Functional characterization of five NR5A1 gene mutations found in patients with 46,XY disorders of sex development

Author(s)

Fabbri-Scallet, Helena ^[1] ; de Mello, Maricilda Palandi ^[1] ; Guerra-Junior, Gil ^{[2, 3]} ; Maciel-Guerra, Andrea Trevas ^{[3, 4]} ; Ribeiro de Andrade, Juliana Gabriel ^{[3, 4]} ; Costa de Queiroz, Camila Maia ^[5] ; Monlleo, Isabella Lopes ^[5] ; Struve, Dagmar ^[6] ; Hiort, Olaf ^[6] ; Werner, Ralf ^[6]

Affiliation

^[1] Univ Estadual Campinas, Ctr Mol Biol & Genet Engn CBMEG, Sao Paulo - Brazil

^[2] Univ Estadual Campinas, Dept Pediat, Fac Med Sci, Sao Paulo - Brazil

^[3] Univ Estadual Campinas, Interdisciplinary Grp Study Sex Determinat & Diff, Sao Paulo - Brazil

^[4] Univ Estadual Campinas, Dept Med Genet, Fac Med Sci, Sao Paulo - Brazil

^[5] Univ Fed Alagoas, Clin Genet Serv, Fac Med, Maceio, Alagoas - Brazil

^[6] Univ Lubeck, Dept Paediat & Adolescent Med, Div Paediat Endocrinol & Diabet, Ctr Brain Behav & Metab, Lubeck - Germany

• Document type: Journal article
• Source: Human mutation; v. 39, n. 1, p. 114-123, JAN 2018.
• Web of Science Citations: 5

Abstract

Steroidogenic factor-1 (SF1), encoded by the NR5A1 gene, is a key regulator of steroidogenesis and reproductive development. NR5A1 mutations described in 46,XY patients with disorders of sex development (DSD) can be associated with a range of conditions of phenotypes; however, the genotype-phenotype correlation remains elusive in many cases. In the present study, we describe the impact of five NR5A1 variants (three novel: p.Arg39Cys, p.Ser32Asn, and p.Lys396Argfs{*}34; and two previously described: p.Cys65Tyr and p.Cys247{*}) on protein function, identified in seven patients with 46,XY DSD. In vitro functional analyses demonstrate that NR5A1 mutations impair protein functions and result in the DSD phenotype observed in our patients. Missense mutations in the DNA binding domain and the frameshift mutation p.Lys396Argfs{*}34 lead to both, markedly affected transactivation assays, and loss of DNA binding, whereas the mutation p.Cys247{*} retained partial transactivation capacity and the ability to bind a consensus SF1 responsive element. SF1 acts in a dose-dependent manner and regulates a cascade of genes involved in the sex determination and steroidogenesis, but in most cases reported so far, still lead to a sufficient adrenal steroidogenesis and function, just like in our cases, in which heterozygous mutations are associated to 46,XY DSD with intact adrenal steroid biosynthesis. (AU)

• FAPESP's process: 13/05603-5 - Functional analyses of new nucleotide variations in NR5A1 gene in patients 46,XY with disorders of sex development
• Grantee: Helena Fabbri Scallet
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 13/24333-9 - Functional analyses of novel nucleotides variations in the NR5A1 gene identified in patients 46,XY with disorders of sex development
• Grantee: Helena Fabbri Scallet
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 09/08320-9 - Serching for mutations on ar and SRD5A2 genes in 46,XY newborn and pre-pubarche patients with genital ambiguity
• Grantee: Maricilda Palandi de Mello
• Support Opportunities: Regular Research Grants