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

Autor(es)

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

• Tipo de documento: Artigo Científico
• Fonte: Human mutation; v. 39, n. 1, p. 10-pg., 2018-01-01.

Resumo

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)

• Processo FAPESP: 09/08320-9 - Investigação de mutações nos genes ar e SRD5A2 em pacientes 46,XY recém-nascidos e pré-púberes com ambiguidade genital
• Beneficiário: Maricilda Palandi de Mello
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 13/05603-5 - Estudo funcional de novas variações nucleotídicas no gene NR5A1 em pacientes 46,XY com distúrbios da diferenciação do sexo
• Beneficiário: Helena Fabbri Scallet
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 13/24333-9 - Estudo funcional de novas variações nucleotídicas no gene NR5A1 em pacientes 46,XY com distúrbios da diferenciação do sexo
• Beneficiário: Helena Fabbri Scallet
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado