Basonuclin 1 deficiency is a cause of primary ovarian insufficiency

Human Molecular Genetics
Dan ZhangHefeng Huang

Abstract

Primary ovarian insufficiency (POI) leads to infertility and premature menopause in young women. The genetic etiology of this disorder remains unknown in most patients. Using whole exome sequencing of a large Chinese POI pedigree, we identified a heterozygous 5 bp deletion inducing a frameshift in BNC1, which is predicted to result in a non-sense-mediated decay or a truncated BNC1 protein. Sanger sequencing identified another BNC1 missense mutation in 4 of 82 idiopathic patients with POI, and the mutation was absent in 332 healthy controls. Transfection of recombinant plasmids with the frameshift mutant and separately with the missense mutant in HEK293T cells led to abnormal nuclear localization. Knockdown of BNC1 was found to reduce BMP15 and p-AKT levels and to inhibit meiosis in oocytes. A female mouse model of the human Bnc1 frameshift mutation exhibited infertility, significantly increased serum follicle-stimulating hormone, decreased ovary size and reduced follicle numbers, consistent with POI. We report haploinsufficiency of BNC1 as an etiology of human autosomal dominant POI.

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Citations

Nov 6, 2018·Biomedicines·Ihor AtabiekovAyman Al-Hendy
Feb 8, 2019·Journal of Medical Genetics·Alexander GheldofWillem Verpoest
Jul 28, 2020·Human Molecular Genetics·Qing ChenXiaojun Chen
Aug 1, 2019·Molecular Genetics and Genomics : MGG·Abdelkader HeddarMicheline Misrahi
Feb 27, 2020·Journal of the Endocrine Society·Monica Malheiros França, Berenice Bilharinho Mendonca
Mar 1, 2021·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Akimasa TakahashiIIana Chefetz
Jul 15, 2021·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Yiyang WangYingying Qin
Dec 21, 2021·Frontiers in Genetics·Abdessamad OuhrouchBadr Benjelloun

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