2. Academic Validation
  3. KHDC3L mutation causes recurrent pregnancy loss by inducing genomic instability of human early embryonic cells

KHDC3L mutation causes recurrent pregnancy loss by inducing genomic instability of human early embryonic cells

  • PLoS Biol. 2019 Oct 14;17(10):e3000468. doi: 10.1371/journal.pbio.3000468.
Weidao Zhang 1 2 3,  Zhongliang Chen 1 2 3,  Dengfeng Zhang 4,  Bo Zhao 1,  Lu Liu 5,  Zhengyuan Xie 6,  Yonggang Yao 3 4 7,  Ping Zheng 1 2 7 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
  • 2 Yunnan Key Laboratory of Animal Reproduction, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
  • 3 Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, China.
  • 4 Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, China.
  • 5 Department of Obstetrics and Gynaecology, Yan An Hospital, Kunming Medical University, Kunming, China.
  • 6 Yunnan Key Laboratory for Fertility Regulation and Birth Health of Minority Nationalities, Key Laboratory of Preconception Health in Western China, NHFPC, Population and Family Planning Institute of Yunnan Province, Kunming, China.
  • 7 KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
  • 8 Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, China.
PMID: 31609975 DOI: 10.1371/journal.pbio.3000468
Abstract

Recurrent pregnancy loss (RPL) is an important complication in reproductive health. About 50% of RPL cases are unexplained, and understanding the genetic basis is essential for its diagnosis and prognosis. Herein, we report causal KH domain containing 3 like (KHDC3L) mutations in RPL. KHDC3L is expressed in human epiblast cells and ensures their genome stability and viability. Mechanistically, KHDC3L binds to poly(ADP-ribose) polymerase 1 (PARP1) to stimulate its activity. In response to DNA damage, KHDC3L also localizes to DNA damage sites and facilitates homologous recombination (HR)-mediated DNA repair. KHDC3L dysfunction causes PARP1 inhibition and HR repair deficiency, which is synthetically lethal. Notably, we identified two critical residues, Thr145 and Thr156, whose phosphorylation by Ataxia-telangiectasia mutated (ATM) is essential for KHDC3L's functions. Importantly, two deletions of KHDC3L (p.E150_V160del and p.E150_V172del) were detected in female RPL patients, both of which harbor a common loss of Thr156 and are impaired in PARP1 activation and HR repair. In summary, our study reveals both KHDC3L as a new RPL risk gene and its critical function in DNA damage repair pathways.

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