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BioMed Research International
Volume 2014, Article ID 787465, 8 pages
http://dx.doi.org/10.1155/2014/787465
Research Article

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

1Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM-42, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Avenida Dr. Eneas de C Aguiar 155, 2 andar Bloco 6, 05403-900 São Paulo, SP, Brazil
2Laboratório de Carboidratos e Radioimunoensaios/LIM-18, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Avenida Dr. Arnaldo 455, 01246-903 São Paulo, SP, Brazil
3Laboratorio de Imunologia Viral, Instituto Butantan, Avenida Vital Brasil 1500, 05503-900 São Paulo, SP, Brazil
4Centro de Biologia Molecular e Engenharia Genética/CBMEG, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, 13083-970 Campinas, SP, Brazil
5Departamento de Genética Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Rua Tessalia Vieira de Camargo 126, 13083-970 Campinas, SP, Brazil
6Departamento de Pediatria, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Rua Tessalia Vieira de Camargo 126, 13083-970 Campinas, SP, Brazil

Received 10 March 2014; Revised 30 May 2014; Accepted 3 June 2014; Published 26 June 2014

Academic Editor: Svetlana Lajic

Copyright © 2014 Mariza G. Santos et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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.Glu120Lys mutation 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.