Homozygous Inactivating Mutation in NANOS3 in Two Sisters with Primary Ovarian Insufficiency

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Santos, Mariza G. ; Machado, Aline Z. ; Martins, Conceicao N. ; Domenice, Sorahia ; Costa, Elaine M. F. ; Nishi, Mirian Y. ; Ferraz-de-Souza, Bruno ; Jorge, Soraia A. C. ; Pereira, Carlos A. ; Soardi, Fernanda C. ; de Mello, Maricilda P. ; Maciel-Guerra, Andrea T. ; Guerra-Junior, Gil ; Mendonca, Berenice B.

• Tipo de documento: Artigo Científico
• Fonte: BIOMED RESEARCH INTERNATIONAL; v. 2014, p. 8-pg., 2014-01-01.

Resumo

Despite the increasing understanding of female reproduction, the molecular diagnosis of primary ovarian insufficiency (POI) is seldom obtained. The RNA-binding protein NANOS3 poses as an interesting candidate gene for POI since members of the Nanos family have an evolutionarily conserved function in germ cell development and maintenance by repressing apoptosis. We performed mutational analysis of NANOS3 in a cohort of 85 Brazilian women with familial or isolated POI, presenting with primary or secondary amenorrhea, and in ethnically-matched control women. A homozygous p.Glu120Lysmutation in NANOS3 was identified in two sisters with primary amenorrhea. The substituted amino acid is located within the second C2HC motif in the conserved zinc finger domain of NANOS3 and in silico molecular modelling suggests destabilization of protein-RNA interaction. In vitro analyses of apoptosis through flow cytometry and confocal microscopy show that NANOS3 capacity to prevent apoptosis was impaired by this mutation. The identification of an inactivating missense mutation in NANOS3 suggests a mechanism for POI involving increased primordial germ cells (PGCs) apoptosis during embryonic cell migration and highlights the importance of NANOS proteins in human ovarian biology. (AU)

• 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: 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