Dominant mutations in CHK1 cause pronuclear fusion failure and zygote arrest that can be rescued by CHK1 inhibitor

Zhang, Honghui; Chen, Tailai; Wu, Keliang; Hou, Zhenzhen; Zhao, Shigang; Zhang, Chuanxin; Gao, Yuan; Gao, Ming; Chen, Zi‐Jiang; Zhao, Han

doi:10.1038/s41422-021-00507-8

Cited by 16 publications

(28 citation statements)

References 11 publications

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“…result in substitutions of single highly conserved amino acids within specific elements of the KA1 structure, Chk1: R379Q, Chk1: R420K, and Chk1: R442Q, whilst the fourth results in a frame shift, Chk1: F441fs*, that replaces the C‐terminal 35 amino acids of the Chk1 polypeptide with 14 amino acids of unrelated sequence (Fig. 1A; [6]). Importantly, none of these Chk1 mutations was found in 300 fertile female controls, nor in public databases of known human pathogenic mutations [6].…”

Section: Germline Mutations In Chk1 Cause Human Female Infertilitymentioning

confidence: 99%

When more is less: heritable gain‐of‐function chk1 mutations impair human fertility

Gillespie

2022

The FEBS Journal

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Heritable loss‐of‐function mutations in genes encoding key regulators of DNA repair and genome stability can result in degenerative progeroid and/or cancer predisposition syndromes; however, such mutations have never been found to affect the Chk1 protein kinase, despite its central role in DNA damage signalling and checkpoint activation. Remarkably, two recent reports now demonstrate that heritable, gain‐of‐function mutations within the Chk1 C‐terminal regulatory domain can cause female infertility in humans. In vitro, oocytes from individuals heterozygous for such mutant Chk1 alleles fail to undergo the first mitotic division after fertilization owing to arrest in G2 phase of the cell cycle. This arrest results from inhibition of the master regulator of mitosis, the cyclin‐dependent kinase CDK1, through the same molecular mechanisms that are engaged by activated Chk1 to impose G2 checkpoint arrest in somatic cells bearing DNA damage. Remarkably, the failure of this first zygotic division in heterozygotes in vitro can be rescued through treatment with selective Chk1 inhibitor drugs, allowing development of apparently normal blastocysts and offering hope that a pharmacological solution to this cause of infertility may be possible.

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Section: Germline Mutations In Chk1 Cause Human Female Infertilitymentioning

confidence: 99%

When more is less: heritable gain‐of‐function chk1 mutations impair human fertility

Gillespie

2022

The FEBS Journal

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“…CHEK1 encodes a serine/threonine-protein kinase, which is required for cell cycle control. Dominant variants in CHEK1 result in G2/M transition arrest of the zygote ( Chen et al, 2021 ; Zhang et al, 2021 ). Here, we established a relationship between the two cell cycle regulators TRIP13 and CHEK1 .…”

Section: Disscusionmentioning

confidence: 99%

“…We defined this phenotype as a Mendelian disease for the first time in 2020, and identified variants in the B-cell translocation gene-4 ( BTG4 ) as a genetic cause for maternal mRNA decay and ZCF ( Zheng et al, 2020 ). In 2021, dominant variants in checkpoint kinase 1 ( CHEK1 ) were proven to cause G2/M transition failure and ZCF owing to overactivation of kinase activity ( Chen et al, 2021 ; Zhang et al, 2021 ). However, known variants in BTG4 and CHEK1 only account for 20% of the ZCF population ( Zhang et al, 2021 ), and the underlying genetic causes for other affected individuals remain largely unknown.…”

Section: Introductionmentioning

confidence: 99%

“…In 2021, dominant variants in checkpoint kinase 1 ( CHEK1 ) were proven to cause G2/M transition failure and ZCF owing to overactivation of kinase activity ( Chen et al, 2021 ; Zhang et al, 2021 ). However, known variants in BTG4 and CHEK1 only account for 20% of the ZCF population ( Zhang et al, 2021 ), and the underlying genetic causes for other affected individuals remain largely unknown.…”

Section: Introductionmentioning

confidence: 99%

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Identification of Novel Variants of Thyroid Hormone Receptor Interaction Protein 13 That Cause Female Infertility Characterized by Zygotic Cleavage Failure

Zhang

Guo

et al. 2022

Front. Physiol.

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Zygotic cleavage failure (ZCF) is a severe, early type of embryonic arrest in which zygotes cannot complete the first cleavage. Although mutations in BTG4 and CHEK1 have been identified as genetic causes of ZCF, these genes only explain a small population of ZCF cases. Thus, the underlying genetic causes for other affected individuals need to be identified. Here, we identified three TRIP13 missense variants responsible for ZCF in two patients and showed that they followed a recessive inheritance pattern. All three variants resulted in obvious changes in hydrogen bonding and consistent increase in DNA damage. Additionally, transcriptomic sequencing of oocytes and arrested embryos containing these variants suggested a greater number of differentially expressed transcripts in germinal vesicle (GV) oocytes than in 1-cell embryos. Vital genes for energy metabolism and cell cycle procession were widely and markedly downregulated, while DNA repair-related genes were significantly upregulated in both GV oocytes and 1-cell embryos of patients. These findings highlight a critical role of TRIP13 in meiosis and mitosis, as well as expand the genetic and phenotypic spectra of TR1P13 variants with respect to female infertility, especially in relation to ZCF.

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“…Nine link to early embryo arrest (TLE6(Alazami et al, 2015), NLRP2(Mu et al, 2019), NLRP5(Mu et al, 2019), PATL2(Chen et al, 2017b), TUBB8(Chen et al, 2017a), CDC20(Zhao et al, 2020), KHDC3L(Wang et al, 2018), REC114, MEI1(Dong et al, 2021) and MOS(Zhang et al, 2021b)). One has been associated with pronuclear fusion failure (CHK1(Zhang et al, 2021a)). Five have been tied to recurrent hydatidiform moles (KDHC3L(Wang et al, 2018), PADI6(Maddirevula et al, 2017b), NLRP5(Rezaei et al, 2021), NLRP7(Rezaei et al, 2021) and MEI1(Nguyen et al,…”

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confidence: 99%

Current and future therapies for abnormal early embryogenesis with assisted reproductive technology

WANG¹,

Yao²,

LIU³

et al. 2022

Biocell

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Each stage of embryonic development, including normal gamete maturation, fertilization, zygotic genome activation, and cleavage, is crucial for human reproduction. Early embryo arrest is a common phenomenon. It is estimated that about 40%-70% of human embryos are arrested at early developmental stages. However, the exact mechanism remains largely uncertain. Embryos can be investigated in vitro by way of the development of in vitro fertilization/intracytoplasmic sperm injection. In addition to iatrogenic factors related to abnormal oocyte/embryo development, multiple gene mutations have been found to be involved in such phenotypes. Based on the knowledge of known etiological factors, several therapies are proposed to improve clinical outcomes. Here, we shed light on current and potential therapies for treating these conditions through reviewing articles and combining with our clinical and research experience.

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Dominant mutations in CHK1 cause pronuclear fusion failure and zygote arrest that can be rescued by CHK1 inhibitor

Cited by 16 publications

References 11 publications

When more is less: heritable gain‐of‐function chk1 mutations impair human fertility

When more is less: heritable gain‐of‐function chk1 mutations impair human fertility

Identification of Novel Variants of Thyroid Hormone Receptor Interaction Protein 13 That Cause Female Infertility Characterized by Zygotic Cleavage Failure

Current and future therapies for abnormal early embryogenesis with assisted reproductive technology

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