Wide spectrum of NR5A1-related phenotypes in 46,XY and 46,XX individuals

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Domenice, Sorahia ; Machado, Aline Zamboni ; Ferreira, Frederico Moraes ; Ferraz-de-Souza, Bruno ; Lerario, Antonio Marcondes ; Lin, Lin ; Nishi, Mirian Yumie ; Gomes, Nathalia Lisboa ; da Silva, Thatiana Evelin ; Silva, Rosana Barbosa ; Correa, Rafaela Vieira ; Montenegro, Luciana Ribeiro ; Narciso, Amanda ; Frade Costa, Elaine Maria ; Achermann, John C. ; Mendonca, Berenice Bilharinho

• Tipo de documento: Artigo de Revisão
• Fonte: BIRTH DEFECTS RESEARCH PART C-EMBRYO TODAY-REVIEWS; v. 108, n. 4, p. 309-320, DEC 2016.
• Citações Web of Science: 12

Resumo

Steroidogenic factor 1 (NR5A1, SF-1, Ad4BP) is a transcriptional regulator of genes involved in adrenal and gonadal development and function. Mutations in NR5A1 have been among the most frequently identified genetic causes of gonadal development disorders and are associated with a wide phenotypic spectrum. In 46,XY individuals, NR5A1-related phenotypes may range from disorders of sex development (DSD) to oligo/azoospermia, and in 46,XX individuals, from 46,XX ovotesticular and testicular DSD to primary ovarian insufficiency (POI). The most common 46,XY phenotype is atypical or female external genitalia with clitoromegaly, palpable gonads, and absence of Mullerian derivatives. Notably, an undervirilized external genitalia is frequently seen at birth, while spontaneous virilization may occur later, at puberty. In 46,XX individuals, NR5A1 mutations are a rare genetic cause of POI, manifesting as primary or secondary amenorrhea, infertility, hypoestrogenism, and elevated gonadotropin levels. Mothers and sisters of 46,XY DSD patients carrying heterozygous NR5A1 mutations may develop POI, and therefore require appropriate counseling. Moreover, the recurrent heterozygous p.Arg92Trp NR5A1 mutation is associated with variable degrees of testis development in 46,XX patients. A clear genotype-phenotype correlation is not seen in patients bearing NR5A1 mutations, suggesting that genetic modifiers, such as pathogenic variants in other testis/ovarian-determining genes, may contribute to the phenotypic expression. Here, we review the published literature on NR5A1-related disease, and discuss our findings at a single tertiary center in Brazil, including ten novel NR5A1 mutations identified in 46,XY DSD patients. The ever-expanding phenotypic range associated with NR5A1 variants in XY and XX individuals confirms its pivotal role in reproductive biology, and should alert clinicians to the possibility of NR5A1 defects in a variety of phenotypes presenting with gonadal dysfunction. Birth Defects Research (Part C) 108:309-320, 2016. (c) 2016 The Authors Birth Defects Research Part C: Embryo Today: Reviews Published by Wiley Periodicals, Inc. (AU)

• Processo FAPESP: 13/02162-8 - Patogênese molecular e caracterização de doenças monogênicas do desenvolvimento: um caminho para a medicina translacional
• Beneficiário: Berenice Bilharinho de Mendonça
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 10/51102-0 - Pesquisa de mutações nos genes BMP15 e GDF9 em mulheres portadoras de insuficiência ovariana prematura: desenvolvimento de metodologia para estudo funcional das mutações em células humanas de granulosa imorta
• Beneficiário: Mariza Augusta Gerdulo dos Santos
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 14/50137-5 - Caracterização molecular de doenças monogênicas do desenvolvimento por sequenciamento em larga escala
• Beneficiário: Berenice Bilharinho de Mendonça
• Modalidade de apoio: Auxílio à Pesquisa - Programa Equipamentos Multiusuários
• Processo FAPESP: 05/04726-0 - Caracterização molecular das doenças endócrinas congênitas que afetam o crescimento e o desenvolvimento
• Beneficiário: Ana Claudia Latronico Xavier
• Modalidade de apoio: Auxílio à Pesquisa - Temático