A common African variant of human connexin 37 is associated with Caucasian primary ovarian insufficiency and has a deleterious effect in vitro

Bachelot,Anne; Gilleron,Jerome; Meduri,Geri; Guberto,Mihelai; Dulon,Jerome; Boucherie,Sylviane; Touraine,Philippe; Misrahi,Micheline

doi:10.3892/ijmm.2017.3257

A common African variant of human connexin 37 is associated with Caucasian primary ovarian insufficiency and has a deleterious effect in vitro

Authors:
- Anne Bachelot
- Jerome Gilleron
- Geri Meduri
- Mihelai Guberto
- Jerome Dulon
- Sylviane Boucherie
- Philippe Touraine
- Micheline Misrahi
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Affiliations: AP-HP, Department of Endocrinology and Reproductive Medicine, Pitié-Salpêtrière Hospital, Reference Center for Rare Endocrine Diseases of Growth, Reference Center for Rare Gynecological Pathologies, F-75013 Paris, France, National Institute of Health and Medical Research INSERM U1065 - University of Nice-Sophia Antipolis, Mediterranean Center for Molecular Medicine C3M, F-06000 Nice, France, National Institute of Health and Medical Research INSERM U1195, F-94275 Le Kremlin Bicêtre, France, University Paris-Sud, University Paris Saclay, Medical Faculty Paris-Sud, Bicêtre Hospital, F-94275 Le Kremlin Bicêtre, France, National Institute of Health and Medical Research UMR-S 757 INSERM, University Paris-Sud, F-91400 Orsay, France
Published online on: November 16, 2017 https://doi.org/10.3892/ijmm.2017.3257
Pages: 640-648
Copyright: © Bachelot et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Folliculogenesis requires communication between granulosa cells and oocytes, mediated by connexin-based gap junctions. Connexin 37 (Cx37)-deficient female mice are infertile. The present study assessed Cx37 deficiency in patients with primary ovarian insufficiency (POI). A candidate gene study was performed in patients and controls from the National Genotyping Center (Evry, France) including 58 Caucasian patients with idiopathic isolated POI and 142 Caucasian controls. Direct genomic sequencing of the coding regions of the GJA4 gene (encoding Cx37) was performed with the aim to identify a deleterious variant associated with POI and absent in ethnically matched controls. A single Cx37 variant absent in the control population was identified, namely a c.946G>A heterozygous substitution leading to a p.Gly316Ser variant that was present in two POI patients. This variant was absent in all Caucasian controls from various databases, and has been observed exclusively in African populations. This variant was identified to have a dominant negative effect in HeLa cells in vitro to alter connexon function (by 67.2±7.17%), as determined by Gap-fluorescence recovery after photobleaching. The alteration principally resulted from a decrease of cell surface connexons due to altered trafficking (by 47.73±8.59%). In marked contrast to this observation, a p.Pro258Ser variant frequent in all ethnic populations in databases had no functional effect in vitro. In conclusion, the present study reported on a Cx37 variant in two Caucasian POI patients, which was absent in control Caucasian populations, and which had a deleterious effect in vitro. It is therefore suggested that in the genetic context of the Caucasian population, this variant may contribute to POI.

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