Mutations in PADI6 Cause Female Infertility Characterized by Early Embryonic Arrest

Am J Hum Genet. 2016 Sep 1;99(3):744-752. doi: 10.1016/j.ajhg.2016.06.024.

Yao Xu ¹, Yingli Shi ², Jing Fu ², Min Yu ², Ruizhi Feng ¹, Qing Sang ¹, Bo Liang ³, Biaobang Chen ¹, Ronggui Qu ¹, Bin Li ⁴, Zheng Yan ⁴, Xiaoyan Mao ⁴, Yanping Kuang ⁴, Li Jin ⁵, Lin He ⁶, Xiaoxi Sun ⁷, Lei Wang ⁸

Affiliations

1 Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China; State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai 200438, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
2 Obstetrics and Gynecology Hospital, Fudan University, Shanghai Ji Ai Genetics and IVF Institute, Shanghai 200011, China.
3 State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
4 Reproductive Medicine Center, Shanghai Ninth Hospital, Shanghai Jiao Tong University, Shanghai 200011, China.
5 State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai 200438, China.
6 Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200030, China.
7 Obstetrics and Gynecology Hospital, Fudan University, Shanghai Ji Ai Genetics and IVF Institute, Shanghai 200011, China. Electronic address: xiaoxi_sun@aliyun.com.
8 Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China; State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai 200438, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China. Electronic address: wangleiwanglei@fudan.edu.cn.

PMID: 27545678 DOI: 10.1016/j.ajhg.2016.06.024

Abstract

Early embryonic arrest is one of the major causes of female infertility. However, because of difficulties in phenotypic evaluation, genetic determinants of human early embryonic arrest are largely unknown. With the development of assisted reproductive technology, the phenotype of early human embryonic arrest can now be carefully evaluated. Here, we describe a consanguineous family with a recessive inheritance pattern of female infertility characterized by recurrent early embryonic arrest in cycles of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). We have identified a homozygous PADI6 nonsense mutation (c.1141C>T [p.Gln381(∗)]) that is responsible for the phenotype. Mutational analysis of PADI6 in a cohort of 36 individuals whose embryos displayed developmental arrest identified two affected individuals with compound-heterozygous mutations (c.2009_2010del [p.Glu670Glyfs(∗)48] and c.633T>A [p.His211Gln]; c.1618G>A [p.Gly540Arg] and c.970C>T [p.Gln324(∗)]). Immunostaining indicated a lack of PADI6 in affected individuals' oocytes. In addition, the amount of phosphorylated RNA polymerase II and expression levels of seven genes involved in zygotic genome activation were reduced in the affected individuals' embryos. This phenotype is consistent with Padi6 knockout mice. These findings deepen our understanding of the genetic basis of human early embryonic arrest, which has been a largely ignored Mendelian phenotype. Our findings lay the foundation for uncovering other genetic causes of infertility resulting from early embryonic arrest.

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