A novel homozygous mutation in the <i>PADI6</i> gene causes early embryo arrest

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Abstract

Background

It has been proved that mutations in the PADI6 gene can cause early embryo arrest. This study describes a newly discovered mutation in PADI6 that expands the genetic spectrum of early embryo arrest.

Methods

Peripheral blood of a patient diagnosed with early embryo arrest was collected for whole-exome sequencing. Sanger sequencing was performed to confirm this mutation. The effects of the variant were investigated in human embryonic kidney 293T (HEK293T) cells using western blotting, real-time quantitative polymerase chain reaction, and immunofluorescence.

Results

A novel homozygous mutation in PADI6 was identified in the proband. The patient carried a frameshift insertion mutation c.558dupA (p.Thr187Asnfs*48), which was located in the protein arginine deiminase middle domain. The variant destroyed PADI6 protein expression and reduced PADI6 mRNA expression in HEK293T cells.

Conclusions

The newly identified mutation in PADI6 accounts for early embryo arrest. It expands the spectrum of genetic causes and phenotypes of infertility in humans. These findings also provide an additional possible diagnostic marker for patients with recurrent in vitro fertilization/intracytoplasmic sperm injection failure.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12978-022-01495-7.

Plain Language Summary

Some infertile patients experience multiple in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) failure owing to recurrent early embryo arrest. However, the underlying mechanisms remain largely unknown. Due to the development of whole-exome sequencing, early embryo arrest has been confirmed as a type of Mendelian disease. This study aimed to identify the genetic cause of early embryo arrest in patients and to expand the genetic spectrum. Furthermore, it can help doctors offer better suggestions to such patients and prevent patients from suffering from multiple IVF/ICSI failures.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12978-022-01495-7.

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Most cited references 27

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GSDS 2.0: an upgraded gene feature visualization server

Bo Hu, Jinpu Jin, An-Yuan Guo … (2014)

Summary: Visualizing genes’ structure and annotated features helps biologists to investigate their function and evolution intuitively. The Gene Structure Display Server (GSDS) has been widely used by more than 60 000 users since its first publication in 2007. Here, we reported the upgraded GSDS 2.0 with a newly designed interface, supports for more types of annotation features and formats, as well as an integrated visual editor for editing the generated figure. Moreover, a user-specified phylogenetic tree can be added to facilitate further evolutionary analysis. The full source code is also available for downloading. Availability and implementation: Web server and source code are freely available at http://gsds.cbi.pku.edu.cn. Contact: gaog@mail.cbi.pku.edu.cn or gsds@mail.cbi.pku.edu.cn Supplementary information: Supplementary data are available at Bioinformatics online.

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HomozygosityMapper—an interactive approach to homozygosity mapping

Dominik Seelow, Markus Schuelke, Friedhelm Hildebrandt … (2009)

Homozygosity mapping is a common method for mapping recessive traits in consanguineous families. In most studies, applications for multipoint linkage analyses are applied to determine the genomic region linked to the disease. Unfortunately, these are neither suited for very large families nor for the inclusion of tens of thousands of SNPs. Even if less than 10 000 markers are employed, such an analysis may easily last hours if not days. Here we present a web-based approach to homozygosity mapping. Our application stores marker data in a database into which users can directly upload their own SNP genotype files. Within a few minutes, the database analyses the data, detects homozygous stretches and provides an intuitive graphical interface to the results. The homozygosity in affected individuals is visualized genome-wide with the ability to zoom into single chromosomes and user-defined chromosomal regions. The software also displays the underlying genotypes in all samples. It is integrated with our candidate gene search engine, GeneDistiller, so that users can interactively determine the most promising gene. They can at any point restrict access to their data or make it public, allowing HomozygosityMapper to be used as a data repository for homozygosity-mapping studies. HomozygosityMapper is available at http://www.homozygositymapper.org/.

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A subcortical maternal complex essential for preimplantation mouse embryogenesis.

Jurrien Dean, Boris Baibakov, Lei Li (2008)

We have identified a subcortical maternal complex (SCMC) that assembles during oocyte growth and is essential for zygotes to progress beyond the first embryonic cell divisions. At least four maternally encoded proteins contribute to this MDa complex: FLOPED, MATER, and TLE6 interact with each other while Filia binds independently to MATER. Although the transcripts encoding these proteins are degraded during meiotic maturation and ovulation, the SCMC proteins persist in the early embryo. The SCMC, located in the subcortex of eggs, is excluded from regions of cell-cell contact in the cleavage-stage embryo and segregates to the outer cells of the morulae and blastocyst. Floped(tm/tm) and/or Mater(tm/tm) eggs lack the SCMC but can be fertilized. However, these embryos do not progress beyond cleavage stage development and female mice are sterile. The proteins are conserved in humans, and similar maternal effect mutations may result in recurrent embryonic loss.

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Author and article information

Contributors

Zhongyuan Yao: 32694395@qq.com

Yanping Li:

ORCID: http://orcid.org/0000-0002-4193-7321

liyanp@csu.edu.cn

Journal

Journal ID (nlm-ta): Reprod Health

Journal ID (iso-abbrev): Reprod Health

Title: Reproductive Health

Publisher: BioMed Central (London )

ISSN (Electronic): 1742-4755

Publication date (Electronic): 10 September 2022

Publication date PMC-release: 10 September 2022

Publication date Collection: 2022

Volume: 19

Electronic Location Identifier: 190

Affiliations

[1 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, , Central South University, ; Changsha, 410078 Hunan China

[2 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, Department of Reproductive Medicine, Xiangya Hospital, , Central South University, ; Changsha, 410000 Hunan China

[3 ]Clinical Research Center for Women’s Reproductive Health in Hunan Province, Changsha, 410000 Hunan China

[4 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, Department of Neurosurgery, Xiangya Hospital, , Central South University, ; Changsha, 410008 Hunan China

[5 ]GRID grid.13402.34, ISNI 0000 0004 1759 700X, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, ; Yiwu, 322000 Zhejiang China

Author information

Yanping Li http://orcid.org/0000-0002-4193-7321

Article

Publisher ID: 1495

DOI: 10.1186/s12978-022-01495-7

PMC ID: 9463787

PubMed ID: 36088419

SO-VID: 1cf6ec91-ee09-4d4d-8810-bd06dec49dd3

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 24 January 2022

Date accepted : 30 August 2022

Custom metadata

ScienceOpen disciplines: Obstetrics & Gynecology

Keywords: infertility,early embryo arrest,peptidylarginine deiminase type vi,mutation,subcortical maternal complex

Data availability:

ScienceOpen disciplines: Obstetrics & Gynecology

Keywords: infertility, early embryo arrest, peptidylarginine deiminase type vi, mutation, subcortical maternal complex

A novel homozygous mutation in the PADI6 gene causes early embryo arrest

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Abstract

Background

Methods

Results

Conclusions

Supplementary Information

Plain Language Summary

Supplementary Information

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Advocacy for Maternal and Women’s Health

Most cited references 27

GSDS 2.0: an upgraded gene feature visualization server

HomozygosityMapper—an interactive approach to homozygosity mapping

A subcortical maternal complex essential for preimplantation mouse embryogenesis.

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