The Experts below are selected from a list of 16410 Experts worldwide ranked by ideXlab platform
Biaobang Chen - One of the best experts on this subject based on the ideXlab platform.
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homozygous variants in panx1 cause human oocyte death and Female Infertility
2021Co-Authors: Weijie Wang, Biaobang Chen, Zhihua Zhang, Wenjing Wang, Zhou Zhou, Qian Dou, Lin Zhao, Jie Dong, Yang Zeng, Ruyi LiuAbstract:PANX1, one of the members of the pannexin family, is a highly glycosylated channel-forming protein. Recently, we identified heterozygous variants in PANX1 that follow an autosomal dominant inheritance pattern and cause Female Infertility characterized by oocyte death. In this study, we screened for novel PANX1 variants in patients with the phenotype of oocyte death and discovered a new type of inheritance pattern accompanying PANX1 variants. We identified two novel homozygous missense variants in PANX1 [NM_015368.4 c.712T>C (p.(Ser238Pro) and c.899G>A (p.(Arg300Gln))] associated with the oocyte death phenotype in two families. Both of the homozygous variants altered the PANX1 glycosylation pattern in cultured cells, led to aberrant PANX1 channel activation, and resulted in mouse oocyte death after fertilization in vitro. It is worth noting that the destructive effect of the two homozygous variants on PANX1 function was weaker than that caused by the recently reported heterozygous variants. Our findings enrich the variational spectrum of PANX1 and expand the inheritance pattern of PANX1 variants to an autosomal recessive mode. This highlights the critical role of PANX1 in human oocyte development and helps us to better understand the genetic basis of Female Infertility due to oocyte death.
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bi allelic missense pathogenic variants in trip13 cause Female Infertility characterized by oocyte maturation arrest
2020Co-Authors: Zhihua Zhang, Biaobang Chen, Wenjing Wang, Zhou Zhou, Zheng Yan, Lin Zhao, Jie Dong, Feiyang Diao, Shuai Liu, Xiaozhen LiangAbstract:Normal oocyte meiosis is a prerequisite for successful human reproduction, and abnormalities in the process will result in Infertility. In 2016, we identified mutations in TUBB8 as responsible for human oocyte meiotic arrest. However, the underlying genetic factors for most affected individuals remain unknown. TRIP13, encoding an AAA-ATPase, is a key component of the spindle assembly checkpoint, and recurrent homozygous nonsense variants and a splicing variant in TRIP13 are reported to cause Wilms tumors in children. In this study, we identified homozygous and compound heterozygous missense pathogenic variants in TRIP13 responsible for Female Infertility mainly characterized by oocyte meiotic arrest in five individuals from four independent families. Individuals from three families suffered from oocyte maturation arrest, whereas the individual from the fourth family had abnormal zygote cleavage. All displayed only the Infertility phenotype without Wilms tumors or any other abnormalities. In vitro and in vivo studies showed that the identified variants reduced the protein abundance of TRIP13 and caused its downstream molecule, HORMAD2, to accumulate in HeLa cells and in proband-derived lymphoblastoid cells. The chromosome mis-segregation assay showed that variants did not have any effects on mitosis. Injecting TRIP13 cRNA into oocytes from one affected individual was able to rescue the phenotype, which has implications for future therapeutic treatments. This study reports pathogenic variants in TRIP13 responsible for oocyte meiotic arrest, and it highlights the pivotal but different roles of TRIP13 in meiosis and mitosis. These findings also indicate that different dosage effects of mutant TRIP13 might result in two distinct human diseases.
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identification novel mutations in tubb8 in Female Infertility and a novel phenotype of large polar body in oocytes with tubb8 mutations
2020Co-Authors: Lin Zhao, Biaobang Chen, Zhihua Zhang, Wenjing Wang, Zhou Zhou, Zheng Yan, Juanzi Shi, Yichun Guan, Rong Shi, Jie DongAbstract:We aimed to identify novel variants in TUBB8 and corresponding new abnormal phenotypes in oocytes/fertilization/ embryonic development responsible for Female Infertility. Sanger sequencing of TUBB8 was performed in infertile women with abnormalities in oocyte maturation or embryonic development. The effects of the variants were evaluated in patients’ oocytes by morphological observations and immunofluorescence. We identified 34 novel variants of TUBB8 in 51 patients who were diagnosed with abnormalities in oocyte maturation or early embryonic development. We found a novel phenotype in which large polar bodies were present in three independent patients possibly associated with a recurrent variant. Moreover, we identified a novel type of TUBB8 variant consisting of an in-frame deletion-insertion, which has not been previously reported. Our present study identified 34 novel variants in TUBB8 in 51 patients. These patients show oocyte maturation arrest, oocytes with large polar body, fertilization failure, early embryonic arrest or embryonic implantation failure. These results expand the kinds of variants and phenotypic spectrum of TUBB8 variants with regard to Female Infertility.
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homozygous mutations in rec114 cause Female Infertility characterised by multiple pronuclei formation and early embryonic arrest
2020Co-Authors: Wenjing Wang, Biaobang Chen, Zhihua Zhang, Zhou Zhou, Xiaoxi Sun, Yanping Kuang, Jie Dong, Zhao LinAbstract:Background Abnormal pronuclear formation during fertilisation and subsequent early embryonic arrest results in Female Infertility. In recent years, with the prevalence of assisted reproductive technology, a few genes have been identified that are involved in Female Infertility caused by abnormalities in oocyte development, fertilisation and embryonic development. However, the genetic factors responsible for multiple pronuclei formation during fertilisation and early embryonic arrest remain largely unknown. Objective We aim to identify genetic factors responsible for multiple pronuclei formation during fertilisation or early embryonic arrest. Methods Whole-exome sequencing was performed in a cohort of 580 patients with abnormal fertilisation and early embryonic arrest. Effects of mutations were investigated in HEK293T cells by western blotting and immunoprecipitation, as well as minigene assay. Results We identified a novel homozygous missense mutation (c.397T>G, p.C133G) and a novel homozygous donor splice-site mutation (c.546+5G>A) in the meiotic gene REC114. REC114 is involved in the formation of double strand breaks (DSBs), which initiate homologous chromosome recombination. We demonstrated that the splice-site mutation affected the normal alternative splicing of REC114, while the missense mutation reduced the protein level of REC114 in vitro and resulted in the loss of its function to protect its partner protein MEI4 from degradation. Conclusions Our study has identified mutations in REC114 responsible for human multiple pronuclei formation and early embryonic arrest, and these findings expand our knowledge of genetic factors that are responsible for normal human Female meiosis and fertility.
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mutations in nlrp2 and nlrp5 cause Female Infertility characterised by early embryonic arrest
2019Co-Authors: Wenjing Wang, Biaobang Chen, Zhihua Zhang, Xiaoxi Sun, Yanping Kuang, Xiaoyan Mao, Qing Sang, Li Jin, Lei WangAbstract:Background Successful human reproduction requires normal spermatogenesis, oogenesis, fertilisation and early embryonic development, and abnormalities in any of these processes will result in Infertility. Early embryonic arrest is commonly observed in infertile patients with recurrent failure of assisted reproductive technology (ART). However, the genetic basis for early embryonic arrest is largely unknown. Objective We aim to identify genetic causes of infertile patients characterised by early embryonic arrest. Methods We pursued exome sequencing in a proband with embryonic arrest from the consanguineous family. We further screened candidate genes in a cohort of 496 individuals diagnosed with early embryonic arrest by Sanger sequencing. Effects of mutations were investigated in HeLa cells, oocytes and embryos. Results We identified five independent individuals carrying biallelic mutations in NLRP2. We also found three individuals from two families carrying biallelic mutations in NLRP5. These mutations in NLRP2 and NLRP5 caused decreased protein expression in vitro and in oocytes and embryos. Conclusions NLRP2 and NLRP5 are novel mutant genes responsible for human early embryonic arrest. This finding provides additional potential diagnostic markers for patients with recurrent failure of ART and helps us to better understand the genetic basis of Female Infertility characterised by early embryonic arrest.
Zhihua Zhang - One of the best experts on this subject based on the ideXlab platform.
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homozygous variants in panx1 cause human oocyte death and Female Infertility
2021Co-Authors: Weijie Wang, Biaobang Chen, Zhihua Zhang, Wenjing Wang, Zhou Zhou, Qian Dou, Lin Zhao, Jie Dong, Yang Zeng, Ruyi LiuAbstract:PANX1, one of the members of the pannexin family, is a highly glycosylated channel-forming protein. Recently, we identified heterozygous variants in PANX1 that follow an autosomal dominant inheritance pattern and cause Female Infertility characterized by oocyte death. In this study, we screened for novel PANX1 variants in patients with the phenotype of oocyte death and discovered a new type of inheritance pattern accompanying PANX1 variants. We identified two novel homozygous missense variants in PANX1 [NM_015368.4 c.712T>C (p.(Ser238Pro) and c.899G>A (p.(Arg300Gln))] associated with the oocyte death phenotype in two families. Both of the homozygous variants altered the PANX1 glycosylation pattern in cultured cells, led to aberrant PANX1 channel activation, and resulted in mouse oocyte death after fertilization in vitro. It is worth noting that the destructive effect of the two homozygous variants on PANX1 function was weaker than that caused by the recently reported heterozygous variants. Our findings enrich the variational spectrum of PANX1 and expand the inheritance pattern of PANX1 variants to an autosomal recessive mode. This highlights the critical role of PANX1 in human oocyte development and helps us to better understand the genetic basis of Female Infertility due to oocyte death.
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bi allelic missense pathogenic variants in trip13 cause Female Infertility characterized by oocyte maturation arrest
2020Co-Authors: Zhihua Zhang, Biaobang Chen, Wenjing Wang, Zhou Zhou, Zheng Yan, Lin Zhao, Jie Dong, Feiyang Diao, Shuai Liu, Xiaozhen LiangAbstract:Normal oocyte meiosis is a prerequisite for successful human reproduction, and abnormalities in the process will result in Infertility. In 2016, we identified mutations in TUBB8 as responsible for human oocyte meiotic arrest. However, the underlying genetic factors for most affected individuals remain unknown. TRIP13, encoding an AAA-ATPase, is a key component of the spindle assembly checkpoint, and recurrent homozygous nonsense variants and a splicing variant in TRIP13 are reported to cause Wilms tumors in children. In this study, we identified homozygous and compound heterozygous missense pathogenic variants in TRIP13 responsible for Female Infertility mainly characterized by oocyte meiotic arrest in five individuals from four independent families. Individuals from three families suffered from oocyte maturation arrest, whereas the individual from the fourth family had abnormal zygote cleavage. All displayed only the Infertility phenotype without Wilms tumors or any other abnormalities. In vitro and in vivo studies showed that the identified variants reduced the protein abundance of TRIP13 and caused its downstream molecule, HORMAD2, to accumulate in HeLa cells and in proband-derived lymphoblastoid cells. The chromosome mis-segregation assay showed that variants did not have any effects on mitosis. Injecting TRIP13 cRNA into oocytes from one affected individual was able to rescue the phenotype, which has implications for future therapeutic treatments. This study reports pathogenic variants in TRIP13 responsible for oocyte meiotic arrest, and it highlights the pivotal but different roles of TRIP13 in meiosis and mitosis. These findings also indicate that different dosage effects of mutant TRIP13 might result in two distinct human diseases.
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identification novel mutations in tubb8 in Female Infertility and a novel phenotype of large polar body in oocytes with tubb8 mutations
2020Co-Authors: Lin Zhao, Biaobang Chen, Zhihua Zhang, Wenjing Wang, Zhou Zhou, Zheng Yan, Juanzi Shi, Yichun Guan, Rong Shi, Jie DongAbstract:We aimed to identify novel variants in TUBB8 and corresponding new abnormal phenotypes in oocytes/fertilization/ embryonic development responsible for Female Infertility. Sanger sequencing of TUBB8 was performed in infertile women with abnormalities in oocyte maturation or embryonic development. The effects of the variants were evaluated in patients’ oocytes by morphological observations and immunofluorescence. We identified 34 novel variants of TUBB8 in 51 patients who were diagnosed with abnormalities in oocyte maturation or early embryonic development. We found a novel phenotype in which large polar bodies were present in three independent patients possibly associated with a recurrent variant. Moreover, we identified a novel type of TUBB8 variant consisting of an in-frame deletion-insertion, which has not been previously reported. Our present study identified 34 novel variants in TUBB8 in 51 patients. These patients show oocyte maturation arrest, oocytes with large polar body, fertilization failure, early embryonic arrest or embryonic implantation failure. These results expand the kinds of variants and phenotypic spectrum of TUBB8 variants with regard to Female Infertility.
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homozygous mutations in rec114 cause Female Infertility characterised by multiple pronuclei formation and early embryonic arrest
2020Co-Authors: Wenjing Wang, Biaobang Chen, Zhihua Zhang, Zhou Zhou, Xiaoxi Sun, Yanping Kuang, Jie Dong, Zhao LinAbstract:Background Abnormal pronuclear formation during fertilisation and subsequent early embryonic arrest results in Female Infertility. In recent years, with the prevalence of assisted reproductive technology, a few genes have been identified that are involved in Female Infertility caused by abnormalities in oocyte development, fertilisation and embryonic development. However, the genetic factors responsible for multiple pronuclei formation during fertilisation and early embryonic arrest remain largely unknown. Objective We aim to identify genetic factors responsible for multiple pronuclei formation during fertilisation or early embryonic arrest. Methods Whole-exome sequencing was performed in a cohort of 580 patients with abnormal fertilisation and early embryonic arrest. Effects of mutations were investigated in HEK293T cells by western blotting and immunoprecipitation, as well as minigene assay. Results We identified a novel homozygous missense mutation (c.397T>G, p.C133G) and a novel homozygous donor splice-site mutation (c.546+5G>A) in the meiotic gene REC114. REC114 is involved in the formation of double strand breaks (DSBs), which initiate homologous chromosome recombination. We demonstrated that the splice-site mutation affected the normal alternative splicing of REC114, while the missense mutation reduced the protein level of REC114 in vitro and resulted in the loss of its function to protect its partner protein MEI4 from degradation. Conclusions Our study has identified mutations in REC114 responsible for human multiple pronuclei formation and early embryonic arrest, and these findings expand our knowledge of genetic factors that are responsible for normal human Female meiosis and fertility.
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mutations in nlrp2 and nlrp5 cause Female Infertility characterised by early embryonic arrest
2019Co-Authors: Wenjing Wang, Biaobang Chen, Zhihua Zhang, Xiaoxi Sun, Yanping Kuang, Xiaoyan Mao, Qing Sang, Li Jin, Lei WangAbstract:Background Successful human reproduction requires normal spermatogenesis, oogenesis, fertilisation and early embryonic development, and abnormalities in any of these processes will result in Infertility. Early embryonic arrest is commonly observed in infertile patients with recurrent failure of assisted reproductive technology (ART). However, the genetic basis for early embryonic arrest is largely unknown. Objective We aim to identify genetic causes of infertile patients characterised by early embryonic arrest. Methods We pursued exome sequencing in a proband with embryonic arrest from the consanguineous family. We further screened candidate genes in a cohort of 496 individuals diagnosed with early embryonic arrest by Sanger sequencing. Effects of mutations were investigated in HeLa cells, oocytes and embryos. Results We identified five independent individuals carrying biallelic mutations in NLRP2. We also found three individuals from two families carrying biallelic mutations in NLRP5. These mutations in NLRP2 and NLRP5 caused decreased protein expression in vitro and in oocytes and embryos. Conclusions NLRP2 and NLRP5 are novel mutant genes responsible for human early embryonic arrest. This finding provides additional potential diagnostic markers for patients with recurrent failure of ART and helps us to better understand the genetic basis of Female Infertility characterised by early embryonic arrest.
Wenjing Wang - One of the best experts on this subject based on the ideXlab platform.
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homozygous variants in panx1 cause human oocyte death and Female Infertility
2021Co-Authors: Weijie Wang, Biaobang Chen, Zhihua Zhang, Wenjing Wang, Zhou Zhou, Qian Dou, Lin Zhao, Jie Dong, Yang Zeng, Ruyi LiuAbstract:PANX1, one of the members of the pannexin family, is a highly glycosylated channel-forming protein. Recently, we identified heterozygous variants in PANX1 that follow an autosomal dominant inheritance pattern and cause Female Infertility characterized by oocyte death. In this study, we screened for novel PANX1 variants in patients with the phenotype of oocyte death and discovered a new type of inheritance pattern accompanying PANX1 variants. We identified two novel homozygous missense variants in PANX1 [NM_015368.4 c.712T>C (p.(Ser238Pro) and c.899G>A (p.(Arg300Gln))] associated with the oocyte death phenotype in two families. Both of the homozygous variants altered the PANX1 glycosylation pattern in cultured cells, led to aberrant PANX1 channel activation, and resulted in mouse oocyte death after fertilization in vitro. It is worth noting that the destructive effect of the two homozygous variants on PANX1 function was weaker than that caused by the recently reported heterozygous variants. Our findings enrich the variational spectrum of PANX1 and expand the inheritance pattern of PANX1 variants to an autosomal recessive mode. This highlights the critical role of PANX1 in human oocyte development and helps us to better understand the genetic basis of Female Infertility due to oocyte death.
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bi allelic missense pathogenic variants in trip13 cause Female Infertility characterized by oocyte maturation arrest
2020Co-Authors: Zhihua Zhang, Biaobang Chen, Wenjing Wang, Zhou Zhou, Zheng Yan, Lin Zhao, Jie Dong, Feiyang Diao, Shuai Liu, Xiaozhen LiangAbstract:Normal oocyte meiosis is a prerequisite for successful human reproduction, and abnormalities in the process will result in Infertility. In 2016, we identified mutations in TUBB8 as responsible for human oocyte meiotic arrest. However, the underlying genetic factors for most affected individuals remain unknown. TRIP13, encoding an AAA-ATPase, is a key component of the spindle assembly checkpoint, and recurrent homozygous nonsense variants and a splicing variant in TRIP13 are reported to cause Wilms tumors in children. In this study, we identified homozygous and compound heterozygous missense pathogenic variants in TRIP13 responsible for Female Infertility mainly characterized by oocyte meiotic arrest in five individuals from four independent families. Individuals from three families suffered from oocyte maturation arrest, whereas the individual from the fourth family had abnormal zygote cleavage. All displayed only the Infertility phenotype without Wilms tumors or any other abnormalities. In vitro and in vivo studies showed that the identified variants reduced the protein abundance of TRIP13 and caused its downstream molecule, HORMAD2, to accumulate in HeLa cells and in proband-derived lymphoblastoid cells. The chromosome mis-segregation assay showed that variants did not have any effects on mitosis. Injecting TRIP13 cRNA into oocytes from one affected individual was able to rescue the phenotype, which has implications for future therapeutic treatments. This study reports pathogenic variants in TRIP13 responsible for oocyte meiotic arrest, and it highlights the pivotal but different roles of TRIP13 in meiosis and mitosis. These findings also indicate that different dosage effects of mutant TRIP13 might result in two distinct human diseases.
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identification novel mutations in tubb8 in Female Infertility and a novel phenotype of large polar body in oocytes with tubb8 mutations
2020Co-Authors: Lin Zhao, Biaobang Chen, Zhihua Zhang, Wenjing Wang, Zhou Zhou, Zheng Yan, Juanzi Shi, Yichun Guan, Rong Shi, Jie DongAbstract:We aimed to identify novel variants in TUBB8 and corresponding new abnormal phenotypes in oocytes/fertilization/ embryonic development responsible for Female Infertility. Sanger sequencing of TUBB8 was performed in infertile women with abnormalities in oocyte maturation or embryonic development. The effects of the variants were evaluated in patients’ oocytes by morphological observations and immunofluorescence. We identified 34 novel variants of TUBB8 in 51 patients who were diagnosed with abnormalities in oocyte maturation or early embryonic development. We found a novel phenotype in which large polar bodies were present in three independent patients possibly associated with a recurrent variant. Moreover, we identified a novel type of TUBB8 variant consisting of an in-frame deletion-insertion, which has not been previously reported. Our present study identified 34 novel variants in TUBB8 in 51 patients. These patients show oocyte maturation arrest, oocytes with large polar body, fertilization failure, early embryonic arrest or embryonic implantation failure. These results expand the kinds of variants and phenotypic spectrum of TUBB8 variants with regard to Female Infertility.
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homozygous mutations in rec114 cause Female Infertility characterised by multiple pronuclei formation and early embryonic arrest
2020Co-Authors: Wenjing Wang, Biaobang Chen, Zhihua Zhang, Zhou Zhou, Xiaoxi Sun, Yanping Kuang, Jie Dong, Zhao LinAbstract:Background Abnormal pronuclear formation during fertilisation and subsequent early embryonic arrest results in Female Infertility. In recent years, with the prevalence of assisted reproductive technology, a few genes have been identified that are involved in Female Infertility caused by abnormalities in oocyte development, fertilisation and embryonic development. However, the genetic factors responsible for multiple pronuclei formation during fertilisation and early embryonic arrest remain largely unknown. Objective We aim to identify genetic factors responsible for multiple pronuclei formation during fertilisation or early embryonic arrest. Methods Whole-exome sequencing was performed in a cohort of 580 patients with abnormal fertilisation and early embryonic arrest. Effects of mutations were investigated in HEK293T cells by western blotting and immunoprecipitation, as well as minigene assay. Results We identified a novel homozygous missense mutation (c.397T>G, p.C133G) and a novel homozygous donor splice-site mutation (c.546+5G>A) in the meiotic gene REC114. REC114 is involved in the formation of double strand breaks (DSBs), which initiate homologous chromosome recombination. We demonstrated that the splice-site mutation affected the normal alternative splicing of REC114, while the missense mutation reduced the protein level of REC114 in vitro and resulted in the loss of its function to protect its partner protein MEI4 from degradation. Conclusions Our study has identified mutations in REC114 responsible for human multiple pronuclei formation and early embryonic arrest, and these findings expand our knowledge of genetic factors that are responsible for normal human Female meiosis and fertility.
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mutations in nlrp2 and nlrp5 cause Female Infertility characterised by early embryonic arrest
2019Co-Authors: Wenjing Wang, Biaobang Chen, Zhihua Zhang, Xiaoxi Sun, Yanping Kuang, Xiaoyan Mao, Qing Sang, Li Jin, Lei WangAbstract:Background Successful human reproduction requires normal spermatogenesis, oogenesis, fertilisation and early embryonic development, and abnormalities in any of these processes will result in Infertility. Early embryonic arrest is commonly observed in infertile patients with recurrent failure of assisted reproductive technology (ART). However, the genetic basis for early embryonic arrest is largely unknown. Objective We aim to identify genetic causes of infertile patients characterised by early embryonic arrest. Methods We pursued exome sequencing in a proband with embryonic arrest from the consanguineous family. We further screened candidate genes in a cohort of 496 individuals diagnosed with early embryonic arrest by Sanger sequencing. Effects of mutations were investigated in HeLa cells, oocytes and embryos. Results We identified five independent individuals carrying biallelic mutations in NLRP2. We also found three individuals from two families carrying biallelic mutations in NLRP5. These mutations in NLRP2 and NLRP5 caused decreased protein expression in vitro and in oocytes and embryos. Conclusions NLRP2 and NLRP5 are novel mutant genes responsible for human early embryonic arrest. This finding provides additional potential diagnostic markers for patients with recurrent failure of ART and helps us to better understand the genetic basis of Female Infertility characterised by early embryonic arrest.
Xiaoxi Sun - One of the best experts on this subject based on the ideXlab platform.
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homozygous mutations in btg4 cause zygotic cleavage failure and Female Infertility
2020Co-Authors: Wei Zheng, Shuoping Zhang, Zhou Zhou, Xiaoxi Sun, Qianqian Sha, Xiangli Niu, Juanzi Shi, Lei Zhao, Jing Dai, Sufen CaiAbstract:Zygotic cleavage failure (ZCF) is a unique early embryonic phenotype resulting in Female Infertility and recurrent failure of in vitro fertilization (IVF) and/or intracytoplasmic sperm injection (ICSI). With this phenotype, morphologically normal oocytes can be retrieved and successfully fertilized, but they fail to undergo cleavage. Until now, whether this phenotype has a Mendelian inheritance pattern and which underlying genetic factors play a role in its development remained to be elucidated. B cell translocation gene 4 (BTG4) is a key adaptor of the CCR4-NOT deadenylase complex, which is involved in maternal mRNA decay in mice, but no human diseases caused by mutations in BTG4 have previously been reported. Here, we identified four homozygous mutations in BTG4 (GenBank: NM_017589.4 ) that are responsible for the phenotype of ZCF, and we found they followed a recessive inheritance pattern. Three of them—c.73C>T (p.Gln25Ter), c.1A>G (p.?), and c.475_478del (p.Ile159LeufsTer15)—resulted in complete loss of full-length BTG4 protein. For c.166G>A (p.Ala56Thr), although the protein level and distribution of mutant BTG4 was not altered in zygotes from affected individuals or in HeLa cells, the interaction between BTG4 and CNOT7 was abolished. In vivo studies further demonstrated that the process of maternal mRNA decay was disrupted in the zygotes of the affected individuals, which provides a mechanistic explanation for the phenotype of ZCF. Thus, we provide evidence that ZCF is a Mendelian phenotype resulting from mutations in BTG4. These findings contribute to our understanding of the role of BTG4 in human early embryonic development and provide a genetic marker for Female Infertility.
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homozygous mutations in rec114 cause Female Infertility characterised by multiple pronuclei formation and early embryonic arrest
2020Co-Authors: Wenjing Wang, Biaobang Chen, Zhihua Zhang, Zhou Zhou, Xiaoxi Sun, Yanping Kuang, Jie Dong, Zhao LinAbstract:Background Abnormal pronuclear formation during fertilisation and subsequent early embryonic arrest results in Female Infertility. In recent years, with the prevalence of assisted reproductive technology, a few genes have been identified that are involved in Female Infertility caused by abnormalities in oocyte development, fertilisation and embryonic development. However, the genetic factors responsible for multiple pronuclei formation during fertilisation and early embryonic arrest remain largely unknown. Objective We aim to identify genetic factors responsible for multiple pronuclei formation during fertilisation or early embryonic arrest. Methods Whole-exome sequencing was performed in a cohort of 580 patients with abnormal fertilisation and early embryonic arrest. Effects of mutations were investigated in HEK293T cells by western blotting and immunoprecipitation, as well as minigene assay. Results We identified a novel homozygous missense mutation (c.397T>G, p.C133G) and a novel homozygous donor splice-site mutation (c.546+5G>A) in the meiotic gene REC114. REC114 is involved in the formation of double strand breaks (DSBs), which initiate homologous chromosome recombination. We demonstrated that the splice-site mutation affected the normal alternative splicing of REC114, while the missense mutation reduced the protein level of REC114 in vitro and resulted in the loss of its function to protect its partner protein MEI4 from degradation. Conclusions Our study has identified mutations in REC114 responsible for human multiple pronuclei formation and early embryonic arrest, and these findings expand our knowledge of genetic factors that are responsible for normal human Female meiosis and fertility.
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mutations in nlrp2 and nlrp5 cause Female Infertility characterised by early embryonic arrest
2019Co-Authors: Wenjing Wang, Biaobang Chen, Zhihua Zhang, Xiaoxi Sun, Yanping Kuang, Xiaoyan Mao, Qing Sang, Li Jin, Lei WangAbstract:Background Successful human reproduction requires normal spermatogenesis, oogenesis, fertilisation and early embryonic development, and abnormalities in any of these processes will result in Infertility. Early embryonic arrest is commonly observed in infertile patients with recurrent failure of assisted reproductive technology (ART). However, the genetic basis for early embryonic arrest is largely unknown. Objective We aim to identify genetic causes of infertile patients characterised by early embryonic arrest. Methods We pursued exome sequencing in a proband with embryonic arrest from the consanguineous family. We further screened candidate genes in a cohort of 496 individuals diagnosed with early embryonic arrest by Sanger sequencing. Effects of mutations were investigated in HeLa cells, oocytes and embryos. Results We identified five independent individuals carrying biallelic mutations in NLRP2. We also found three individuals from two families carrying biallelic mutations in NLRP5. These mutations in NLRP2 and NLRP5 caused decreased protein expression in vitro and in oocytes and embryos. Conclusions NLRP2 and NLRP5 are novel mutant genes responsible for human early embryonic arrest. This finding provides additional potential diagnostic markers for patients with recurrent failure of ART and helps us to better understand the genetic basis of Female Infertility characterised by early embryonic arrest.
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the comprehensive mutational and phenotypic spectrum of tubb8 in Female Infertility
2019Co-Authors: Biaobang Chen, Zhihua Zhang, Wenjing Wang, Xiaoxi Sun, Yanping Kuang, Xueqian Wang, Xiandong Peng, Huafeng Jiang, Shaozhen Zhang, Zhou ZhouAbstract:Human oocyte maturation is a precondition for fertilization and ensuing embryonic development. Previously, we identified TUBB8 variants as a genetic determinant of human oocyte maturation arrest and showed that these variants cause variable and mixed phenotypes in oocyte maturation and early embryo development. We also estimated that rare inherited or de novo variants in the TUBB8 gene accounted for 30% of individuals in a small cohort of patients affected by oocyte maturation arrest. In the present study, we recruited a further 87 patients from unrelated families diagnosed with oocyte maturation or early embryonic arrest and identified 30 patients carrying TUBB8 variants. The corresponding phenotypes not only include oocyte maturation arrest, failure of fertilization, and early embryonic arrest, but also extend to the new phenotype of failure of embryo implantation. These observations provide the most detailed mutational and phenotypic spectrum of TUBB8, further extend the spectrum of variants and dysfunctional oocyte and embryo phenotypes caused by TUBB8 variants, and confirm previous findings for a critical role of TUBB8 during oocyte maturation and early embryonic development. Thus, TUBB8 mutation screening might not only be a genetic diagnostic marker for patients with oocyte maturation arrest, but might also have clinical implications for evaluating the competence of patients’ functional oocytes with first polar body (PB1).
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Biallelic Mutations in PATL2 Cause Female Infertility Characterized by Oocyte Maturation Arrest
2017Co-Authors: Biaobang Chen, Zhihua Zhang, Xiaoxi Sun, Yanping Kuang, Xiaoyan Mao, Xueqian Wang, Zheng YanAbstract: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.
Zhou Zhou - One of the best experts on this subject based on the ideXlab platform.
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homozygous variants in panx1 cause human oocyte death and Female Infertility
2021Co-Authors: Weijie Wang, Biaobang Chen, Zhihua Zhang, Wenjing Wang, Zhou Zhou, Qian Dou, Lin Zhao, Jie Dong, Yang Zeng, Ruyi LiuAbstract:PANX1, one of the members of the pannexin family, is a highly glycosylated channel-forming protein. Recently, we identified heterozygous variants in PANX1 that follow an autosomal dominant inheritance pattern and cause Female Infertility characterized by oocyte death. In this study, we screened for novel PANX1 variants in patients with the phenotype of oocyte death and discovered a new type of inheritance pattern accompanying PANX1 variants. We identified two novel homozygous missense variants in PANX1 [NM_015368.4 c.712T>C (p.(Ser238Pro) and c.899G>A (p.(Arg300Gln))] associated with the oocyte death phenotype in two families. Both of the homozygous variants altered the PANX1 glycosylation pattern in cultured cells, led to aberrant PANX1 channel activation, and resulted in mouse oocyte death after fertilization in vitro. It is worth noting that the destructive effect of the two homozygous variants on PANX1 function was weaker than that caused by the recently reported heterozygous variants. Our findings enrich the variational spectrum of PANX1 and expand the inheritance pattern of PANX1 variants to an autosomal recessive mode. This highlights the critical role of PANX1 in human oocyte development and helps us to better understand the genetic basis of Female Infertility due to oocyte death.
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homozygous mutations in btg4 cause zygotic cleavage failure and Female Infertility
2020Co-Authors: Wei Zheng, Shuoping Zhang, Zhou Zhou, Xiaoxi Sun, Qianqian Sha, Xiangli Niu, Juanzi Shi, Lei Zhao, Jing Dai, Sufen CaiAbstract:Zygotic cleavage failure (ZCF) is a unique early embryonic phenotype resulting in Female Infertility and recurrent failure of in vitro fertilization (IVF) and/or intracytoplasmic sperm injection (ICSI). With this phenotype, morphologically normal oocytes can be retrieved and successfully fertilized, but they fail to undergo cleavage. Until now, whether this phenotype has a Mendelian inheritance pattern and which underlying genetic factors play a role in its development remained to be elucidated. B cell translocation gene 4 (BTG4) is a key adaptor of the CCR4-NOT deadenylase complex, which is involved in maternal mRNA decay in mice, but no human diseases caused by mutations in BTG4 have previously been reported. Here, we identified four homozygous mutations in BTG4 (GenBank: NM_017589.4 ) that are responsible for the phenotype of ZCF, and we found they followed a recessive inheritance pattern. Three of them—c.73C>T (p.Gln25Ter), c.1A>G (p.?), and c.475_478del (p.Ile159LeufsTer15)—resulted in complete loss of full-length BTG4 protein. For c.166G>A (p.Ala56Thr), although the protein level and distribution of mutant BTG4 was not altered in zygotes from affected individuals or in HeLa cells, the interaction between BTG4 and CNOT7 was abolished. In vivo studies further demonstrated that the process of maternal mRNA decay was disrupted in the zygotes of the affected individuals, which provides a mechanistic explanation for the phenotype of ZCF. Thus, we provide evidence that ZCF is a Mendelian phenotype resulting from mutations in BTG4. These findings contribute to our understanding of the role of BTG4 in human early embryonic development and provide a genetic marker for Female Infertility.
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bi allelic missense pathogenic variants in trip13 cause Female Infertility characterized by oocyte maturation arrest
2020Co-Authors: Zhihua Zhang, Biaobang Chen, Wenjing Wang, Zhou Zhou, Zheng Yan, Lin Zhao, Jie Dong, Feiyang Diao, Shuai Liu, Xiaozhen LiangAbstract:Normal oocyte meiosis is a prerequisite for successful human reproduction, and abnormalities in the process will result in Infertility. In 2016, we identified mutations in TUBB8 as responsible for human oocyte meiotic arrest. However, the underlying genetic factors for most affected individuals remain unknown. TRIP13, encoding an AAA-ATPase, is a key component of the spindle assembly checkpoint, and recurrent homozygous nonsense variants and a splicing variant in TRIP13 are reported to cause Wilms tumors in children. In this study, we identified homozygous and compound heterozygous missense pathogenic variants in TRIP13 responsible for Female Infertility mainly characterized by oocyte meiotic arrest in five individuals from four independent families. Individuals from three families suffered from oocyte maturation arrest, whereas the individual from the fourth family had abnormal zygote cleavage. All displayed only the Infertility phenotype without Wilms tumors or any other abnormalities. In vitro and in vivo studies showed that the identified variants reduced the protein abundance of TRIP13 and caused its downstream molecule, HORMAD2, to accumulate in HeLa cells and in proband-derived lymphoblastoid cells. The chromosome mis-segregation assay showed that variants did not have any effects on mitosis. Injecting TRIP13 cRNA into oocytes from one affected individual was able to rescue the phenotype, which has implications for future therapeutic treatments. This study reports pathogenic variants in TRIP13 responsible for oocyte meiotic arrest, and it highlights the pivotal but different roles of TRIP13 in meiosis and mitosis. These findings also indicate that different dosage effects of mutant TRIP13 might result in two distinct human diseases.
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identification novel mutations in tubb8 in Female Infertility and a novel phenotype of large polar body in oocytes with tubb8 mutations
2020Co-Authors: Lin Zhao, Biaobang Chen, Zhihua Zhang, Wenjing Wang, Zhou Zhou, Zheng Yan, Juanzi Shi, Yichun Guan, Rong Shi, Jie DongAbstract:We aimed to identify novel variants in TUBB8 and corresponding new abnormal phenotypes in oocytes/fertilization/ embryonic development responsible for Female Infertility. Sanger sequencing of TUBB8 was performed in infertile women with abnormalities in oocyte maturation or embryonic development. The effects of the variants were evaluated in patients’ oocytes by morphological observations and immunofluorescence. We identified 34 novel variants of TUBB8 in 51 patients who were diagnosed with abnormalities in oocyte maturation or early embryonic development. We found a novel phenotype in which large polar bodies were present in three independent patients possibly associated with a recurrent variant. Moreover, we identified a novel type of TUBB8 variant consisting of an in-frame deletion-insertion, which has not been previously reported. Our present study identified 34 novel variants in TUBB8 in 51 patients. These patients show oocyte maturation arrest, oocytes with large polar body, fertilization failure, early embryonic arrest or embryonic implantation failure. These results expand the kinds of variants and phenotypic spectrum of TUBB8 variants with regard to Female Infertility.
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homozygous mutations in rec114 cause Female Infertility characterised by multiple pronuclei formation and early embryonic arrest
2020Co-Authors: Wenjing Wang, Biaobang Chen, Zhihua Zhang, Zhou Zhou, Xiaoxi Sun, Yanping Kuang, Jie Dong, Zhao LinAbstract:Background Abnormal pronuclear formation during fertilisation and subsequent early embryonic arrest results in Female Infertility. In recent years, with the prevalence of assisted reproductive technology, a few genes have been identified that are involved in Female Infertility caused by abnormalities in oocyte development, fertilisation and embryonic development. However, the genetic factors responsible for multiple pronuclei formation during fertilisation and early embryonic arrest remain largely unknown. Objective We aim to identify genetic factors responsible for multiple pronuclei formation during fertilisation or early embryonic arrest. Methods Whole-exome sequencing was performed in a cohort of 580 patients with abnormal fertilisation and early embryonic arrest. Effects of mutations were investigated in HEK293T cells by western blotting and immunoprecipitation, as well as minigene assay. Results We identified a novel homozygous missense mutation (c.397T>G, p.C133G) and a novel homozygous donor splice-site mutation (c.546+5G>A) in the meiotic gene REC114. REC114 is involved in the formation of double strand breaks (DSBs), which initiate homologous chromosome recombination. We demonstrated that the splice-site mutation affected the normal alternative splicing of REC114, while the missense mutation reduced the protein level of REC114 in vitro and resulted in the loss of its function to protect its partner protein MEI4 from degradation. Conclusions Our study has identified mutations in REC114 responsible for human multiple pronuclei formation and early embryonic arrest, and these findings expand our knowledge of genetic factors that are responsible for normal human Female meiosis and fertility.
