A pannexin 1 channelopathy causes human oocyte death

Sci Transl Med. 2019 Mar 27;11(485):eaav8731. doi: 10.1126/scitranslmed.aav8731.

Qing Sang ¹, Zhihua Zhang ², Juanzi Shi ³, Xiaoxi Sun ⁴, Bin Li ⁵, Zheng Yan ⁵, Songguo Xue ⁶, Ai Ai ⁵, Qifeng Lyu ⁵, Wei Li ⁷, Jilin Zhang ⁷, Ling Wu ⁵, Xiaoyan Mao ⁵, Biaobang Chen ², Jian Mu ², Qiaoli Li ², Jing Du ⁸, Qiang Sun ⁷, Li Jin ², Lin He ⁹, Shujia Zhu ⁷, Yanping Kuang ¹⁰, Lei Wang ¹ ¹¹

Affiliations

1 Zhongshan Hospital, State Key Laboratory of Genetic Engineering, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China. [email protected] [email protected] [email protected].
2 Zhongshan Hospital, State Key Laboratory of Genetic Engineering, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
3 Reproductive Medicine Center, Shaanxi Maternal and Child Care Service Center, Shaanxi 710069, China.
4 Shanghai Ji Ai Genetics and IVF Institute, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China.
5 Reproductive Medicine Center, Shanghai Ninth Hospital, Shanghai Jiao Tong University, Shanghai 200011, China.
6 Reproductive Medicine Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 2000120, China.
7 Institute of Neuroscience, Key Laboratory of Primate Neurobiology, CAS Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
8 Shanghai Institute of Planned Parenthood Research, Shanghai 200011, China.
9 Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200030, China.
10 Reproductive Medicine Center, Shanghai Ninth Hospital, Shanghai Jiao Tong University, Shanghai 200011, China. [email protected] [email protected] [email protected].
11 Shanghai Center for Women and Children's Health, Shanghai 200062, China.

PMID: 30918116 DOI: 10.1126/scitranslmed.aav8731

Abstract

Connexins and pannexins are two protein families that play an important role in cellular communication. Pannexin 1 (PANX1), one of the members of pannexin family, is a channel protein. It is glycosylated and forms three species, GLY0, GLY1, and GLY2. Here, we describe four independent families in which mutations in PANX1 cause familial or sporadic female infertility via a phenotype that we term "oocyte death." The mutations, which are associated with oocyte death, alter the PANX1 glycosylation pattern, influence the subcellular localization of PANX1 in cultured cells, and result in aberrant PANX1 channel activity, ATP release in oocytes, and mutant PANX1 GLY1. Overexpression of a patient-derived mutation in mice causes infertility, recapitulating the human oocyte death phenotype. Our findings demonstrate the critical role of PANX1 in human oocyte development, provide a genetic explanation for a subtype of infertility, and suggest a potential target for therapeutic intervention for this disease.

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