Biallelic Mutations in PATL2 Cause Female Infertility Characterized by Oocyte Maturation Arrest

Am J Hum Genet. 2017 Oct 5;101(4):609-615. doi: 10.1016/j.ajhg.2017.08.018.

Biaobang Chen ¹, Zhihua Zhang ², Xiaoxi Sun ³, Yanping Kuang ⁴, Xiaoyan Mao ⁴, Xueqian Wang ², Zheng Yan ⁴, Bin Li ⁴, Yao Xu ², Min Yu ³, Jing Fu ³, Jian Mu ², Zhou Zhou ², Qiaoli Li ², Li Jin ², Lin He ⁵, Qing Sang ⁶, Lei Wang ⁷

Affiliations

1 State Key Laboratory of Genetic Engineering, Zhongshan Hospital, Institutes of Biomedical Sciences, School of Life Sciences, Fudan University, Shanghai 200032, China; Guangzhou Medical University and Guangzhou Institutes of Biomedicine and Health Joint School of Life Sciences, Guangzhou Medical University, Guangzhou 511436, China.
2 State Key Laboratory of Genetic Engineering, Zhongshan Hospital, Institutes of Biomedical Sciences, School of Life Sciences, Fudan University, Shanghai 200032, China.
3 Shanghai Ji Ai Genetics and IVF Institute, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China.
4 Reproductive Medicine Center, Shanghai Ninth Hospital, Shanghai Jiao Tong University, Shanghai 200011, China.
5 Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Bio-X Center, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200030, China; Lin He's Academician Workstation of New Medicine and Clinical Translation at the Third Affiliated Hospital, Guangzhou Medical University, Guangzhou 510150, China.
6 State Key Laboratory of Genetic Engineering, Zhongshan Hospital, Institutes of Biomedical Sciences, School of Life Sciences, Fudan University, Shanghai 200032, China; Guangzhou Medical University and Guangzhou Institutes of Biomedicine and Health Joint School of Life Sciences, Guangzhou Medical University, Guangzhou 511436, China. Electronic address: sangqing@fudan.edu.cn.
7 State Key Laboratory of Genetic Engineering, Zhongshan Hospital, Institutes of Biomedical Sciences, School of Life Sciences, Fudan University, Shanghai 200032, China; Guangzhou Medical University and Guangzhou Institutes of Biomedicine and Health Joint School of Life Sciences, Guangzhou Medical University, Guangzhou 511436, China. Electronic address: wangleiwanglei@fudan.edu.cn.

PMID: 28965849 DOI: 10.1016/j.ajhg.2017.08.018

Abstract

Oocyte maturation arrest results in female infertility, but the genetic determinants of human oocyte maturation arrest remain largely unknown. Previously, we identified TUBB8 mutations responsible for human oocyte maturation arrest, indicating the important role of genetic factors in the disorder. However, TUBB8 mutations account for only around 30% of individuals with oocyte maturation arrest; thus, the disorder is likely to involve Other genetic factors that are as yet unknown. Here, we initially identified a homozygous nonsense mutation of PATL2 (c.784C>T [p.Arg262^∗]) in a consanguineous family with a phenotype characterized by human oocyte germinal vesicle (GV) arrest. Subsequent mutation screening of PATL2 in a cohort of 179 individuals identified four additional independent individuals with compound-heterozygous PATL2 mutations with slight phenotypic variability. A genetic burden test further confirmed the genetic contribution of PATL2 to human oocyte maturation arrest. By western blot in HeLa cells, identification of splicing events in affected individuals' granulosa cells, and immunostaining in affected individuals' oocytes, we provide evidence that mutations in PATL2 lead to decreased amounts of protein. These findings suggest an important role for PATL2 mutations in oocyte maturation arrest and expand our understanding of the genetic basis of female infertility.

Keywords

Mendelian disease; female infertility; mutations; oocyte maturation arrest.

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