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Novel NOBOX loss‐of‐function mutations account for 6.2% of cases in a large primary ovarian insufficiency cohort
Author(s) -
Bouilly Justine,
Bachelot Anne,
Broutin Isabelle,
Touraine Philippe,
Binart Nadine
Publication year - 2011
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21543
Subject(s) - biology , haploinsufficiency , genetics , missense mutation , mutation , gene , nonsense mutation , human genetics , phenotype
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.