Basonuclin 1 deficiency is a cause of primary ovarian insufficiency

Hum Mol Genet. 2018 Nov 1;27(21):3787-3800. doi: 10.1093/hmg/ddy261.

Dan Zhang ¹, Yifeng Liu ¹, Zhou Zhang ² ³, Pingping Lv ¹, Yun Liu ⁴, Jingyi Li ¹, Yiqing Wu ¹, Runjv Zhang ¹, Yun Huang ¹, Gufeng Xu ¹, Yeqing Qian ¹, Yuli Qian ¹, Songchang Chen ¹, Chenming Xu ¹, Jun Shen ⁵, Linling Zhu ¹, Kai Chen ¹, Bo Zhu ⁶, Xiaoqun Ye ¹, Yuchan Mao ¹, Xingsheng Bo ⁶, Caiyun Zhou ⁷, Tingting Wang ¹ ⁸, Dianfu Chen ⁹, Weijun Yang ⁹, Yajing Tan ¹, Yang Song ¹, Daizhan Zhou ⁴, Jianzhong Sheng ¹ ¹⁰, Huijuan Gao ¹, Yimin Zhu ¹, Meigen Li ¹, Liping Wu ¹, Lin He ¹ ² ⁴, Hefeng Huang ¹ ¹¹

Affiliations

1 Key Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Zhejiang, China.
2 Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, China.
3 Institute of Biliary Tract Disease, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
4 Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
5 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
6 Department of Clinical Laboratory, Women's Hospital, Zhejiang University School of Medicine, Zhejiang, China.
7 Department of Pathology, Women's Hospital, Zhejiang University School of Medicine, Zhejiang, China.
8 Vancouver Prostate Center, Department of Urologic Sciences, University of British Columbia, Vancouver, BC Canada V6T, Canada.
9 Key Laboratory of Conservation Biology for Endangered Wildlife of the Ministry of Education and College of Life Sciences, Zhejiang University, Zhejiang, China.
10 Department of Pathology & Pathophysiology, Zhejiang University School of Medicine, Zhejiang, China.
11 International Peace Maternal and Child Health Hospital, Shanghai Jiao Tong University, Shanghai, China.

PMID: 30010909 DOI: 10.1093/hmg/ddy261

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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