{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T17:45:42Z","timestamp":1773251142631,"version":"3.50.1"},"reference-count":21,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T00:00:00Z","timestamp":1773187200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>\n                      Preimplantation embryonic lethality (PREMBL) is a major cause of female infertility, characterized by early embryonic arrest. Homozygous or compound heterozygous mutations in\n                      <jats:italic>PADI6<\/jats:italic>\n                      underlie preimplantation embryonic lethality-2 (PREMBL2). This study aims to conduct a systematic genetic investigation on a case with\n                      <jats:italic>PADI6<\/jats:italic>\n                      biallelic variants.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A patient clinically diagnosed with PREMBL was systematically evaluated via chromosomal karyotyping analysis, high-resolution chromosomal microarray analysis (CMA), whole-exome sequencing (WES), molecular dynamics analysis (MD), immunofluorescence (IF), and Western blotting (WB) to identify PREMBL-associated variants.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      WES identified two biallelic frameshift variants in\n                      <jats:italic>PADI6<\/jats:italic>\n                      : c.707dupT (L237Afs*24) and c.2009_2010delAG (E670Gfs*48). MD, IF, and WB analyses demonstrated that: The L237A variant generates a 259-aa truncated protein lacking the essential C-terminal domain. The E670G variant produces a 716-aa elongated protein with significant C-terminal structural alterations. Both variants cause complete loss of protein function and markedly reduced abundance.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This study implicates a previously unreported compound heterozygous combination of the\n                      <jats:italic>PADI6<\/jats:italic>\n                      variants c.707dupT and c.2009_2010delAG as the potential genetic basis of PREMBL2 in this individual, based on their predicted disruptive effects. However, as a single-case study, these findings cannot be generalized. Future research should focus on validating these variants in additional patients and functionally characterizing their effects to definitively establish causality and understand their role in early embryonic arrest.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fgene.2026.1667814","type":"journal-article","created":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T22:10:25Z","timestamp":1773180625000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Case Report: Biallelic PADI6 frameshift variants contribute to preimplantation embryonic lethality"],"prefix":"10.3389","volume":"17","author":[{"given":"Shun-Tao","family":"Jiao","sequence":"first","affiliation":[{"name":"Beijing Jiaen Hospital, Heen Life Medical Research Institute","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zi-Hui","family":"Tan","sequence":"additional","affiliation":[{"name":"Beijing Jiaen Hospital, Heen Life Medical Research Institute","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tian-Ying","family":"Wei","sequence":"additional","affiliation":[{"name":"Beijing Jiaen Hospital, Heen Life Medical Research Institute","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ge-Han","family":"Zhang","sequence":"additional","affiliation":[{"name":"Medical Innovation Research Division of Chinese PLA General Hospital","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ti-Ling","family":"Hu","sequence":"additional","affiliation":[{"name":"Beijing Jiaen Hospital, Heen Life Medical Research Institute","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Song-Jun","family":"Li","sequence":"additional","affiliation":[{"name":"The Reproduction Medical Center, The Third Affiliated Hospital of Shenzhen University","place":["Shenzhen, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ya-Ping","family":"Tian","sequence":"additional","affiliation":[{"name":"Medical Innovation Research Division of Chinese PLA General Hospital","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jia-En","family":"Liu","sequence":"additional","affiliation":[{"name":"Beijing Jiaen Hospital, Heen Life Medical Research Institute","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hua-Ying","family":"Hu","sequence":"additional","affiliation":[{"name":"Beijing Jiaen Hospital, Heen Life Medical Research Institute","place":["Beijing, China"]},{"name":"Medical Innovation Research Division of Chinese PLA General Hospital","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1186\/s13059-015-0792-0","article-title":"TLE6 mutation causes the earliest known human embryonic lethality","volume":"16","author":"Alazami","year":"2015","journal-title":"Genome Biol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"gaab043","DOI":"10.1093\/molehr\/gaab043","article-title":"The subcortical maternal complex: emerging roles and novel perspectives","volume":"27","author":"Bebbere","year":"2021","journal-title":"Mol. Hum. Reprod."},{"key":"B3","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.gene.2003.12.038","article-title":"Comparative analysis of the mouse and human peptidylarginine deiminase gene clusters reveals highly conserved non-coding segments and a new human gene, PADI6","volume":"330","author":"Chavanas","year":"2004","journal-title":"Gene"},{"key":"B4","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.mce.2007.05.005","article-title":"Peptidylarginine deiminase (PAD) 6 is essential for oocyte cytoskeletal sheet formation and female fertility","volume":"273","author":"Esposito","year":"2007","journal-title":"Mol. Cell. Endocrinol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1016\/j.ajhg.2016.08.016","article-title":"REVEL: an ensemble method for predicting the pathogenicity of rare missense variants","volume":"99","author":"Ioannidis","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"B6","doi-asserted-by":"publisher","first-page":"5308","DOI":"10.1016\/j.cell.2023.10.003","article-title":"Mammalian oocytes store proteins for the early embryo on cytoplasmic lattices","volume":"186","author":"Jentoft","year":"2023","journal-title":"Cell"},{"key":"B7","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1016\/j.ydbio.2010.11.033","article-title":"Regulation of mouse oocyte microtubule and organelle dynamics by PADI6 and the cytoplasmic lattices","volume":"350","author":"Kan","year":"2011","journal-title":"Dev. Biol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1016\/j.devcel.2008.07.010","article-title":"A subcortical maternal complex essential for preimplantation mouse embryogenesis","volume":"15","author":"Li","year":"2008","journal-title":"Dev. Cell"},{"key":"B9","doi-asserted-by":"publisher","first-page":"3586","DOI":"10.1021\/jp973084f","article-title":"All-atom empirical potential for molecular modeling and dynamics studies of proteins","volume":"102","author":"MacKerell","year":"1998","journal-title":"J. Phys. Chem. B"},{"key":"B10","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1111\/cge.12866","article-title":"The human knockout phenotype of PADI6 is female sterility caused by cleavage failure of their fertilized eggs","volume":"91","author":"Maddirevula","year":"2017","journal-title":"Clin. Genet."},{"key":"B11","doi-asserted-by":"publisher","first-page":"44130","DOI":"10.1063\/5.0014475","article-title":"Scalable molecular dynamics on CPU and GPU architectures with NAMD","volume":"153","author":"Phillips","year":"2020","journal-title":"J. Chem. Phys."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1007","DOI":"10.1038\/s41431-018-0141-3","article-title":"Biallelic PADI6 variants linking infertility, miscarriages, and hydatidiform moles","volume":"26","author":"Qian","year":"2018","journal-title":"Eur. J. Hum. Genet."},{"key":"B13","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med. Off. J. Am. Coll. Med. Genet."},{"key":"B14","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1002\/prot.340230306","article-title":"Evaluation of comparative protein modeling by MODELLER","volume":"23","author":"Sali","year":"1995","journal-title":"Proteins"},{"key":"B15","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1016\/S0140-6736(10)60280-2","article-title":"Gestational trophoblastic disease","volume":"376","author":"Seckl","year":"2010","journal-title":"Lancet"},{"key":"B16","doi-asserted-by":"publisher","first-page":"e164","DOI":"10.1093\/nar\/gkq603","article-title":"ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"B17","doi-asserted-by":"publisher","first-page":"698","DOI":"10.1016\/j.rbmo.2018.03.009","article-title":"Novel mutations in genes encoding subcortical maternal complex proteins may cause human embryonic developmental arrest","volume":"36","author":"Wang","year":"2018","journal-title":"Reprod. Biomed. Online"},{"key":"B18","doi-asserted-by":"publisher","first-page":"744","DOI":"10.1016\/j.ajhg.2016.06.024","article-title":"Mutations in PADI6 cause female infertility characterized by early embryonic arrest","volume":"99","author":"Xu","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"B19","doi-asserted-by":"publisher","first-page":"2492590","DOI":"10.1155\/2019\/2492590","article-title":"Genetic analysis in fetal skeletal dysplasias by trio whole-exome sequencing","volume":"2019","author":"Yang","year":"2019","journal-title":"Biomed. Res. Int."},{"key":"B20","doi-asserted-by":"publisher","first-page":"2627","DOI":"10.1242\/dev.016329","article-title":"Role for PADI6 and the cytoplasmic lattices in ribosomal storage in oocytes and translational control in the early mouse embryo","volume":"135","author":"Yurttas","year":"2008","journal-title":"Dev. Camb. Engl."},{"key":"B21","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1007\/s10815-019-01606-7","article-title":"New biallelic mutations in PADI6 cause recurrent preimplantation embryonic arrest characterized by direct cleavage","volume":"37","author":"Zheng","year":"2020","journal-title":"J. Assist. Reprod. Genet."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2026.1667814\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T22:10:28Z","timestamp":1773180628000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2026.1667814\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,11]]},"references-count":21,"alternative-id":["10.3389\/fgene.2026.1667814"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2026.1667814","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,11]]},"article-number":"1667814"}}