fertilization; differentiation of the from undif ­ ofthegonadsfrom differentiation fertilization; established at whichischromosomally determination, stages: Sex developmentisclassically dividedintothree (1,2). anddifferentiation and femalesexdetermination mans, islinked,respectively, ofmale to theprocesses Arq Bras Metab. Endocrinol 2011;55/8 T Steroidogenic factor1;NR5A1gene;disordersofsexdevelopment Keywords funcionais de SF1 e as últimas descobertas relacionadas a mutações em seu , e receptornuclear1(SF1).Estarevisãocobriráalgunsdosdadosmaisrecentessobreospapéis Uma dasprincipaisproteínasnadiferenciaçãogonadaldemamíferoséofatoresteroidogênico NR5A1, NR0B1WT1SOX9, entreoutros,eovariana, taiscomoWNT4, DAX1, FOXL2 eRSPO1. manos sãoprocessosqueenvolvem interaçõesentreváriosgenesnasviastesticular, taiscomo de característicassexuaissecundárias. A determinaçãoeadiferenciação do sexo emsereshu- nitália ambígua,outrassãodiagnosticadasapenasnapuberdadeporatrasonoaparecimento gonadal. Algumas dessasdoençaspodemsemanifestaraonascimentoprincipalmente porge- anormalidades quepodemacontecertantonadeterminaçãocomoduranteadiferenciação Os distúrbiosdodesenvolvimento sexual(DDS)envolvem váriascondiçõesqueresultamde SUMÁRIO that involve theinteractionofseveralgenessuch asWT1, condary sexualcharacteristics. Sex determinationanddifferentiation inhumansareprocesses birth are diagnosed only at puberty, by ambiguous genitalia; others by the delayed onset of se- during gonadal determination and differentiation. Some maymanifest at of these disorders ofsex development (DSD) involveDisorders several conditions that result from abnormalities SUMMARY PalandiMaricilda deMello as doençasdodesenvolvimento sexual Papel multifuncional dofator esteroidogênico 1e disorders ofsex development steroidogenic factor 1 and Multifunctional role of Helena CamposFabbri Fator esteroidogênico1;geneNR5A1;doençasdodesenvolvimentosexual Descritores Bras EndocrinolMetab. 2011;55(8):607-12 findings relatedtomutationsinitscodinggene,NR5A1. factor 1(SF1). This reviewwillcover someofthemostrecentdataonSF1functionalrolesand the majorproteinsinmammaliangonadaldifferentiation isthesteroidogenicnuclearreceptor in thetesticularpathway, andWNT4, the ofmostmammals,includinghu­ the karyotype in orabsenceoftheYchromosome he presence 1 ,Andréa Trevas Maciel-Guerra 1 , EmersonSalvador deSouzaFrança DAX1, FOXL2 andRSPO1,intheovarian pathway. Oneof Arq BrasEndocrinolMetab. 2011;55(8):607-12 NR5A1, in one of the three stages. Some of these disorders may stages. Some ofthese disorders in oneofthethree abnormalities from volve severalconditionsthat result ofsexdevelopment(DSD) in­ (3).Disorders puberty either gonadstocomplete sexualmaturationduring by produced tissuestohormones ponse ofinnumerous whichistheres­ sexualdifferentiation, and secondary intotestesorovaries; structures embryonic ferentiated 2 NR0B1, , GilGuerra-Júnior SOX9 , amongothers, 1 ,

NR5A1. 3

Arq Campinas, SP, Brazil Médicas (FCM),Unicamp, Médica, Faculdade deCiências (Unicamp), Campinas,SP, Brazil Universidade deCampinas Estadual Engenharia Genética(CBMEG), Unicamp, Campinas,SP, Brazil 2 1 Accepted on19/Oct/2011 Received on6/Oct/2011 [email protected] 13083-875 –Campinas,SP, Brazil Av. CândidoRondon, 400 CBMEG Universidade deCampinas, Estadual Maricilda Palandi deMello Correspondence to: 3 review Departamento deGenética Departamento Centro deBiologiaMoleculare Departamento dePediatria,Departamento FCM- 607

Copyright© ABE&M todos os direitos reservados. Copyright© ABE&M todos os direitos reservados. SF1 anddisorders ofsex development responsible for initiatingmaledevelopment,itiswell responsible ontheYchromosome region as thesex-determining nadal dysgenesis(14). characterizesmixedgo­ senting 45,Xinthekaryotype ­ ofasecondcelllineagepre ducts (12).Thepresence consists ofderivativesbothWolffian andMüllerian genitalia Internal similartoovarianstroma. with areas ally, andassociated present tubulesare seminiferous vatives ofMüllerianductsandgenitalambiguity. Usu­ deri­ testiculardifferentiation, mosaicism, with partial sis (DGI)ischaracterizedbyindividuals46,XYwithout tumors (13).Conversely, incompletegonadaldysgene­ todevelopinggonadal prone duals withXYCGDare 46,XXor 46,XY(12).Indivi­ , with normal mal Müllerianderivatives.Itmayoccurinindividuals ambiguity, ofdysgeneticgonads,andnor andpresence by phenotypically femaleindividuals without genital Complete (CGD)ischaracterized (incomplete)ormixeddysgenesis(11). plete), partial ofMüllerianducts(10). in theregression the Wolffian genitaliavirilization,and ducts,inexternal of inthedifferentiation associated withabnormalities dysgenetictestesare gametes;whereas able toproduce functionthatisnot tissuewithouthormonal by fibrous mainly formed velopment (4,9). Dysgenetic gonads are orfunctionofgenes involved intesticularde­ pression intheex­ offailures by dysgeneticgonadsasaresult characterized toasetofabnormalities dysgenesis refers fallopian tubes(8).Incasesof46,XYDSD,gonadal and as fully developed uterus may be absent or present that and Müllerian structures production, or null sperm dysgenetictestes,reduced chordee, thout penoscrotal hypospadias,withorwi­ mildtosevere from may vary femaleorambiguousgenitaliathat These casespresent (6,7). sex, speciallyinindividualswith46,XYkaryotype ces betweengeneticsex,gonadalsexandphenotypic gonadal orgenitaldevelopment,leadingtodivergen­ for physiciansandscientistsingeneral. hasbeenachallenge anddifferentiation determination thatinvolvesex understanding of the intricate processes therapyandcounseling(5).The hormone procedures, aseriesofsurgical urgent, becauseitgenerallyrequires sexis ambiguous genitalia,thedefinitionofappropriate with sexual characteristics(4,5).Incasesofnewborns by delayed onsetofsecondary agnosed onlyatpuberty di­ by ambiguous genitalia; others are manifest at birth 608 After twodecadesoftheidentification ofSRY (com­ Gonadal dysgenesismaybeclassifiedaspure characterizedbyincompleteordisordered DSD are gene ­ several ,suchasWT1, thatinvolvetheinteractionof processes humans are in and differentiation known thatsexdetermination SF1 is expressed inovarianthecacellsandgranulosa SF1 isexpressed nal genitaliaandtesticulardescent(24,25).Infemales, invirilizationofexter nic enzymaticsystem,resulting ­ of steroidoge Leydig cells, SF1 activates the expression during fetaldevelopment(18).In Müllerian structures of cells, which leads to regression in Sertoli hormone of anti-Mülllerian the expression tion, SF1 regulates ­ 1,aftertesticulardetermina As illustratedinfigure system(21). inthecentralnervous physiological roles butalsoplaysimportant ment andsexdifferentiation, andgonadaldevelop­ is essentialnotonlyinadrenal (23). It to thisprocess almost all the enzymes related andplacenta, andregulates such asgonads,adrenals, tissues, insteroidogenic ishighlyexpressed SF1 enzyme(22). P45021-hydroxylase of thecytochrome region promoter theproximal elements thatregulate ds, pituitary, hypothalamus(20,21). andventromedial gona­ acts lateroninthedevelopmentofadrenals, ridge,and earlyintheurogenital very gene isexpressed inmice,showingthatthe evident afterobservations became (19). Thewiderangeofactionthisprotein stepsofovariandevelopmentandfunction in different and participates development, itisalsoactivelypresent ofmalespecificgenes.Infemale intheexpression role itplaysanimportant (17,18).Therefore, hormones anumberofsteroid theexpression cells, toregulate gene(AMH);andintheLeydig -Müllerian hormone ofanti­ theexpression cells,toregulate in theSertoli ofbipotentialgonads; intheformation fferentiation: anddi­ testisdetermination stagesthroughout at three isnecessary NR5A1 gene,whichencodesSF1protein, of (16).Theexpression SRY gonadsbefore fferentiated inundi­ andisexpressed and gonadalsteroidogenesis, ofenzymesinvolvedinadrenal themainregulator red family,member oftheorphannuclearreceptor conside­ by461aminoacidsandisa isformed man SF1protein Amember1(NR5A1[MIM184757]).Thehu­ group subfamily5 tor 1(SF1)nowknownasnuclearreceptor fac­ nuclearreceptor isthesteroidogenic differentiation and femalecharacteristics. inmale thatresult involved ingonadaldifferentiation 1illustratesthemainstepsandgenes (8,15). Figure DAX1, among others,inthetesticularpathway;andWNT4, SF1 was first isolated in 1992 during the search for SF1 wasfirstisolatedin1992duringthesearch inmammaliangonadal One ofthemajorproteins FOXL2 andRSPO1,intheovarianpathway Arq Bras Metab. Endocrinol 2011;55/8 NR5A1, NR0B1, SOX9, ­ Arq Bras Metab. Endocrinol 2011;55/8 box that, in turn, interactsco-operativelywiththeP­ A-box that,inturn, anchoring. Thisboxcontains aT forDNA tended byaFTZ-F1box,whichisimportant member oftheNR5Asubfamily, ithastheDBD ex­ Y=T/C,RGA)(31).Asa GGYCR’3 (where region 5’YCAA­ forthe monomer withhighaffinity SF1bindsDNAasa unlike mostnuclearreceptors, forSF1transcriptionalactivity(30).Moreover, portant isim­ that stabilizesDNAbinding.Thehingeregion box containsanaccessory sequences (29).Theregion recognition ofDNAtarget specific in nuclearreceptor thatisinvolved (P box) region, ger contains a proximal Thefirstzincfin­ andahingeregion. region, accessory two functionalactivationdomains(AF-1andAF2);an ning twozincfingers,aligand-bindingdomain(LBD), tein includes:aDNA-bindingdomain(DBD)contai­ ­ ofhumanSF1pro coding exons(28).Thestructure DNA dividedintoonenon-codingexonfollowedbysix (OMIM 184757).Itexpandsover30kbofgenomic biosynthesis(27). hormone and factors involvedinthemobilizationofcholesterol of almost all dogenic cells, stimulating the expression ­ in steroi of cholesterol the main regulator cells, earlyinfolliculogenesis(26).Inaddition,SF1is SF1-regulation isalsoimportant. , besidegermcells,therearefolliclecellsandthecainwhich differentiation ofthemale-specificinternalandexternalgenitalia.In regulated productionofAMH,Insl3,andtestosteroneinducethe In thetestis,germcells,SertoliandLeydigcellsdifferentiate.SF1- develops withadditionalactionofSOX9,DHHandDMRT1, amongothers. FOXL2, RSPO1andWNT4,whereasinthepresenceofSRY, atestis undertheactionofLIM1, bipotential gonadthatdevelopsintoanovary pathways areshowninthefigure.WT1andSF1expressed Biason-Lauber (2)].Themostimportantproteinsinmaleandfemale Figure 1. deferens seminal Epididymus vas NR5A1 Somatic cellsfrom Germ cellsfrom vesicles mesonephros yolk sac Penis Prostate Sexual developmentcascade Genital ridge is anautosomalgenelocatedat9q33 tubercle Genital Urogenital Wolffian duct sinus DAX1 LIM1 WT1 SF1 DHT Bipotential SOX9 SRY DHH DMRT1 Testoterone Steroidogenic descent Testis Testis enzymes Theca cells [adapted fromSwain(1)and box that supports an -box thatsupports SF1 WNT4 RSPO1 FOXL2 Steroidogenic Sertoli cells enzymes Germ cellsin mitotic arrest Follicle cells SF1 AMH SF1 SF1 Germ cellsin regression meiosis Müllerian Insl3 Leydig duct cells SF1 nesis without than in patients with than inpatientswith insufficiency nesis withoutadrenal in patients with gonadal dysge­ frequent may be more (41-43).Actually,failure mutationsintheNR5A1gene individuals withgonadaldysgenesisandwithoutadrenal mutations intheNR5A1gene46,XYheterozygous causedbyinactivating effect wed anhaploinsufficiency (40).Severalstudiessho­ normal were zygous carriers ­ of SF1functionin vitro, whatexplainedthathetero loss Thisinheritedmutationcausedpartial -box region. thep.Arg92Gln mutationlocatedintheA­ as carrying with similarphenotypehadbeensubsequentlydescribed SF1function(38,39).Ahomozygouspatient affecting severely first zincfingerP-boxDNAbindingregion, mutation, leadingto an amino acid substitution inthe Müllerian ductpersistence.Itwasadenovoheterozygous insufficiency,adrenal complete gonadal dysgenesis, and primary patientpresented in humans,andthereported p.Gly35Glu (38).Thiswasthefirstmutationdescribed forthemissense mutation aled theheterozygosity are alsoattributedtotheNr5A1deletion(21). are hypothalamus, brain, specifically intheventromedial and in the in the pituitary mals (36,37). Abnormalities ofMüllerianducts inXYani­ virilization andretention andgonadalagenesis, defectsin cause completeadrenal Nr5A1 genedeletionsinsuchanimals lamus regions. changesintheventraland medianhipota­ structural and gonadotropins velopment, theabsenceofpituitary andgonadalde­ manifested bythe absence of adrenal Homozygous mutationsthatinactivateSF1inmiceare no acidsimilaritybetweenmiceandhumansis95%. amongspecies,andtheoverallami­ highly conserved enhancers(35). well asatintronic as region, (20), andmethylationatthebasalpromoter elements regulatory withdifferent region sal promoter 1 and 2 (USF1, USF2) (34), interactions at the ba­ factors stimulatory coding exons1(32,33),upstream non­ alternative through formed manner bypromoters inatime-andtissuedependent regulated is precisely acetylation and SUMOylation (20,21). Its expression fications suchasphosphorylation/dephosphorylation, activity ofSF-1ismodified bypost-translational modi­ transcriptional activation domains(20).Furthermore, itsprotein through the interactionwithotherproteins the activationofSF1transcriptionalactivityrequires specificity ofthemonomericDNAbinding(20). -box inthefirstZnfingerofDBD,anddefines Sequencing Several studieshaveshownthattheNR5A1geneis majorityoftranscriptionfactors, Similar tothegreat ­ NR5A1 geneofan XY female reve SF1 anddisorders ofsex development 609

Copyright© ABE&M todos os direitos reservados. Copyright© ABE&M todos os direitos reservados. affected parent, indicatingadominantinheritan­ parent, a non-affected patients eitherasdenovomutationsorinheritedfrom fficiency. foundinheterozygous Mostmutationswere insu­ withoutadrenal hypospadia, andcryptorchidism tients with,respectively, penoscrotal XYDSDandsevere p.Cis16Ter identifiedinpa­ andp.Glu51ArgfsX23 were mutationssuchasp.Glu11Ter, heterozygous vertheless, insufficiency. ,includingadrenal severe Ne­ go mRNAnonsense-mediateddecay, the do not present tounder considered other frameshiftmutationsthatare inthefirstandsecondcodingexons,aswell occurring nonsensemutations forsevere all patientsheterozygous tounderstandwhy itisdifficult isadosageeffect, there 2).Ifweconsiderthat (Figure -genotype correlation in identified Considering thetypeofeachmutationalready (43). insufficiency both gonadaldysgenesisandadrenal SF1 anddisorders ofsex development 610 mutations areinred.Mutationsgreen andblueare,respectively, anin-framedeletionandinsertionthateliminatesthenaturalstopcodon. the presumedconsequenceonprotein sequenceofnucleotideinsertionsordeletions.Missensemutations areinblack;nonsenseandframeshift MI,maleinfertility;BAM,bilateralanorchiawithmicrophallus. Mutationsinparenthesisare cryptorchidism; SPH, severepenoscrotalhypospadia; Crypt, present ovarian in insufficiency; heterozygosis, except those denoted in bold. AI, adrenal insufficiency; DSD, disorder of sex development; POI, primary boxes”, ZnIandII;zincfingers IIarealsodenoted.Underlinedmutationsweredetectedinboth46,XX and46,XYindividuals.Allchangeswere activation functiondomains1and2,NLS; nuclearlocalizationsignal,Pro-rich;proline-richregion,Ftz-F1;Fushi-tarazu factor-1 box,P/T/A;“DNAbinding intheresidueS203withinhingeregionareindicatedabove.AF-1andAF-2; Ftz-F1), SUMOylationintheresidueK119andK194,phosphorylation domains, and interacts with other that control SF1 transcriptional activity. Post-translational modifications such as acetylation (in the DBD and zinc fingerIisindicatedbyadashedsquare.ThehingeregionbetweenDNA- andligand-bindingdomainsisimportantforstabilizingthe FTZ-F1 domainthatstabilizesproteinbindingtoDNAisalsoillustrated.The twozincfingers(ZnI,ZnII)oftheDBDarehighlightedontop.TheP-boxwithin main functionaldomainsoftheSF1proteinareshown,indicatingposition oftheDNA-bindingdomain(DBD)andligand-binding(LBD). Figure 2. , it is difficult to establish a direct phenotype­ toestablishadirect NR5A1, itisdifficult Schematic overview ofSF-1andlocations eachNR5A1mutation Schematic overview ­ [adapted fromHoivikandcols.(20)Ferraz-de-Souza(46)].The infertility, and premature ovarian failure, affecting both both infertility, affecting ovarianfailure, andpremature male butalsowithhypospadias,anorchia, failure, adrenal may beassociatednotonlywithgonadaldysgenesisand complete gonadaldysgenesis(44,45). sufficiency, XYincompletegonadaldysgenesis,and ovarianin­ :XXprimary different in three inafamily,which wasfoundsegregating andresulted described aboveisone,andtheotherp.Asp293Asn, manner.transmitted inarecessive Thep.Arg92Gln the conclusionthat,inthosecases,mutationwas cases ofhomozygosityforinheritedmutationsenabling of themhadbeeninherited.Conversely, two are there 2),andmost nonsense orframeshiftmutations(Figure ovarianinsufficiency, eightare DSD andinXXprimary theninemutationsidentifiedinXY to notethatfrom of penetrance. It is interesting degree ce with different ManystudieshaveshownthatvariationsintheNR5A1 Arq Bras Metab. Endocrinol 2011;55/8

Arq Bras Metab. Endocrinol 2011;55/8 ach affected phenotype. to identifythesegenesforeachaffected and howothergenesmodulatetheirexpressivity, and phenotypes,whether withdifferent mutations correlate outhow hastobedonefigure research more of inheritanceNR5A1mutations,andsuggestthat ofthephenotype,penetrance,andmodes pressivity insufficiency. withoutadrenal failure ovarian orpremature causesofeitherprimary frequent toindicateNR5A1genemutationsas gs isnecessary ­ (53). However, onmutationscreenin research more quent thanintheSRY ­ fre more so farthatmutationsintheNR5A1geneare alldatareported from Itcanbeinferred of anorchia. that anymutation(52), indicating condition didnotreveal ver, studyinvolving26patientswiththesame arecent evaluated (51).Howe­ tion inoneoutof24children ofp.Val355Met asaresult tations, wasreported muta­ inadditiontoallothermanifes­ or testicularregression, cleotide changesintheNR5A1gene.Bilateralanorchia nu­ clinical manifestations for different dicate different (50). and cryptorchidism se associated with micropenis hasbeendescribed asamissen­ ted inthehingeregion, (44,49).Inaddition,p.Gly146Ala,alsoloca­ infertility ormale been associatedtoeitherovarianinsufficiency whichhas withintheSF1hingeregion, p.Pro129Leu themutationsp.Gly123Alaand is theallelecarrying bothmaleandfemaledevelopment allele affecting (8,15,44,45,48). AnotherexampleofamutatedSF1 ofSF1protein ofmultifunctionalroles bly asaresult carrying bility isverifiedforeither46,XYor46,XXindividuals folliculogenesis. Phenotypicvaria­ causing abnormal integrity, cells,damaging stroma number ofgerm and the atseverallevels:reducing theovary mayaffect lure withovariandevelopment(47).SF1fai­ not interfere thatNR5A1mutationsmight before was considered and functionofovariesinhumans(44),althoughit tes thatSF1isindeedakeyfactorinthedevelopment in women tumorsandendometriosis(46). associated withadrenal 46,XY and46,XXindividuals.Insomecases,itmaybealso was reported. relevant tothisarticle nopotential conflictofinterest Disclosure: Brasil) fortheirfinancialsupport. Nacional deDesenvolvimentoCientífico e Tecnológico (CNPq - àPesquisa doEstadodeSãoPauloandConselho de Amparo Acknowledgements: theauthorswouldliketothankFundação The findings reviewed here indicateacomplexex­ reviewed here The findings Finally, sofarin­ allthemolecularstudiesreported The identificationofNR5A1 mutation might be not a frequent cause NR5A1 mutationmightbenotafrequent ­ NR5A1 mutationswithinfamilies,proba with primary ovarian failure clearly indica­ ovarianfailure with primary geneincasesof46,XYDSD nucleotide changes NR5A1

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