PMID- 35670744 OWN - NLM STAT- MEDLINE DCOM- 20220802 LR - 20220813 IS - 1460-2350 (Electronic) IS - 0268-1161 (Linking) VI - 37 IP - 8 DP - 2022 Jul 30 TI - Biallelic variants in MOS cause large polar body in oocyte and human female infertility. PG - 1932-1944 LID - 10.1093/humrep/deac120 [doi] AB - STUDY QUESTION: What is the genetic basis of female infertility involving abnormal oocyte morphology with the production of a large first polar body (PB1)? SUMMARY ANSWER: The homozygous missense variant (c.791C>G) and compound missense variants (c.596A>T and c.875C>T) in MOS proto-oncogene, serine/threonine kinase (MOS) (Online Mendelian Inheritance in Man (OMIM) reference: 190060; NM_005372.1) are responsible for abnormal oocyte morphology with the production of a large PB1 to cause infertility in women. WHAT IS KNOWN ALREADY: MOS, an oocyte-specific gene, encodes a serine/threonine-protein kinase that directly phosphorylates mitogen-activated protein kinase (MAPK) kinase (MEK) to activate MAPK (also called extracellular-signal-regulated kinase (ERK)) signal cascade in the oocyte. Female mice lacking Mos remained viable, but infertile because of oocyte symmetric division, spontaneous parthenogenetic activation and early embryonic arrest. Recently, two independent studies demonstrated that female infertility with early embryonic arrest and fragmentation can be caused by biallelic mutations in MOS. However, so far, MOS variants have not been associated with the phenotype of large PB1 extrusion in human oocytes to contribute to female infertility. STUDY DESIGN, SIZE, DURATION: Two independent infertile families characterized by the presence of large PB1 in oocytes were recruited between December 2020 and February 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: Genomic DNA was extracted from the peripheral blood samples of the subjects for whole-exome sequencing. Pedigree analysis was validated by Sanger sequencing. Then, the pathogenic effects of the MOS variants on MOS protein properties and ERK1/2 activation were determined in HEK293 cells and mouse oocytes. MAIN RESULTS AND THE ROLE OF CHANCE: We identified three rare missense variants in MOS, including a homozygous missense variant (c.791C>G) from Patient 1 in Family 1 and two compound missense variants (c.596A>T and c.875C>T) from twin sisters in Family 2. The MOS variants followed a recessive inheritance pattern in infertile patients. All three patients displayed a high percentage of large PB1 extrusion in the oocytes. The three MOS variants could not activate MEK1/2 and ERK1/2 in oocytes and HEK293 cells. In addition, when compared with wild-type MOS, the MOS variants decreased the MOS protein level and attenuated the binding capacity with MEK1. Microinjection of wild-type human MOS complementary RNAs (cRNAs) reversed the symmetric division of oocytes after siMos treatment. In contrast, the three MOS variants demonstrated no rescuing ability. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Owing to the scarcity of human oocyte samples and the associated ethical restrictions, we could not perform the rescue attempt for the study patients. WIDER IMPLICATIONS OF THE FINDINGS: Our findings expand the genetic and phenotypic spectrum of MOS variants in causing female infertility. Our study findings facilitate the early genetic diagnosis of abnormal oocyte morphology characterized as large PB1 that eventually causes infertility in women. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the National Natural Science Foundation of China (82071640 and 82001633), Natural Science Foundation of Zhejiang Province (LD22C060001), the Key Projects Jointly Constructed by the Ministry and the Province of Zhejiang Medical and Health Science and Technology Project (WKJ-ZJ-2005), China Postdoctoral Science Foundation (2020M682575 and 2021T140198), the Changsha Municipal Natural Science Foundation (kq2007022) and Hunan Provincial Grant for Innovative Province Construction (2019SK4012). None of the authors declare any competing interests. TRIAL REGISTRATION NUMBER: N/A. CI - (c) The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com. FAU - Zhang, Yin-Li AU - Zhang YL AUID- ORCID: 0000-0001-8353-9615 AD - Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China. AD - Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, China. FAU - Zheng, Wei AU - Zheng W AUID- ORCID: 0000-0002-1397-4176 AD - Laboratory of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, Central South University, Changsha, China. AD - Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-XIANGYA, Changsha, China. FAU - Ren, Peipei AU - Ren P AD - Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China. AD - Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, China. FAU - Jin, Jiamin AU - Jin J AD - Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China. AD - Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, China. FAU - Hu, Zhanhong AU - Hu Z AD - Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China. AD - Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, China. FAU - Liu, Qing AU - Liu Q AD - Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China. AD - Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, China. FAU - Fan, Heng-Yu AU - Fan HY AD - Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, China. AD - Life Sciences Institute, Zhejiang University, Hangzhou, China. FAU - Gong, Fei AU - Gong F AD - Laboratory of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, Central South University, Changsha, China. AD - Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-XIANGYA, Changsha, China. FAU - Lu, Guang-Xiu AU - Lu GX AD - Laboratory of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, Central South University, Changsha, China. AD - Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-XIANGYA, Changsha, China. FAU - Lin, Ge AU - Lin G AUID- ORCID: 0000-0002-3877-2546 AD - Laboratory of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, Central South University, Changsha, China. AD - Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-XIANGYA, Changsha, China. FAU - Zhang, Songying AU - Zhang S AUID- ORCID: 0000-0001-8044-6237 AD - Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China. AD - Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, China. FAU - Tong, Xiaomei AU - Tong X AUID- ORCID: 0000-0002-6982-445X AD - Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China. AD - Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - England TA - Hum Reprod JT - Human reproduction (Oxford, England) JID - 8701199 RN - 452VLY9402 (Serine) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) SB - IM MH - Animals MH - Female MH - HEK293 Cells MH - Humans MH - *Infertility, Female/metabolism MH - Mice MH - Oocytes/metabolism MH - Polar Bodies MH - Protein Serine-Threonine Kinases MH - Serine/metabolism OTO - NOTNLM OT - MOS OT - female infertility OT - human oocyte OT - large polar body OT - mitogen-activated protein kinase OT - mutation EDAT- 2022/06/08 06:00 MHDA- 2022/08/03 06:00 CRDT- 2022/06/07 10:33 PHST- 2021/11/10 00:00 [received] PHST- 2022/04/29 00:00 [revised] PHST- 2022/06/08 06:00 [pubmed] PHST- 2022/08/03 06:00 [medline] PHST- 2022/06/07 10:33 [entrez] AID - 6603695 [pii] AID - 10.1093/humrep/deac120 [doi] PST - ppublish SO - Hum Reprod. 2022 Jul 30;37(8):1932-1944. doi: 10.1093/humrep/deac120.