review Multifunctional role of steroidogenic factor 1 and disorders of sex development Papel multifuncional do fator esteroidogênico 1 e as doenças do desenvolvimento sexual Maricilda Palandi de Mello1, Emerson Salvador de Souza França1, Helena Campos Fabbri1, Andréa Trevas Maciel-Guerra2, Gil Guerra-Júnior3 SUMMARY Disorders of sex development (DSD) involve several conditions that result from abnormalities 1 Centro de Biologia Molecular e during gonadal determination and differentiation. Some of these disorders may manifest at Engenharia Genética (CBMEG), birth by ambiguous genitalia; others are diagnosed only at puberty, by the delayed onset of se- Universidade Estadual de Campinas (Unicamp), Campinas, SP, Brazil condary sexual characteristics. Sex determination and differentiation in humans are processes 2 Departamento de Genética that involve the interaction of several genes such as WT1, NR5A1, NR0B1, SOX9, among others, Médica, Faculdade de Ciências in the testicular pathway, and WNT4, DAX1, FOXL2 and RSPO1, in the ovarian pathway. One of Médicas (FCM), Unicamp, Campinas, SP, Brazil the major proteins in mammalian gonadal differentiation is the steroidogenic nuclear receptor 3 Departamento de Pediatria, FCM- factor 1 (SF1). This review will cover some of the most recent data on SF1 functional roles and Unicamp, Campinas, SP, Brazil findings related to mutations in its coding gene, NR5A1. Arq Bras Endocrinol Metab. 2011;55(8):607-12 Keywords Steroidogenic factor 1; NR5A1 gene; disorders of sex development SUMÁRIO Os distúrbios do desenvolvimento sexual (DDS) envolvem várias condições que resultam de Correspondence to: Maricilda Palandi de Mello anormalidades que podem acontecer tanto na determinação como durante a diferenciação Universidade Estadual de Campinas, gonadal. Algumas dessas doenças podem se manifestar ao nascimento principalmente por ge- CBMEG Av. Cândido Rondon, 400 nitália ambígua, outras são diagnosticadas apenas na puberdade por atraso no aparecimento 13083-875 – Campinas, SP, Brazil de características sexuais secundárias. A determinação e a diferenciação do sexo em seres hu- [email protected] manos são processos que envolvem interações entre vários genes nas vias testicular, tais como NR5A1, NR0B1, WT1, SOX9, entre outros, e ovariana, tais como WNT4, DAX1, FOXL2 e RSPO1. Received on 6/Oct/2011 Uma das principais proteínas na diferenciação gonadal de mamíferos é o fator esteroidogênico Accepted on 19/Oct/2011 e receptor nuclear 1 (SF1). Esta revisão cobrirá alguns dos dados mais recentes sobre os papéis funcionais de SF1 e as últimas descobertas relacionadas a mutações em seu gene, NR5A1. Arq Bras Endocrinol Metab. 2011;55(8):607-12 Descritores Fator esteroidogênico 1; gene NR5A1; doenças do desenvolvimento sexual he presence or absence of the Y chromosome in ferentiated embryonic structures into testes or ovaries; Tthe karyotype of most mammals, including hu­ and secondary sexual differentiation, which is the res­ mans, is linked, respectively, to the processes of male ponse of innumerous tissues to hormones produced by and female sex determination and differentiation (1,2). either gonads to complete sexual maturation during Sex development is classically divided into three stages: puberty (3). Disorders of sex development (DSD) in­ ABE&M todos os direitos reservados. os direitos ABE&M todos determination, which is chromosomally established at volve several conditions that result from abnormalities © fertilization; differentiation of the gonads from undif­ in one of the three stages. Some of these disorders may Copyright Arq Bras Endocrinol Metab. 2011;55/8 607 SF1 and disorders of sex development manifest at birth by ambiguous genitalia; others are di­ known that sex determination and differentiation in agnosed only at puberty by delayed onset of secondary humans are processes that involve the interaction of sexual characteristics (4,5). In cases of newborns with several genes, such as WT1, NR5A1, NR0B1, SOX9, ambiguous genitalia, the definition of appropriate sex is among others, in the testicular pathway; and WNT4, urgent, because it generally requires a series of surgical DAX1, FOXL2 and RSPO1, in the ovarian pathway procedures, hormone therapy and counseling (5). The (8,15). Figure 1 illustrates the main steps and genes understanding of the intricate processes that involve sex involved in gonadal differentiation that result in male determination and differentiation has been a challenge and female characteristics. for physicians and scientists in general. One of the major proteins in mammalian gonadal DSD are characterized by incomplete or disordered differentiation is the steroidogenic nuclear receptor fac­ gonadal or genital development, leading to divergen­ tor 1 (SF1) now known as nuclear receptor subfamily 5 ces between genetic sex, gonadal sex and phenotypic group A member 1 (NR5A1 [MIM 184757]). The hu­ sex, specially in individuals with 46,XY karyotype (6,7). man SF1 protein is formed by 461 amino acids and is a These cases present female or ambiguous genitalia that member of the orphan nuclear receptor family, conside­ may vary from mild to severe hypospadias, with or wi­ red the main regulator of enzymes involved in adrenal thout penoscrotal chordee, dysgenetic testes, reduced and gonadal steroidogenesis, and is expressed in undi­ or null sperm production, and Müllerian structures that fferentiated gonads before SRY (16). The expression of may be absent or present as fully developed uterus and NR5A1 gene, which encodes SF1 protein, is necessary fallopian tubes (8). In cases of 46,XY DSD, gonadal at three stages throughout testis determination and di­ dysgenesis refers to a set of abnormalities characterized fferentiation: in the formation of bipotential gonads; by dysgenetic gonads as a result of failures in the ex­ in the Sertoli cells, to regulate the expression of anti­ pression or function of genes involved in testicular de­ ­Müllerian hormone gene (AMH); and in the Leydig velopment (4,9). Dysgenetic gonads are mainly formed cells, to regulate the expression a number of steroid by fibrous tissue without hormonal function that is not hormones (17,18). Therefore, it plays an important able to produce gametes; whereas dysgenetic testes are role in the expression of male specific genes. In female associated with abnormalities in the differentiation of development, it is also actively present and participates the Wolffian ducts, in external genitalia virilization, and in different steps of ovarian development and function in the regression of Müllerian ducts (10). (19). The wide range of action of this protein became Gonadal dysgenesis may be classified as pure (com­ evident after observations in mice, showing that the plete), partial (incomplete) or mixed dysgenesis (11). gene is expressed very early in the urogenital ridge, and Complete gonadal dysgenesis (CGD) is characterized acts later on in the development of the adrenals, gona­ by phenotypically female individuals without genital ds, pituitary, and ventromedial hypothalamus (20,21). ambiguity, and presence of dysgenetic gonads, and nor­ SF1 was first isolated in 1992 during the search for mal Müllerian derivatives. It may occur in individuals elements that regulate the proximal promoter region with normal karyotypes, 46,XX or 46,XY (12). Indivi­ of the cytochrome P450 21­hydroxylase enzyme (22). duals with XY CGD are prone to developing gonadal SF1 protein is highly expressed in steroidogenic tissues, tumors (13). Conversely, incomplete gonadal dysgene­ such as gonads, adrenals, and placenta, and regulates sis (DGI) is characterized by individuals 46,XY without almost all the enzymes related to this process (23). It mosaicism, with partial testicular differentiation, deri­ is essential not only in adrenal and gonadal develop­ vatives of Müllerian ducts and genital ambiguity. Usu­ ment and sex differentiation, but also plays important ally, seminiferous tubules are present and associated physiological roles in the central nervous system (21). with areas similar to ovarian stroma. Internal genitalia As illustrated in figure 1, after testicular determina­ consists of derivatives of both Wolffian and Müllerian tion, SF1 regulates the expression of anti­Mülllerian ducts (12). The presence of a second cell lineage pre­ hormone in Sertoli cells, which leads to regression of senting 45,X in the karyotype characterizes mixed go­ Müllerian structures during fetal development (18). In nadal dysgenesis (14). Leydig cells, SF1 activates the expression of steroidoge­ After two decades of the identification ofSRY gene nic enzymatic system, resulting in virilization of exter­ ABE&M todos os direitos reservados. os direitos ABE&M todos © as the sex­determining region on the Y chromosome nal genitalia and testicular descent (24,25). In females, Copyright responsible for initiating male development, it is well SF1 is expressed in ovarian theca cells and granulosa 608 Arq Bras Endocrinol Metab. 2011;55/8 SF1 and disorders of sex development Epididymus vas Testis ­box in the first Zn­finger of the DBD, and defines the deferens seminal Wolffian descent Insl3 duct specificity of the monomeric DNA binding (20). vesicles SF1 Steroidogenic SF1 Genital Testoterone Leydig Similar to the great majority of transcription factors, Penis DHT enzymes cells tubercle the activation of SF1 transcriptional activity requires Prostate Urogenital the interaction with other proteins through its protein sinus SF1 Müllerian Sertoli cells duct Testis AMH activation domains