title: Mutations in PADI6 Cause Female Infertility Characterized by Early Embryonic Arrest.
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.
authors.affiliation: 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.
authors.forename: Yao
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Obstetrics and Gynecology Hospital, Fudan University, Shanghai Ji Ai Genetics and IVF Institute, Shanghai 200011, China.
authors.forename: Yingli
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Obstetrics and Gynecology Hospital, Fudan University, Shanghai Ji Ai Genetics and IVF Institute, Shanghai 200011, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Fu
authors.affiliation: Obstetrics and Gynecology Hospital, Fudan University, Shanghai Ji Ai Genetics and IVF Institute, Shanghai 200011, China.
authors.forename: Min
authors.initials: M
authors.lastname: Yu
authors.affiliation: 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.
authors.forename: Ruizhi
authors.initials: R
authors.lastname: Feng
authors.affiliation: 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.
authors.forename: Qing
authors.initials: Q
authors.lastname: Sang
authors.affiliation: 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.
authors.forename: Bo
authors.initials: B
authors.lastname: Liang
authors.affiliation: 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.
authors.forename: Biaobang
authors.initials: B
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Ronggui
authors.initials: R
authors.lastname: Qu
authors.affiliation: Reproductive Medicine Center, Shanghai Ninth Hospital, Shanghai Jiao Tong University, Shanghai 200011, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: Reproductive Medicine Center, Shanghai Ninth Hospital, Shanghai Jiao Tong University, Shanghai 200011, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yan
authors.affiliation: Reproductive Medicine Center, Shanghai Ninth Hospital, Shanghai Jiao Tong University, Shanghai 200011, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Mao
authors.affiliation: Reproductive Medicine Center, Shanghai Ninth Hospital, Shanghai Jiao Tong University, Shanghai 200011, China.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Kuang
authors.affiliation: State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai 200438, China.
authors.forename: Li
authors.initials: L
authors.lastname: Jin
authors.affiliation: 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.
authors.forename: Lin
authors.initials: L
authors.lastname: He
authors.affiliation: Obstetrics and Gynecology Hospital, Fudan University, Shanghai Ji Ai Genetics and IVF Institute, Shanghai 200011, China. Electronic address: xiaoxi_sun@aliyun.com.
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Sun
authors.affiliation: 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.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
mesh_terms: D000328:Adult; D000818:Animals; D018389:Codon, Nonsense / Q000235:genetics; D003241:Consanguinity; D020964:Embryo Loss / Q000235:genetics* / Q000473:pathology; D005260:Female; D005307:Fertilization in Vitro; D006720:Homozygote; D006801:Humans; D006867:Hydrolases / Q000172:deficiency / Q000235:genetics*; D007247:Infertility, Female / Q000150:complications* / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009865:Oocytes / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D000080065:Protein-Arginine Deiminase Type 6; D000076342:Protein-Arginine Deiminases; D012319:RNA Polymerase II / Q000737:chemistry / Q000378:metabolism; D020554:Sperm Injections, Intracytoplasmic; D017211:Treatment Failure
chemical_list: D018389:Codon, Nonsense; D006867:Hydrolases; D000080065:Protein-Arginine Deiminase Type 6; D000076342:Protein-Arginine Deiminases; D012319:RNA Polymerase II; C523190:PADI6 protein, mouse; C488263:PADI6 protein, human