NR5A1 molecular analysis in 46,XY patients with disorders of sex development

Author(s)

Helena Fabbri Scallet

• Document type: Master's Dissertation
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia
• Defense date: 2013-07-22

Examining board members

Maricilda Palandi de Mello; Andrea Trevas Maciel Guerra; Edmilson Ricardo Gonçalves

• Advisor: Maricilda Palandi de Mello

Abstract

The term Disorders of Sex Differentiation (DSD) characterize incomplete or disorganized genital or gonadal development. The DSD with 46, XY karyotype may present either ambiguous or female genitalia and also dysgenetic gonads in some cases, with presence or absence of Müllerian derivatives. The most frequent are androgen insensitivity, 5-alpha-reductase type 2 deficiency, gonadal dysgenesis and ovarian-testicular DSD. There are several genes that participate in both sex determination and differentiation processes. Mutations in NR5A1 gene, which encoding SF-1, a transcription factor, are responsible for different phenotypes of DSD. The protein SF-1, which is expressed mainly in steroidogenic tissues (gonads, adrenal glands and placenta), is also express in Sertoli and Leydig cells, in the ovaries, and is the major regulator of cholesterol metabolism in steroidogenic cells. Moreover, it regulates the activity of other genes, such as CYPs, HSD3B, StAR, SOX9, DAX1, among others. The literature describes the association of changes in NR5A1 gene with 46, XY DSD, bilateral anorchia, primary amenorrhea, premature ovarian failure, hypospadias, male infertility, and some cases of adrenal tumors and endometriosis. The present work involved the molecular analysis of NR5A1 gene in 86 patients with 46, XY DSD including complete gonadal dysgenesis (n = 7), partial gonadal dysgenesis (n = 18), idiopathic 46, XY DSD (n = 41) and others (n = 20). Twelve variations had been identified: seven in the coding region (p.Ser32Asn, p.Arg39Cis, p.Lis38*, p.Cis65Tir, p.L80Wfs*8, p.Cis247*, and p.Asp364Trefs*18), one at a splice site (c.1138+1 G>T), two in the noncoding exon 1 (c.-133G>A and c.-156_-136ins18pb), three in the 5'UTR region (c.- 413G>A, c.-208C>A and c.-762C>T) and one in the 3'UTR (c.*1286C>T). The variations herein described, have not been identified in healthy controls. In silico analysis showed possible deleterious effects for each change and its correlations to individual phenotypes. Although those results demonstrate the importance of each change for the phenotype, there in vitro functional effects must be investigated. The potentially deleterious changes were identified more frequently in cases of disorders of gonadal development (20%) and idiopathic 46, XY DSD (22%) (AU)

• FAPESP's process: 11/02865-3 - NR5A1 molecular analysis in 46,XY patients with sex development disorders
• Grantee: Helena Fabbri Scallet
• Support Opportunities: Scholarships in Brazil - Master