PMID- 36229297
OWN - NLM
STAT- MEDLINE
DCOM- 20221221
LR  - 20230112
IS  - 1556-5653 (Electronic)
IS  - 0015-0282 (Linking)
VI  - 118
IP  - 6
DP  - 2022 Dec
TI  - Pathogenic variants in TSC2 might cause premature ovarian insufficiency through 
      activated mTOR induced hyperactivation of primordial follicles.
PG  - 1139-1149
LID - S0015-0282(22)01375-9 [pii]
LID - 10.1016/j.fertnstert.2022.08.853 [doi]
AB  - OBJECTIVE: To investigate the role of tuberous sclerosis complex (TSC) genes, 
      including TSC1 and TSC2, in the pathogenesis of human premature ovarian 
      insufficiency (POI). DESIGN: Genetic and functional study. SETTING: 
      University-based reproductive medical center. PATIENT(S): Six patients from a 
      cohort of 1,030 cases with idiopathic POI. INTERVENTION(S): Variants in TSC1 and 
      TSC2 were screened through the largest in-house database of whole exome 
      sequencing performed in 1,030 patients with idiopathic POI. The pathogenic 
      effects of the variants were further verified by functional studies. MAIN OUTCOME 
      MEASURE(S): TSC1 or TSC2 variant and functional characteristics. RESULT(S): Five 
      pathogenic heterozygous variants in TSC2 were identified in 6 patients with POI. 
      Functional studies showed these variants impaired the repressive effect of TSC2 
      on mammalian target of rapamycin (mTOR) pathway by disrupting the formation of 
      TSC complex or its GTPase-activating protein activity. Furthermore, in vitro 
      ovarian culture assay showed that TSC2 p.R98Q led to hyperactivation of mTOR 
      pathway thereby triggering primordial follicle activation. CONCLUSION(S): The 
      present study identified pathogenic variants of TSC2 in patients with POI, 
      firstly suggested defective TSC/mTOR pathway mediated hyperactivation of 
      primordial follicle participating in the pathogenesis of POI, giving insights 
      into new targets of genetic counseling and clinical prevention for POI. 
      Considering the pivotal role of TSC2 variants in diagnosis of TSC syndrome, the 
      present study also highlighted the importance of history collection and long-term 
      follow-up for the TSC2 variants carriers.
CI  - Copyright (c) 2022 American Society for Reproductive Medicine. Published by 
      Elsevier Inc. All rights reserved.
FAU - Xu, Bingying
AU  - Xu B
AD  - Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong 
      University, Jinan, Shandong, People's Republic of China; National Research Center 
      for Assisted Reproductive Technology and Reproductive Genetics, Shandong 
      University, Jinan, Shandong, People's Republic of China; Key laboratory of 
      Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, 
      Shandong, People's Republic of China; Shandong Provincial Clinical Medicine 
      Research Center for Reproductive Health, Shandong University, Jinan, Shandong, 
      People's Republic of China.
FAU - Li, Zhuqing
AU  - Li Z
AD  - Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong 
      University, Jinan, Shandong, People's Republic of China; National Research Center 
      for Assisted Reproductive Technology and Reproductive Genetics, Shandong 
      University, Jinan, Shandong, People's Republic of China; Key laboratory of 
      Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, 
      Shandong, People's Republic of China; Shandong Provincial Clinical Medicine 
      Research Center for Reproductive Health, Shandong University, Jinan, Shandong, 
      People's Republic of China.
FAU - Li, Shan
AU  - Li S
AD  - Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong 
      University, Jinan, Shandong, People's Republic of China; National Research Center 
      for Assisted Reproductive Technology and Reproductive Genetics, Shandong 
      University, Jinan, Shandong, People's Republic of China; Key laboratory of 
      Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, 
      Shandong, People's Republic of China; Shandong Provincial Clinical Medicine 
      Research Center for Reproductive Health, Shandong University, Jinan, Shandong, 
      People's Republic of China.
FAU - Ke, Hanni
AU  - Ke H
AD  - Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong 
      University, Jinan, Shandong, People's Republic of China; National Research Center 
      for Assisted Reproductive Technology and Reproductive Genetics, Shandong 
      University, Jinan, Shandong, People's Republic of China; Key laboratory of 
      Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, 
      Shandong, People's Republic of China; Shandong Provincial Clinical Medicine 
      Research Center for Reproductive Health, Shandong University, Jinan, Shandong, 
      People's Republic of China.
FAU - Zhang, Qian
AU  - Zhang Q
AD  - Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong 
      University, Jinan, Shandong, People's Republic of China; National Research Center 
      for Assisted Reproductive Technology and Reproductive Genetics, Shandong 
      University, Jinan, Shandong, People's Republic of China; Key laboratory of 
      Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, 
      Shandong, People's Republic of China; Shandong Provincial Clinical Medicine 
      Research Center for Reproductive Health, Shandong University, Jinan, Shandong, 
      People's Republic of China.
FAU - Qin, Yingying
AU  - Qin Y
AD  - Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong 
      University, Jinan, Shandong, People's Republic of China; National Research Center 
      for Assisted Reproductive Technology and Reproductive Genetics, Shandong 
      University, Jinan, Shandong, People's Republic of China; Key laboratory of 
      Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, 
      Shandong, People's Republic of China; Shandong Provincial Clinical Medicine 
      Research Center for Reproductive Health, Shandong University, Jinan, Shandong, 
      People's Republic of China.
FAU - Guo, Ting
AU  - Guo T
AD  - Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong 
      University, Jinan, Shandong, People's Republic of China; National Research Center 
      for Assisted Reproductive Technology and Reproductive Genetics, Shandong 
      University, Jinan, Shandong, People's Republic of China; Key laboratory of 
      Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, 
      Shandong, People's Republic of China; Shandong Provincial Clinical Medicine 
      Research Center for Reproductive Health, Shandong University, Jinan, Shandong, 
      People's Republic of China. Electronic address: gtlyp2008@126.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20221010
PL  - United States
TA  - Fertil Steril
JT  - Fertility and sterility
JID - 0372772
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - 0 (Tuberous Sclerosis Complex 2 Protein)
RN  - 0 (TSC2 protein, human)
SB  - IM
MH  - Female
MH  - Humans
MH  - *Menopause, Premature
MH  - Ovarian Follicle/metabolism
MH  - *Primary Ovarian Insufficiency/genetics
MH  - TOR Serine-Threonine Kinases/genetics/metabolism
MH  - *Tuberous Sclerosis Complex 2 Protein/genetics
OTO - NOTNLM
OT  - Premature ovarian insufficiency
OT  - TSC2
OT  - WES
OT  - primordial follicle activation
EDAT- 2022/10/14 06:00
MHDA- 2022/12/15 06:00
CRDT- 2022/10/13 22:04
PHST- 2021/09/19 00:00 [received]
PHST- 2022/08/18 00:00 [revised]
PHST- 2022/08/22 00:00 [accepted]
PHST- 2022/10/14 06:00 [pubmed]
PHST- 2022/12/15 06:00 [medline]
PHST- 2022/10/13 22:04 [entrez]
AID - S0015-0282(22)01375-9 [pii]
AID - 10.1016/j.fertnstert.2022.08.853 [doi]
PST - ppublish
SO  - Fertil Steril. 2022 Dec;118(6):1139-1149. doi: 10.1016/j.fertnstert.2022.08.853. 
      Epub 2022 Oct 10.