Mutant ZP1 in Familial Infertility

Huang, Haowen; Lv, Chao; Zhao, Ying-Chun; Li, Wen; He, Xuemei; Li, Ping; Sha, Aihua; Tian, Xiao; Papasian, Christopher J.; Deng, Hong−Wen; Lu, Guangxiu; Xiao, Hong‐Mei

doi:10.1056/nejmoa1308851

Cited by 131 publications

(107 citation statements)

References 25 publications

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“…This mutation was absent in our in‐house ethnic‐matched 2,200 individual genomes and the public databases including 1000 Genome, ExAc database, and ESP6500 database. Interestingly, the second heterozygous mutation, a frameshift deletion of 8 nt, c.1169_1176del (p.I390Tfs*16), in exon 7 of ZP1 (Refseq: NM_207341.3), transmitted from the mother of the proband (Figure a, I‐2 and 1h), was the same mutation reported by a previous work (Huang et al, ). In that work, Huang et al found in a familial infertility case a homozygous mutation, caused a premature stop codon (I390fs404X), which resulted in a truncated protein of 404 amino acids, instead of the 638‐amino‐acid original ZP1 protein (Figure g), posited that the defective ZP1 hindered the transportation of ZP3, another key element in zona pellucida, from the cytoplasm to the surface of oocyte (Huang et al, ).…”

Section: The Art Cycles Descriptionsupporting

confidence: 79%

“…The model of zona pellucida development includes intraplasmic synthesis and maturation of the component proteins, transportation to the cell surface, and interweaving among the four ZP proteins (Huang et al, ). Among this process, ZP1 plays a critical role which cross‐links the long chains of filaments made of consecutive alternates of ZP2, ZP3, and ZP4.…”

Section: The Art Cycles Descriptionmentioning

confidence: 99%

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Compound heterozygousZP1mutations cause empty follicle syndrome in infertile sisters

et al. 2019

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Empty follicle syndrome (EFS) is a condition in which no oocyte is retrieved from mature follicles after proper ovarian stimulation in an in vitro fertilization procedure. Genetic evidence accumulates for the etiology of recurrent EFS without pharmacological or iatrogenic problems. In this study, we present two infertile sisters in a family with EFS after three cycles of standard ovarian stimulation with human chorionic gonadotrophin and/or gonadotropin‐releasing hormone agonist therapy. Via whole‐exome sequencing and cosegregation test, we identified compound heterozygous mutations in the gene of ZP1 in both of the infertile sisters. Coimmunoprecipitation tests and homology modeling analysis confirmed that both mutated ZP1 disrupt the formation of oocyte zona pellucida by interrupting the interaction among ZP1, ZP2, and ZP3. We thus propose that the specific mutations in ZP1 gene render a causality for the intractable EFS.

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Section: The Art Cycles Descriptionsupporting

confidence: 79%

Section: The Art Cycles Descriptionmentioning

confidence: 99%

Compound heterozygousZP1mutations cause empty follicle syndrome in infertile sisters

et al. 2019

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“…Previously, Huang et al identified a homozygous frameshift mutation of ZP1 (MIM: 195000) inherited in recessive fashion from a family exhibiting oocytes devoid of a ZP. 20 The frameshift mutation formed a premature stop codon and resulted in a truncated ZP1, which was postulated to sequester ZP3 in the cytoplasm and prevent the formation of a ZP by working in loss-of-function way. In our study, the heterozygous p.Ala134Thr substitution in ZP3 impeded the interaction between ZP3 and ZP2 and eventually led to oocyte degeneration, by working in a dominantnegative way.…”

Section: Efs Can Be Classified As Either False Efs (Fefs) or Genuine mentioning

confidence: 99%

A Recurrent Missense Mutation in ZP3 Causes Empty Follicle Syndrome and Female Infertility

Chen

Bian

Liu

et al. 2017

The American Journal of Human Genetics

103

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Empty follicle syndrome (EFS) is defined as the failure to aspirate oocytes from mature ovarian follicles during in vitro fertilization. Except for some cases caused by pharmacological or iatrogenic problems, the etiology of EFS remains enigmatic. In the present study, we describe a large family with a dominant inheritance pattern of female infertility characterized by recurrent EFS. Genome-wide linkage analyses and whole-exome sequencing revealed a paternally transmitted heterozygous missense mutation of c.400 G>A (p.Ala134Thr) in zona pellucida glycoprotein 3 (ZP3). The same mutation was identified in an unrelated EFS pedigree. Haplotype analysis revealed that the disease allele of these two families came from different origins. Furthermore, in a cohort of 21 cases of EFS, two were also found to have the ZP3 c.400 G>A mutation. Immunofluorescence and histological analysis indicated that the oocytes of the EFS female had degenerated and lacked the zona pellucida (ZP). ZP3 is a major component of the ZP filament. When mutant ZP3 was co-expressed with wild-type ZP3, the interaction between wild-type ZP3 and ZP2 was markedly decreased as a result of the binding of wild-type ZP3 and mutant ZP3, via dominant negative inhibition. As a result, the assembly of ZP was impeded and the communication between cumulus cells and the oocyte was prevented, resulting in oocyte degeneration. These results identified a genetic basis for EFS and oocyte degeneration and, moreover, might pave the way for genetic diagnosis of infertile females with this phenotype.During in vitro fertilization (IVF) treatment, oocyte retrieval is performed after ovarian stimulation via vaginal puncture. Cumulus-oocyte complexes (COCs), which consist of cumulus cells surrounding the centrally located oocyte, are isolated from the individual's follicular fluid. As was first described by Coulam et al. in 1986, empty follicle syndrome (EFS) is a condition in which the ovarian response to stimulation and follicular development seems normal but no oocytes are retrieved for fertilization.1 EFS can be classified as either false EFS (FEFS) or genuine EFS (GEFS). FEFS is mainly caused by pharmacological or iatrogenic problems; however, the etiology of GEFS, which is responsible for about 33% of EFS, still remains enigmatic. 2 It has been proposed that GEFS is caused by dysfunctional folliculogenesis, ovarian aging, or genetic factors including pericentric inversion of chromosome 2 and LHCGR (MIM: 152790) mutations. 3-7 A retrospective study of 12,359 individuals who underwent assisted reproductive technology (ART) revealed that the prevalence of GEFS was about 0.016%. 8 Without oocytes for fertilization, these individuals fail to achieve pregnancy after a demanding and expensive medical intervention, resulting in stress to both physicians and the individuals themselves.9

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“…Presence of ZP2 (A) and ZP4 (B) transcripts was evaluated by RT-qPCR analysis MFCS = oocytes isolated from medium follicles of cycling sows, SFJG = oocytes from small follicles of juvenile gilts, SFCS = oocytes from small follicles of cycling sows Results are presented as mean ± SEM with the level of significance of P < 0.001 (*P < 0.01) a-c values with different superscripts are significantly different secondary sperm receptors, playing a significant role in gamete fusion during successful monospermic fertilization (Topfer-Petersen 1999). It has been previously shown in several species that oocytes lacking ZPs proteins are unable to fertilize (Harada et al 2003;Wassarman and Litscher 2012;Huang et al 2014). Ovarian follicle size significantly influences the ability of oocytes to mature and the gamete fertilizability.…”

Section: Discussionmentioning

confidence: 99%

Expression of genes encoding zona pellucida glycoproteins and cortical granule distribution in porcine oocytes isolated from small and medium follicles in relation to puberty status of donors

Ješeta¹,

Budna²,

Kranc³

et al. 2017

CZECH J ANIM SCI

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Jeseta M., Budna J., Kranc W., Hanulakova S., Bryja A., Chachuła A., Ciesiółka S., WojtanowiczMarkiewicz K., Bukowska D., Brüssow K.-P., Bruska M., Nowicki M., Antosik P., Hulinska P., Machatkova M., Zabel M., Kempisty B. (2017): Expression of genes encoding zona pellucida glycoproteins and cortical granule distribution in porcine oocytes isolated from small and medium follicles in relation to puberty status of donors. Czech J. Anim. Sci., 62, 234-241.The zona pellucida proteins belong to a group of proteins that regulate the processes of gamete recognition, interaction, and fusion, since they are recognized as primary and secondary sperm receptors. It is suggested that cortical granule distribution is significantly associated with the zona pellucida structure and membrane preparation to cortical and acrosome reaction. Therefore, this study investigated the zona pellucida marker gene expression (ZP2 and ZP4 protein) in relation to cortical granules distribution in oocytes and puberty status of donors. Oocytes were collected from adult cyclic sows (isolated from medium and small follicles) and juvenile gilts (isolated only from small follicles). The oocytes were examined by RT-qPCR and by confocal microscopy. The expression of genes for ZP2 and ZP4 protein in oocytes collected from small follicles from

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Mutant ZP1 in Familial Infertility

Cited by 131 publications

References 25 publications

Compound heterozygousZP1mutations cause empty follicle syndrome in infertile sisters

Compound heterozygousZP1mutations cause empty follicle syndrome in infertile sisters

A Recurrent Missense Mutation in ZP3 Causes Empty Follicle Syndrome and Female Infertility

Expression of genes encoding zona pellucida glycoproteins and cortical granule distribution in porcine oocytes isolated from small and medium follicles in relation to puberty status of donors

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