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Functional analyses of new nucleotide variations in NR5A1 gene in patients 46,XY with disorders of sex development

Grant number: 13/05603-5
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): November 01, 2013
Effective date (End): July 31, 2017
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Principal researcher:Maricilda Palandi de Mello
Grantee:Helena Fabbri Scallet
Home Institution: Centro de Biologia Molecular e Engenharia Genética (CBMEG). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Associated scholarship(s):13/24333-9 - Functional analyses of novel nucleotides variations in the NR5A1 gene identified in patients 46,XY with disorders of sex development, BE.EP.DR

Abstract

Disorders of Sex Differentiation (DSD) characterize incomplete or disorganized genital or gonadal development. 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 condition in 46,XY DSD is androgen insensitivity followed by 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 encodes SF-1, a transcription factor, are responsible for different DSD phenotypes. SF-1 protein, which is expressed mainly in steroidogenic tissues (gonads, adrenal glands and placenta), is also expressed in Sertoli and Leydig cells, in ovaries, and it 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. Nucleotide variations in NR5A1 gene are associated with 46,XY DSD, bilateral anorchia, primary amenorrhea, premature ovarian failure, hypospadias, male infertility, and some cases of adrenal tumors and endometriosis.Nucleotide variations in introns and exons, and in the 5' regulatory region as well, had been identified in the NR5A1 gene in patients with 46,XY DSD. Each variation was identified only in the affected individual and was absent in 100 control individuals. For this reason, the purpose of the present project is to evaluate functional effects of these nucleotide substitutions. Through cloning and expressing NR5A1 gene, the following mutations will be analyzed: p.Cis65Tir, p.Ser32Asn, p.Cis247*, p.Arg39Cis and p.Asp364Trefs*18 (located in the coding region). The following will be investigated by EMSA assays: c.-133G>A e c.-156_-136ins18pb (described in the noncoding exon 1); c.-413G>A, c.-208C>A e c.-762C>T (5'UTR region). The intronic variation c.1138+1G>T will be studied through minigene techniques.For a long time, mutations in NR5A1 gene had been associated with adrenal insufficiency and DSD, nowadays more than 50 variations have been described in patients with only 46,XY DSD as diagnosis. Therefore, this study will analyze functional effects to elucidate their roles in each DSD phenotype. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
FABBRI-SCALLET, HELENA; DE SOUSA, LIZANDRA MAIA; MACIEL-GUERRA, ANDREA TREVAS; GUERRA-JUNIOR, GIL; DE MELLO, MARICILDA PALANDI. Mutation update for the NR5A1 gene involved in DSD and infertility. Human mutation, v. 41, n. 1, p. 58-68, JAN 2020. Web of Science Citations: 0.
FABBRI-SCALLET, HELENA; DE MELLO, MARICILDA PALANDI; GUERRA-JUNIOR, GIL; MACIEL-GUERRA, ANDREA TREVAS; RIBEIRO DE ANDRADE, JULIANA GABRIEL; COSTA DE QUEIROZ, CAMILA MAIA; MONLLEO, ISABELLA LOPES; STRUVE, DAGMAR; HIORT, OLAF; WERNER, RALF. Functional characterization of five NR5A1 gene mutations found in patients with 46,XY disorders of sex development. Human mutation, v. 39, n. 1, p. 114-123, JAN 2018. Web of Science Citations: 5.
FABBRI, HELENA C.; RIBEIRO DE ANDRADE, JULIANA G.; MACIEL-GUERRA, ANDREA T.; GUERRA-JUNIOR, GIL; DE MELLO, MARICILDA P. NR5A1 Loss-of-Function Mutations Lead to 46,XY Partial Gonadal Dysgenesis Phenotype: Report of Three Novel Mutations. SEXUAL DEVELOPMENT, v. 10, n. 4, p. 191-199, 2016. Web of Science Citations: 7.
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
SCALLET, Helena Fabbri. Functional analyses of new nucleotide variations in NR5A1 gene in patients 46,XY with disorders of sex development. 2017. 146 f. Doctoral Thesis - Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia.

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