis.Primaryaldosteronism(PA), characterizedbyautonomousaldosteroneoverproduction Aldosterone isthemainmineralocorticoidhormoneinhumansandplaysakeyrolemaintainingwater Abstract Italy and 1 and Silvia Monticone aldosteronism The expandinggenetichorizonofprimary GENETICS INENDOCRINOLOGY Division ofInternalMedicineandHypertensionUnit,DepartmentMedicalSciences,UniversityTorino, Torino, https://doi.org/10.1530/EJE-17-0946 www.ej Review secondary hypertensionandtheevaluationofcardiovascularrisk factors. secondary II); clinicalgeneticsofthemonogenic formsofhypertension;thegeneticandpathophysiology ofessentialand aldosteronism, glucocorticoid-remediablealdosteronism,aldosterone synthasedeficiencytypeIand primary (CYP11B1 andCYP11B2)theirroleinhumanpathologies(essential , andgeneticsof11b-hydroxylase aldosteronism;biochemistry clinical andmoleculargenetics ofprimary of MedicalSciencesattheUniversityTorino, Italy. Hismainresearch interestsincludepathophysiology, Paolo MulateroisanAssociateProfessorofInternalMedicineand HeadoftheHypertensionUnit,Department Invited Author’s profile Paolo Mulatero e-online.org 2 Division ofMedicalGenetics,DepartmentSciences,UniversityTorino, Torino, Italy 1 ). Itsprincipalsiteofactionisthedistal 1 , Fabrizio Buffolo 1 3 © 2018EuropeanSociety ofEndocrinology S Monticoneandothers KCNJ5, ATP1A1, ATP2B3 1 , Martina Tetti Printed inGreatBritain 1 , Franco Veglio and the generalhypertensivepopulation( aldosteronism (PA), thatcanaffectupto6%of glands isaclinicalsyndromeknownasprimary aldosterone overproductionbyoneorbothadrenal water andelectrolytehomeostasis.Theautonomous excretion, playing a key rolein maintaining aldosteronism Genetics ofprimary CACNA1D Published byBioscientifica Ltd. CACNA1D 1 , Barbara Pasini ), differently implicatedinintracellularion causetherarePASNA syndrome, Downloaded fromBioscientifica.com at09/28/202104:44:53PM 2

KCNJ5 (2018) Endocrinology European Journal of [email protected] Email to PMulatero should beaddressed Correspondence 178

178 and :3 , R101–R111 2 CACNA1H ). Itsmain

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via freeaccess European Journal of Endocrinology www.eje-online.org hypertension andhypokalaemia. affected patientsdisplayed a florid PA phenotype, with of aldosteroneoverproduction), themajorityof was clinical(basedon suppression data ( ( administration oftheglucocorticoiddexamethasone and suppressedPRA)thatcouldberelievedbythe the clinical features of PA (hypertension, hypokalaemia and coworkers reported on a father and son displaying This conditionisknownsince1966,whenSutherland common formofmonogenicarterialhypertension( autosomal dominantdisorder, anditisthemost FH-I orGRA(OMIM#103900)istransmittedasan Familial typeI Genetics offamilialhyperaldosteronism the fieldof PA. ofthemostrecentgeneticacquisitionsin an overview both sporadic and familialPA. This review willprovide underlying autonomousaldosteroneoverproductionin to ourunderstandingofthemolecularmechanisms synthase (CYP11B2)( of monoclonal antibodies directedtowards aldosterone sequencing (NGS)( the developmentandwideapplicationofnext-generation basis wasclearlyelucidated( aldosteronism) wastheonlysubtypeofPA whosegenetic Until recently, FH-I(orGRA,glucocorticoid-remediable is a genetic disease, but not a familial form of PA ( seizures, neurologicabnormalities)syndrome,which so far(FH-ItoFH-IV)( of familialhyperaldosteronism(FH)havebeenreported work-up includingadrenalveinsampling( with familialdiseasecanavoidfurtherdiagnostic 94% of cases withadrenalectomy( because patientswith an APA arebiochemicallycuredin a familialdisease( bilateral adrenalhyperplasia(BAH),1–6%ofcasescarry either duetoaldosterone-producingadenoma(APA) or majority ofaffectedpatientsdisplayasporadicform, hypertension andsimilarriskprofile( alterations comparedtopatientsaffectedbyessential an increasedriskofcardiovasculareventsandmetabolic activityratio(ARR);moreover, PA patientsdisplay hypokalaemia andelevatedaldosterone-plasma clinical andbiochemicalfeaturesarehypertension, upeetr al 1 Table Supplementary 12 Review ). Until1990,lessthan100casesweredescribed givenattheendofthisarticle): sincethediagnosis 4 7 ). Subtypediagnosisisimportant ), togetherwiththedevelopment 7 , seesectionon ), togetherwiththePASNA (PA, 10 ), significantlycontributed 9 ). Overthelastfewyears, S Monticoneandothers 5 ) andmanypatients 3 ). Whilethevast supplementary supplementary 6 ). Fourforms 11 8 ). ). ).

between so far, therecombination break-point is comprised therefore in allthe chimeric genes causing FH-I reported toretainaldosteronesynthaseactivityand are necessary considered ( a mineralocorticoid receptor antagonist should be to avoid glucocorticoid-related adverse effects, adding day) shouldbestartedtosuppress ACTHsecretionand glucocorticoid (suchasdexamethasone 0.125–0.25 established, atherapywithlowdosesofanexogenous atayoungage( and/orearlyonset( history testing forFH-Iisappropriate in PA patientswithafamily rupture) ( haemorrhagic ,asaresultofintracranialaneurysms prevalence of cerebrovascular events at young age (mainly is infrequent,andaffectedpatientsdisplayanelevated forGRAshowedthat hypokalaemia International Registry phenotype. Moreover, aretrospectivereportfromthe indicating thatthediseasecandisplayavariableclinical mild hypertension or eveninnormotensivesubjects( testing, allowingtodiagnosethediseaseinpatientswith available fortheeasyandrelativelyinexpensivegenetic changed ( gene ( chain reactionstrategyfortheamplificationofhybrid subsequent introductionofthelong-rangepolymerase regarded asanessentialdiagnosticfeature. until thedescriptionofchimericgene,havebeen activity ( The hybrid steroids display weak mineralocorticoid chimeric enzymecancatalyseitsC-18hydroxylationand zona fasciculata,cortisolisavailableassubstrateandthe throughout theentireadrenalcortex.In zona glomerulosa,thechimericenzymeisexpressed aldosterone synthaseexpressionislimitedtotheouter the 3 sequences at5 ACTH control,sinceitcontains chimeric enzyme, that can synthesize aldosterone under CYP11B2 between non-homologous crossingoveronchromosome8q24.3 chimeric Lifton andcoworkersin1992( ‘hybrid steroids’, 18OH- and 18-oxo cortisol( C-18 oxidation,resultingintheproductionofso-called aldosteronism Genetics ofprimary The molecularbasisofGRAwaselucidatedby According totheEndocrineSocietyguideline,genetic After theidentificationofchimericgene,and ′ ( 16 Fig. 1 CYP11B1 , encoding aldosterone synthase. The result is a 14 ), theclinicalspectrumofFH-Idramatically 18 CYP11B2 upeetr al 1 Table Supplementary CYP11B1 , ) ( 19 ). Two residues(Gly288andAla320, 15 Supplementary Table 1Supplementary ). ′ andcodingsequencesfrom ) butareahallmarkofthediseaseand, geneencoding11beta-hydroxylaseand intron2andexon4( / CYP11B2 19 Downloaded fromBioscientifica.com at09/28/202104:44:53PM ). Oncethediagnosishasbeen < 20 years) ofPA20 years) orincaseof gene, resulting from a ). Large kindreds were 9 ) andresidesinthe CYP11B1 ). 178 :3 CYP11B2 regulatory regulatory 13 ). While R102 Fig. 1 mg/ 11 17 at via freeaccess ). ) ) European Journal of Endocrinology respectively andarethereforeindispensabletoretainaldosteronesynthaseactivity. coding regionof CYP11B1 coding for11 should undergoscreeningtest ( hypertensive first-degreerelatives ofpatientswith PA the EndocrineSocietyguideline recommendsthatall genetic tests ( other formsofFHhavebeenexcludedthroughavailable members ofthesamefamilyareaffectedbyPA, andthe molecular basisisyettobeelucidated. be aheterogeneousgroupofgeneticformsPA whose ( affected byFH-IIwheresubsequentlyre-classifiedasFH-III continents ( linkage with7p22wasreportedinsomekindredsfrom 3 from theonesaffected by asporadicform of PA ( that allowtodistinguishpatientsaffectedbyFH-II BAH. Therearenoclinicalorbiochemicalcharacteristics patients withPA) ( most common form of FH (with a prevalence of 5% among the modeofinheritanceislesscertaininothers.It autosomal dominantpatterninmostofthefamilies,but of PA inAustralia1991( first timeasanovel,notglucocorticoidremediable,form Familial hyperaldosteronismtypeIIwasreportedforthe Familial hyperaldosteronism typeII cortex (dashedcircle),originatesfromanunequalcrossingoverbetweenthehighlyhomologous Schematic representationofthe Figure 1 22 Review AC 5’ ). ThereisnowgeneralagreementthatFH-IImight The diagnosisismadewhenatleasttwofirst-degree TH intron2andexon4sothatthechimericgenecontainspromoterregionof 21 β -hydroxylase andaldosteronesynthase,respectively. Thecrossingoverbreak-pointsarecomprisedbetween 19 ), butnotably, somefamiliesthoughttobe 1 CYP11B2 ). Due to its relatively high prevalence, CYP11B 4 ) andcanbeduetoeitheranAPA ora . ThetwoCYP11B2residuesGly288andAla320areresponsiblefor18-hydroxylation18-oxidation 1 23 Aldos 20 CYP11B1/CYP11B2 ). Itistransmittedwithan 19 S Monticoneandothers ). te ro ne Cr ossing-o 5’ chimericgene.Thegene,expressedthroughouttheentireadrenal ve 4 CYP11B ). A r regio 45 n dexamethasone suppression testsdidnotconfirmthe hybrid steroids and FH-I was suspected, but two urinary Notably, both girls displayed extremely elevated levels of suppressed plasma renin activity (0.2–0.3 plasma aldosteronelevels(137–185 severe hypokalaemia(1.8–1.9 phenotype characterizedbyresistanthypertension, years,withasimilarclinicalandbiochemical 7 and4 two daughtersoftheindexcasepresented,atage of nodular hyperplasiamainlyofthezonafasciculata.The the removedadrenalswerebilaterallyenlarged,with adrenalectomy. Athistopathologicalexamination, day) ( aldosterone(67 urinary (2.1–3.0 recorded readingof300/190 diagnosed onthebasisofhypertension(maximum hypertension (knownsincetheageof5)( by ,polydipsia,nicturia,headacheandsevere in 2008( a peculiarclinicalandbiochemicalphenotypesolely disorder wasrecognizedasadistinctclinicalentitywith The first case of FH-III dates back to 1959 ( Familial hyperaldosteronism typeIII aldosteronism Genetics ofprimary 2 pr AC omot 23 Gly28 TH regula ) and at the age of 9 years, he underwent bilateral ) andattheageof9years,heunderwent mEq/L), and elevated average CYP11B1/CYP11B 24 er 8 ). Theindexcasewasayoungboyaffected regio Hybrid te d n Ala320 CYP11B1 67 μ

CYP11B Downloaded fromBioscientifica.com at09/28/202104:44:53PM g perday, normalrange1–8 CYP11B1 (regulatedbyACTH)anda 2 mmHg), hypokalaemia mEq/L) andelevated 2 and 178 89 CYP11B www.eje-online.org :3 CYP11B2 ng/dL) despite ng/mL/h) ( 23 23 1 ). PA was ), but the genes R103 3’ μ g per 24 3’ via freeaccess ). European Journal of Endocrinology www.eje-online.org of the p.Gly151Glu mutation (7 patients form 3 different of thep.Gly151Glumutation (7patientsform3different hypertension andhypokalaemia. However, thecarriers form ofPA, requiringbilateraladrenalectomy tocontrol the patientspresentedwith anearlyonsetandsevere described byGellerandcoworkers ( cases displayedthepeculiarhormonalphenotype members ( ( mutations associatedwithFH-IIIhavebeenreported < overproduction ( leads to in intracellular Ca of thevoltage-gatedCa cell membranedepolarizationwithsubsequentopening are responsible for loss of ion selectivity, Na mutations disrupttheselectivityfilterofchanneland maintain thecellmembraneinahyperpolarizedstate.The adrenal zonaglomerulosa( potassium channel4,(GIRK4),whichisexpressedin and encodestheGprotein-activatedinwardrectifier disease ( p.Thr158Ala mutationthatco-segregatedwiththe and targeted sequencing of the gene revealed a germline that inheritedmutationsin evidences obtainedfromsporadicadenomassuggested a cohortof22sporadicAPAs ( somatic mutations(p.Gly151Argandp.Leu168Arg)in the authorsidentified2recurrentheterozygous and coworkersin2011( disease anditsmolecularbasiswasuncoveredbyChoi high productionofhybridsteroidsinthesepatients( CYP17 (17 the entireadrenalcortexandfrequentlyco-expressedwith revealed that aldosterone synthase is expressed throughout enzymes involvedincortisolandaldosteronebiosynthesis staining and immunofluorescence studiesfor themain loss ofnormalzonation( adrenal glandsweremarkedlyenlarged,withacomplete of bloodpressure and plasma potassium. In both cases, adrenalectomy was required to obtain normalization functioning. As for the father, bilateral administration, indicating a complete deregulation of cortisol levelswerenotsuppressedafterdexamethasone paradoxical increase( administration, butalsoshowedanunexpectedand not onlyfailedtobesuppressedbydexamethasone diagnosis. Surprisingly, blood pressure and aldosterone i. 2 Fig. 1% ofpatientswithPA ( Review FH-III (OMIM # 613677) is a rare condition, affecting FH-III (OMIM#613677)isararecondition,affecting FH-III istransmittedasanautosomaldominant ), for a total of 12 families and 22 affected family ), foratotalof12familiesand22affectedfamily CYP11B2 26 29 ). α -hydroxylase), explainingtheabnormally ). Notably, noneofthefurtherreported KCNJ5 27 expressionandautonomousaldosterone 2+ ). activates the signalling cascade that islocatedonchromosome11q24 24 2+ channels( ). Similarly, inbothpatients, 26 24 7 26 ). To date,6 ). ThroughNGStechnology, , , 25 27 KCNJ5 ). Immunohistochemical S Monticoneandothers ), whereitcontributesto 26 26 ). Theexperimental 24 couldcauseFH-III , ). The majority of ). Themajorityof 28 KCNJ5 ). Theincrease + entry and entry germline germline KCNJ5 25 ).

indicates theN-terminusandCC-terminus. near orwithintheselectivityfilterofGIRK4channel.N causing Germline mutationsinGIRK4associatedwithFH-III.FH-III- Figure 2 ( 26 Ca channel, Cav3.2. encoding the pore-forming gene locatedonchromosome16p13( #617027) causedbygermlinemutationsinthe aldosteronism (OMIM FH-IV isafamilialformofprimary Familial hyperaldosteronism typeIV youngpatientswithPAappropriate invery ( testing forgermlinemutationsin inthese patients( lack ofadrenalhyperplasiaobserved partially accountforthemildclinicalpresentationand cell death.Ithasbeenpostulatedthatthiscouldatleast functioning, withmassiveNa with aparticularlysevereimpairmentofthechannel showed thatthep.Gly151Glusubstitutionwasassociated in aChineseboy( typical Cushing’s syndromehasrecentlybeenreported p.Glu145Gln mutation)presentingwithseverePA and ( p.Tyr152Cys mutationdisplayedalessseverephenotype hyperplasia atimaging.Similarly, the thepatientcarrying adrenalectomy); none of the patients displayed adrenal bilateral adrenalectomyandtheotherhad90%left adrenalectomy(onehad only twoofthemunderwent families) ( aldosteronism Genetics ofprimary 31 34 ), where it isactivated at small depolarizing potentials 2+ ). Interestingly, acaseofFH-III(duetotheKCNJ5 ). ThroughNGSanalysis,a novel germline According totheEndocrineSocietyguideline, channelgeneintheadrenal zonaglomerulosa( N KCNJ5 22 , germlinemutations(blackdots)arelocated 30 ) displayed a favourable disease progress: ) displayedafavourablediseaseprogress: CACNA1H 32 Glu145Gln ). In vitro Downloaded fromBioscientifica.com at09/28/202104:44:53PM Ile157Se α isthesecondmostexpressed subunit of a T-type calcium electrophysiological studies electrophysiologicalstudies + Gly151Glu Gly151Ar r entry, osmoticshockand KCNJ5 g 178 33 :3 ) ( causingFH-IIIis Fig. 3 Thr158Al 19 Ty C r152Cy ). CACNA1H CACNA1H , panelA) a R104 s 30 via freeaccess 8 ). ,

European Journal of Endocrinology segment ofdomainsIandII.NindicatestheN-terminus C indicatestheC-terminus. each (S1–S6).ThetwogermlinemutationsassociatedwithPASNA syndromeareindicatedasblackdotsandlocatedinS6 voltage-gated calciumchannel.The mutation. Ofnote,two mutation carriersdidnot thep.Met1549Validentify 5additionalsubjects carrying gene inthefamilymembers oftheindexcases,allowedto at CT scanning ( biochemical featureandnormalappearingadrenalglands cases wasuniform,withoutanydistinctiveclinical or childhood ( unrelated patients affected by hypertension and PA in mutation (p.Met1549Val) wasidentifiedin5outof40 Germline mutationsinCav1.3causingPASNA syndrome. domain IIIandintheC-terminalcytoplasmicdomain.NindicatesN-terminusCC-terminus.Panel(B) germline mutationsassociatedwithFH-IVareindicatedasblackdotsandlocatedinS4segmentofdomainI,S6 of calcium channel.Cav3.2iscomposedoffourrepeateddomains(I–IV),withsixtransmembranesegmentseach(S1–S6).The Panel (A)GermlinemutationsinCav3.2causingFH-IV. Figure 3 Review A B N N S1 Cav3.2 -α1poreformingunit S1 Cav1.3 -α1poreformingunit Ser196Leu S2 S2 33 S3 S3 ). Theclinicalpresentationoftheindex S4 S4 33 Gly403Asp I I S5 ). Target sequencing of the S5 S5 S6 S6 S Monticoneandothers α S1 1 subunitiscomposedoffourrepeateddomains(I–IV),with six transmembranesegments S1 Ile770Me II II CACNA1H S5 CACNA1H t CACNA1D S6 S6

encodesthepore-formingalphasubunit(Cav3.2)ofaT-type S1 encodesthe S1 Ca likely tocause an increase in intracellular that are very to more hyperpolarizedpotentials ( of normalinactivationtogether withashiftofactivation revealed thatthep.Met1549Val CACNA1Hdisplaysloss penetrance ( normotensives as adults, suggesting an incomplete receive adiagnosisofearly-onsethypertensionandwere aldosteronism Genetics ofprimary 2+ The concentration in adrenal zona glomerulosa cells. concentrationinadrenal zona glomerulosacells. Me Me in vitro II II α t1549 t1549Il 33 II 1 (pore-forming)subunit(Cav1.3)ofanL-type II S5 ). Va e electrophysiological characterization electrophysiological characterization l S6 S6 Downloaded fromBioscientifica.com at09/28/202104:44:53PM S1 S1 Pr o2083Le 178 u V V www.eje-online.org :3 S5 33 ), alterations ), alterations S6 S6 R105 C C via freeaccess European Journal of Endocrinology www.eje-online.org syndrome ( inpatientswithPASNAoverlapping withthatobserved affected byautismandepilepsy withaphenotypepartially mutation (p.Val104Leu) wasidentifiedina patient CACNA1D treatment forindividualsaffectedbyAPAs a carrying calcium channel blockers might represent aspecific channel blockeramlodipine,raisingthepossibilitythat blood pressurewassuccessfullycontrolledbythecalcium seizures and cerebral palsy. In one of the two patients, hypokalaemia andneurologicalmanifestations,including cases presentedwithearly-onsetseverehypertension, and p.Ile770Met) have been reported ( due to subsequent abnormalcalciumsignalling( potentials andalteredchannelinactivation,with mutations causechannelactivationatlessdepolarized cells. Electrophysiological (Cav 1.3), whichisexpressed in adrenal zona glomerulosa α chromosome 3p14.3( function mutationsinthe and neurologicalsymptoms.Itiscausedbygain-of- aldosteronism syndrome characterizedbyprimary neurologic abnormalities,OMIM#615474)isaclinical PASNA aldosteronism with seizures and (primary PASNA syndrome phenotypes ( that could present with a wide range of clinical might representasusceptibilitygeneforPA development adrenalectomy ( apparently sporadic APA who was cured by unilateral the p.Val1951Glu wasidentifiedinapatientaffectedby in pairsofbrothers/sistersaffectedbyPA. Interestingly, p.Ser196Leu and p.Pro2083Leumutations were detected de novo p.Val1951Glu) ( PA (p.Met1549Ile,p.Ser196Leu,p.Pro2083Leuand CACNA1H to thecellsexpressingwild-typechannel( and a3.7-foldincreaseinaldosteroneproductioncompared resulting ina7.1-foldincrease channel wasexpressedinHAC15adrenocorticalcells, aldosterone overproduction,thep.Met1549Val mutant To elucidatetheroleofmutationinautonomous 1D subunitofaL-typevoltage-gatedcalciumchannel Review Interestingly, anew missense Two paediatricpatientsaffectedbyPASNA syndrome Subsequently, fouradditionalgermline de novoCACNA1D eventidentifiedinasporadic PA patientandboth somaticmutation. mutationswereidentifiedinpatientswith 37 36 ). ). 36 36 ). Thep.Met1549Ilesubstitutionwasa ). Thesedataindicatethat 8 ) ( germlinemutations(p.Gly403Asp Fig. 3 in vitro CACNA1D , panelB),codingforthe S Monticoneandothers studiesshowedthatthe CYP11B2 CACNA1D genelocatedonthe 8 8 ). transcription transcription ). The index 35 CACNA1H germline ).

(in bothAPA andBAH)arestillpoorlyelucidated. hyperaldosteronism andadrenalcellproliferation partially unravelled,themolecularbasisofbilateral aldosterone overproductionhavebeenatleast While themoleculardeterminantsofautonomous Germline mutationsinsporadicPA of sporadicAPAs ( stimulating somatic mutations ina significant proportion technology allowedtheidentificationofaldosterone- B2 receptorpolymorphisms( phenotype, includingCYP11B2, the susceptibilitytodiseaseoraffectclinical focused on genetic variants potentially able to increase Until recently, geneticstudiesonsporadicPA weremainly Genetic ofsporadicprimaryaldosteronism proximity oftheselectivityfilter thechannel ( not associatedwithFH-IIIandarelocatedin p.Arg52His, p.Glu246Lys andp.Gly247Arg)are missense germlinemutations.Themutations(p. hyperaldosteronism revealedthreeheterozygous from 251patientsaffectedbysporadicbilateral forAPAnecessary formation( cells growth( GIRK4 hasanegativeeffectonHAC15adrenocortical studies demonstratedthattheexpressionofmutant might promotecellproliferation.However, subsequent mutations, otherthandrivingaldosteronesecretion, the intracellularcalciuminfluxinducedby It was postulated by Choi and coworkers ( recently ruledout( Similarly, apotential roleofARMC5inFH-IIhasbeen ( this associationinpatients ofEuropeanancestry descent ( significant proportion of PA patients of African American hyperplasia andCushingsyndrome( ARMC5 suppressor gene.Somaticandgermlinemutations in currently unknown,butislikelytoactasatumour- armadillo repeatcontaining5,whosefunction is mutation didnotaltertherestingpotential( cell membranedepolarization,whilethep.Gly247Arg p.Arg52His andp.Glu246Lys substitutionsresultedin oocytes showedthattheexpressionofboth Electrophysiological studiesconductedinXenopus aldosteronism Genetics ofprimary KCNJ5 ARMC5 arefrequentlyfoundinmacronodularadrenal 41 sequencinginperipheralbloodDNA gene maps on16p11 and encodes the ). However, anotherstudyfailedtoconfirm 28 ) suggestingthatasecondhitmightbe 7 ). 43 ). Downloaded fromBioscientifica.com at09/28/202104:44:53PM 7 38 ). TheintroductionofNGS α ). -adducin andbradykinin 178 :3 40 ) andina 39 26 ). R106 KCNJ5 ) that 39 42 via freeaccess ). ). ). ).

European Journal of Endocrinology pharmacological studies. mutation wouldbeanextremely valuabletoolforfurther finding, amurinemodelof PA duetoagermline lacking theantibioticactivity ( macrolide classofantibioticsandbysyntheticderivatives inhibited byaseriesofmoleculesbelongingtothe mutant GIRK4,butnotthewild-typechannel,iseffectively therapeutic useofthisdrug( p.Leu168Arg mutant channel, suggesting a potential calcium channel blocker verapamil strongly inhibits the profile comparedtothewildtype,inparticular, the mutated GIRK4exhibitedadifferentpharmacological differentiation inthisspecificsubpopulation( potential diagnostic value of18-oxocortisol in subtype KCNJ5 mutations ( hybrid steroidsdetectedinAPA patientscarrying might at least partially account for the high amount of ( and arecomposedmainlyofzonafasciculata-likecells mutationsin carrying lower levelsofaldosteronesynthasecomparedtoAPAs Moreover, adenomascarrying diagnosis andhigherpreoperativealdosteronelevels( than inmales( carrying histopathological studiesshowedthattheadenomas ( somatic mutationassociatedwithsporadicunilateralPA Sequencing analysisallowedtoidentify15further for adrenalveinsamplinginterpretationwereused( populations, and also in those centres where strict criteria higher inEastAsianpopulationscomparedtoWestern centres ( of studies foratotalof1,636patients,theoverallprevalence ( reported, inacohortof168samples,78%prevalence be 38% ( (ENS@T), the prevalence of the EuropeanNetworkforStudyofAdrenalTumours comprising 474adrenaladenomascollectedthrough the largeststudyconductedinaWestern population, the prevalenceof ( Following the seminal report by Choi and coworkers KCNJ5 48 45 26 49 Review KCNJ5 ). Accordingtoarecentmeta-analysisincluding13 ), severalcentresfromfourcontinentsinvestigated ) expressing CYP17A1 ( ). In vitro Comprehensive clinical,biochemicaland mutationsintheEastAsianpatients,explain somaticmutations 44 46 KCNJ5 mutationsis43%,withwidevariationacross ), while the largest studyconductedin East Asia ). Theprevalenceappearstobeconsistently 51 pharmacological studies showed that ) and,consideringthehighprevalenceof 46 mutationsaremoreprevalentinfemales ) andareassociatedwithyoungerageat KCNJ5 ATP1A1 somaticmutationsinAPAs. In KCNJ5 53 50 54 KCNJ5 ). Evenmoresurprisingly, , ). These characteristics S Monticoneandothers ). Inlightofthisrecent ATP2B3 mutations resulted to mutationsexpress or 52 CACNA1D ). KCNJ5 KNCJ5 KCNJ5 47 46 ). ).

excitability; Ca the resting membrane potential and thecellular ions againsttheconcentration gradient thus maintaining cytoplasmic sodiumionsfortwoextracellularpotassium ATPase 3. The sodium/potassium ATPase exchanges three and encodestheplasmamembranecalcium-transporting while the sodium/potassium-transporting ATPase subunit alpha-1, ATP1A1 but, surprisinglynotincellmembranedepolarization( gating properties,resultinginloweredintracellularpH, Na homeostasis. in exchange for two H 56 of fourdifferentsomaticmutationsaffecting sporadic The applicationoftheNGStechnologytoaseries ATP1A1 the Cre-loxPtransgenicstrategy, causesadrenalaplasia adrenocortical function:inactivation of constitute adherensjunctions. β CTNNB1 CTNNB1 cross-sectional imagine-negativePA ( alteration inCYP11B2-positivecorticalmicro-nodules in CACNA1D KCNJ5 cells ( mutations arecomposedmainlyofzona-glomerulosa-like for 9.3%ofthesporadicAPAs ( CACNA1D Since itsoriginaldescription( CACNA1D samples ( ATP2B3 mutations account for 5.3% of the sporadic APAs while mutations havebeenreportedsofar( influx ( become permeable to cations, permitting Na a completelossofitsphysiologicalpumpfunction,that depolarized theplasmamembrane,asaconsequenceof 57 aldosteronism Genetics ofprimary -catenin, whichispartof a complexofproteinsthat ) andtwodifferentin-framedeletionsof ). Onthecontrary, themutantCa + /K A total of 13 different ATP1A1 and 9 ATPB3 somatic + 49 ornomutations( ATPase exhibits reduced K 58 mutationshavebeenidentifiedin1.7%ofthe islocatedonchromosome1p21andencodesthe and , somaticmutations geneislocatedonchromosome3andencodes 44 KCNJ5 ). 50 ATB2B3 mutationsarethemostfrequentgenetic mutations have been reported ( somaticmutations ). ) and are smaller compared with those with ATP2B3 In vitro wild-typeAPAs ledtotheidentification 2+ -ATPase3 removesonecytosolicCa geneislocatedonchromosomeXq28 somaticmutations studies showed that the mutant + and plays a key role in calcium Downloaded fromBioscientifica.com at09/28/202104:44:53PM 44 44 , 8 β , 49 -catenin playsakeyrolein ). APAs carrying 56 ). Accordingly, somatic + ), atotalof31different affinity and disturbed 59 48 178 2+ ). ). -ATPase3 strongly www.eje-online.org :3 β ATP1A1 48 -catenin, using ), accounting ATP2B3 ATP1A1 + CACNA1D and Ca somatic R107 ( ( 56 55 55 via freeaccess 2+ 2+ ). , ,

European Journal of Endocrinology www.eje-online.org CACNA1D CT-negative PA, assuggestedby theelevatedprevalenceof time ( aldosterone overproduction andprogresstoovertPA over the hypothesisthattheymightdisplayautonomous and proportion ofthemcarriessomaticmutationsin in the cortex adjacent to an APA ( The APCCs were found in both normal adrenals and named aldosterone-producingcellclusters(APCCs)( the zonafasciculataandstronglyexpressingCYP11B2, subcapsular nestsofadrenocorticalcellsextending in staining ofadrenalspecimensrevealedthepresence of Histological examinationandimmunohistochemical the classical view ofadrenocortical zonation ( unilateral PA, openinganewscenariothatgoesbeyond specific characterizationofbothnormaladrenalsand homologous CYP11B1 and CYP11B2 alloweda more antibodies abletodistinguishbetweenthehighly and theadjacentadrenalcortex( revealed significantheterogeneityinboththenodules adrenal glands, following a diagnosis of unilateral PA, ( frequently displayazona-glomerulosa-likephenotype (large cellswithlipid-ladencytoplasm)andonlyless APAs arecomposedmainlyofzona-fasciculata-likecells expression and aldosterone production ( cells formingnests,istheexclusivesiteofCYP11B2 The adrenalzonaglomerulosa,composedofcompact cell clusters Somatic mutationsinaldosterone-producing that areinvolvedin activation ofWntsignalling,byalteringspecificresidues are locatedonexon3( large .APAs-associated have been associated to female gender and relatively identified inaround3%ofsporadicAPAs ( tumours ( detected inbothbenignandmalignantadrenocortical activation ( in APAs islikelytocauseWNT/ supporting theevidencethat inhibitor production ( murine adrenal cortex results in increased aldosterone in newborn mice ( 49 Review ). Moreover, histologicalexaminationoftheremoved The recentdevelopmentofspecificmonoclonal CACNA1D 68 ). Inparticular, APCCsarelikelytoprogress to SFRP2 63 mutationsinthisparticular subtypeofPA ( 62 ). Somaticmutationsin 61 ). Activating displayincreasedaldosteroneproduction, genes(butnotin ). Similarly, mice lackingtheWNT 60 β ) while its constitutive activation in -catenin degradation. 64 CTNNB1 , 65 ) andresultinaberrant S Monticoneandothers 49 SFRP2 β , mutationshavebeen 68 -catenin constitutive CTNNB1 66 KCNJ5 CTNNB1 ) and a significant ). downregulation 1 ); however, the ), supporting 64 mutations havebeen , 65 ATP1A1 ) and 59 67 10 ), ). ).

in APCCs,whichmightrepresenttheprecursorsof some ofthesomaticmutationshavealsobeendetected overproduction inaround60%ofsporadicAPAs. Notably, altering intracellularionhomeostasis,drivealdosterone forms havebeencharacterizedandsomaticmutations, field ofbothsporadicandfamilial PA. Threenovelfamilial The lastsixyearshavewitnessedmajoradvancesinthe Conclusions physiology ( for theage-relatedchangesinreninandaldosterone pattern inolder-ageadrenalglands,whichmightaccount transition towardsadiscontinuousCYP11B2expression size increasewithage,( frequently harboursomaticmutationsin but lesslikelytoCT-detectable adenomas(whichmore References 60%-2017). P MandBareinreceiptofagrantfromUniversityTorino (MIURex- Funding perceived asprejudicingtheimpartialityofresearchreported. The authorsdeclarethatthereisnoconflictofinterestcouldbe Declaration ofinterest EJE-17-0946. This is linked to the online version of the paper at Supplementary data affected byPA duetoanaldosterone-producingadenoma. to changetheclassicalclinicalapproachpatients likely and targetedinhibitionofmutatedGIRK4arevery CT-undetectable PA. Inthenearfuture,steroidprofiling aldosteronism Genetics ofprimary 3 2 1 Monticone S, D’Ascenzo F, Moretti C,Williams TA, Veglio F, Gaita F Monticone S, Burrello J,Tizzani D, Bertello C,Viola A, Buffolo F, Hattangady NG, Olala LO,Bollag WB&Rainey WE.Acuteand (https://doi.org/10.1016/S2213-8587(17)30319-4) systematic reviewandmeta-analysis. aldosteronism comparedwithessentialhypertension:a primary & Mulatero P. Cardiovasculareventsand targetorgandamagein 2017 carepractice. primary aldosteronismencounteredin clinical manifestationsofprimary Gabetti L, Mengozzi G,Williams TA, Rabbia F mce.2011.07.034) Endocrinology chronic regulationofaldosteroneproduction. Clinical correlatesindicatedthatAPCCsnumberand 69 1811–1820. 70 2012 ). 350 (https://doi.org/10.1016/j.jacc.2017.01.052) Journal oftheAmericanCollegeCardiology Journal 151–162. Downloaded fromBioscientifica.com at09/28/202104:44:53PM 69 ) paralleledbyaprogressive (https://doi.org/10.1016/j. Lancet DiabetesEndocrinology 178 et al https://doi.org/10.1530/ Molecular andCellular :3 KCNJ5 . Prevalenceand ). R108

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17 16 15 14 13 12 11 10 9 8 7 6 5 4 Review Mulatero P, diCella SM,Williams TA, Milan A,Mengozzi G, Mulatero P, Curnow KM,Aupetit-Faisant B,Foekling M,Gomez- Gomez-Sanchez EP, Gomez-Sanchez CE,Smith JS,Ferris MW Ulick S, Land M&Chu MD.18-oxocortisol,anaturallyoccurring Curnow KM, Mulatero P, Emeric-Blanchouin N,Aupetit-Faisant B, Sutherland DJ, Ruse JL&Laidlaw JC.Hypertension,increased Halperin F &Dluhy RG.Glucocorticoid-remediablealdosteronism. Gomez-Sanchez CE, Qi X,Velarde-Miranda C, Plonczynski MW, Lifton RP, Dluhy RG,Powers M,Rich GM,Cook S,Ulick S Scholl UI, Goh G,Stölting G,deOliveira RC,Choi M,Overton JD, Monticone S, Else T, Mulatero P, Williams TA &Rainey WE. Monticone S, Viola A, Rossato D,Veglio F, Reincke M,Gomez- Williams TA, Lenders JWM,Mulatero P, Burrello J,Rottenkolber M, Mulatero P, Tizzani D, Viola A, Bertello C,Monticone S, four-generation Italianpedigree. remediable aldosteronism:lowmorbidity andmortalityina Chiandussi L, Gomez-Sanchez CE& Veglio F. Glucocorticoid 83 18-oxocortisol. conversion of11-deoxycortisoltocortisol,18-hydroxycortisol,and Recombinant CYP11Bgenesencodeenzymesthatcancatalyze Sanchez C, Veglio F, &Pascoe L. Jeunemaitre X,Corvol P org/10.1210/endo-115-2-462) 18-hydroxycortisol. & Foecking M.Receptorbindingandbiologicalactivityof (https://doi.org/10.1210/endo-113-6-2320) mineralocorticoid agonist. 32–35. an aldosteroneproducingenzyme. Val320Ala convertthecortisolproducingenzyme,CYP11B1,into &Pascoe L.TheaminoacidsubstitutionsSer288Glyand Corvol P 1109–1119. dexamethasone. aldosterone secretionandlowplasmareninactivityrelievedby 333–341. America Endocrinology andMetabolismClinicsofNorth 111–117. and CYP11B2. al Parker CR, Rainey W, Satoh F, Maekawa T, Nakamura Y, Sasano H org/10.1038/355262a0) and humanhypertension. synthase genecausesglucocorticoid-remediablealdosteronism & Lalouel JM.Achimaeric11beta-hydroxylase/aldosterone 2013 aldosteronism. producing adenomasandprimary germline CACNA1Dcalciumchannelmutationsinaldosterone- Fonseca AL, Korah R,Starker LF, Kunstman JW mce.2014.09.015) Endocrinology sequencing andexpressionprofiling. aldosteronism:impactofnextgeneration Understanding primary 8587(14)70069-5) Endocrinology aldosteronism: towardsastandardisedprotocol. Sanchez C &Mulatero P. Adrenalveinsamplinginprimary (https://doi.org/10.1016/S2213-8587(17)30135-3) international cohort. consensus onoutcomemeasuresandanalysisofremissionratesinan aldosteronism:aninternational adrenalectomy forunilateralprimary Adolf C, Satoh F, Amar L,Quinkler M,Deinum J HYPERTENSIONAHA.111.175083) forms). the PATOGEN AldosteronisminTorino study(Primary –GENetic al Mengozzi G, Schiavone D,Williams TA, Einaudi S,LaGrotta A . DevelopmentofmonoclonalantibodiesagainsthumanCYP11B1 . Prevalenceandcharacteristicsoffamilialhyperaldosteronism: 3996–4001. 45 Hypertension 1050–1054. (https://doi.org/10.1016/j.mce.2013.11.022) (https://doi.org/10.1016/j.ecl.2011.01.012) 2015 2015 Molecular andCellularEndocrinology (https://doi.org/10.1210/jcem.83.11.5237) Journal ofClinicalEndocrinologyandMetabolism Journal Canadian MedicalAssociationJournal 399 3 2011 Endocrinology 296–303. (https://doi.org/10.1038/ng.2695) Lancet DiabetesEndocrinology 311–320. 58 Nature Endocrinology 797–803. (https://doi.org/10.1016/S2213- Journal ofClinicalEndocrinology Journal 1992 1984 (https://doi.org/10.1016/j. Nature Structural Biology Nature Structural Molecular andCellular S Monticoneandothers (https://doi.org/10.1161/ 355 115 1983 262–265. 462–466. 113 et al Lancet Diabetes et al 2014 Nature Genetics 2017 2320–2322. . Somaticand 2011 1966 . Outcomesafter (https://doi. (https://doi. 383 5 689–699. 40 1997 95

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et et (https:// (https:// β 2014 - Accepted 18January2018 Revised versionreceived16December2017 Received 11November2017

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