Novel NOBOX loss-of-function mutations account for 6.2% of cases in a large primary ovarian insufficiency cohort

Authors

  • Justine Bouilly,

    1. Univ Paris-Sud, Faculté de Médecine Paris-Sud, UMR-S693, Kremlin-Bicêtre, France
    2. INSERM U693, Kremlin-Bicêtre, France
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    • These four authors contributed equally to this work.

  • Anne Bachelot,

    1. Département d'Endocrinologie et Médecine de la Reproduction, Centre de référence des Maladies Endocriniennes Rares de la Croissance, Université Pierre et Marie Curie, AP-HP, Paris, France
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    • These four authors contributed equally to this work.

  • Isabelle Broutin,

    1. Laboratoire de Cristallographie et RMN Biologiques, CNRS
    2. Univ Paris Descartes, Paris, France
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  • Philippe Touraine,

    1. Département d'Endocrinologie et Médecine de la Reproduction, Centre de référence des Maladies Endocriniennes Rares de la Croissance, Université Pierre et Marie Curie, AP-HP, Paris, France
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    • These four authors contributed equally to this work.

  • Nadine Binart

    Corresponding author
    1. Univ Paris-Sud, Faculté de Médecine Paris-Sud, UMR-S693, Kremlin-Bicêtre, France
    2. INSERM U693, Kremlin-Bicêtre, France
    • Inserm, 63 rue Gabriel Peri, Kremlin Bicêtre, 94276, France
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    • These four authors contributed equally to this work.


  • Communicated by Sergiu Ottolenghi

Abstract

Primary ovarian insufficiency (POI) is a disorder associated with female infertility, which affects approximately 1% of women under 40 years of age. A genetic component has been suggested as one possible cause of the majority of cases of nonsyndromic forms. Newborn Ovary Homeobox(NOBOX) is an ovary-specific gene, playing a critical role in ovary in mice, as its absence leads to sterility mimicking a POI. In this study, we sequenced NOBOX in a cohort of 178 women with idiopathic POI. Among 19 identified variations, we described one nonsense (c.907C>T/p.R303X) and four missense (c.271G>T/p.G91W, c.349C>T/p.R117W, c.1025G>C/p.S342T, and c.1048G>T/p.V350L) NOBOX heterozygous mutations in 12 patients. We reproduced each of the five mutations and tested their effects on the signaling activity in transfected cells. We demonstrated that these mutations compromised the ability of the proteins to bind to and transactivate the well-known growth differentiation factor 9 (GDF9) promoter. The pattern of our findings suggests that the genetic mechanism in humans responsible for POI in women involves haploinsufficiency rather than dominant negative gene action. The identification, characterization, and the very high 6.2% prevalence of these new mutations in POI patients suggest considering NOBOX as the first autosomal candidate gene involved in this syndrome. Hum Mutat 32:1108–1113, 2011. ©2011 Wiley-Liss, Inc.

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