PMID- 35477840
OWN - NLM
STAT- MEDLINE
DCOM- 20220808
LR  - 20220819
IS  - 1933-7205 (Electronic)
IS  - 1933-7191 (Linking)
VI  - 29
IP  - 8
DP  - 2022 Aug
TI  - Assessment of the Role of Nuclear ENDOG Gene and mtDNA Variations on Paternal 
      Mitochondrial Elimination (PME) in Infertile Men: An Experimental Study.
PG  - 2208-2222
LID - 10.1007/s43032-022-00953-8 [doi]
AB  - In humans and most animals, maternal inheritance of mitochondria and 
      mitochondrial DNA (mtDNA) is considered as an universal assumption. Recently, 
      several lines of evidence suggest that different species seem to employ distinct 
      mechanisms to prevent the inheritance of paternal mtDNA. There are few studies in 
      the literature on the molecular basis of sperm mtDNA elimination in mammals and 
      paternal mtDNA transmission in humans. Endonuclease G (ENDOG) is a mitochondrial 
      nuclease encoded by nuclear ENDOG gene. The critical importance of ENDOG gene on 
      paternal mitochondrial elimination (PME) has been previously demonstrated in 
      model organisms such as C. elegans and D. melanogaster. However, its mechanism in 
      human is still unclear. Therefore, we aimed to evaluate whether nuclear ENDOG 
      gene copy number could be a potential marker of paternal mtDNA transmission or 
      not.Male factor infertility patients diagnosed with different infertility 
      subgroups such as azoospermia, oligoteratozoospermia, astheno-teratozoospermia 
      were included in this study: 13 infertile men and 25 healthy men as control 
      group. Quantitative real-time polymerase chain reaction (qPCR) analysis and 
      dual-color Fluorescence in situ hybridization (FISH) method were used to compare 
      the groups. FISH method was applied to verify qPCR results and two signals were 
      observed in nearly all patients. ENDOG gene copy number data were evaluated by 
      comparing them with entire human mtDNA next-generation sequencing (NGS) analysis 
      results obtained through bioinformatics and proteomics tools. Mitochondrial whole 
      genome sequencing (WGS) data allowed determination of novel and reported 
      variations such as single nucleotide polymorphisms (SNPs), multiple nucleotide 
      polymorphism (MNP), insertion/deletion (INDEL). Missense variants causing amino 
      acid substitution were filtered out from patients' mtDNA WGS data.Relative copy 
      number of target ENDOG gene in male infertility patients [0.49 (0.31 - 0.77)] was 
      lower than healthy controls [1.00 (0.66 - 1.51)], and statistical results showed 
      significant differences between the groups (p < 0.01). A total of 38 missense 
      variants were detected in the genes encoding the proteins involved in the 
      respiratory chain complex. Moreover, we detected paternal mtDNA transmissions in 
      the children of these patients who applied to assisted reproductive techniques.In 
      conclusion, this study reveals that ENDOG gene may be an important factor for the 
      PME mechanism in humans. To the best of our knowledge, this is the first study in 
      humans about this topic and assessment of ENDOG gene sequencing and gene 
      expression studies in a larger sample size including patients with male factor 
      infertility would be our future project.
CI  - (c) 2022. Society for Reproductive Investigation.
FAU - Eker, Candan
AU  - Eker C
AUID- ORCID: 0000-0001-9049-6131
AD  - Department of Molecular Biology and Genetics, Faculty of Science, Istanbul 
      University, 34134, Vezneciler, Istanbul, Turkey.
AD  - Argenit Technology, ITU ARI Technocity, ITU Ayazaga Campus, 34467, Sariyer, 
      Istanbul, Turkey.
FAU - Bilir, Mehmet Ulas
AU  - Bilir MU
AUID- ORCID: 0000-0001-8469-705X
AD  - Department of Molecular Biology and Genetics, Faculty of Science, Istanbul 
      University, 34134, Vezneciler, Istanbul, Turkey.
FAU - Celik, Hale Goksever
AU  - Celik HG
AUID- ORCID: 0000-0002-5162-3262
AD  - Department of Molecular Biology and Genetics, Faculty of Science, Istanbul 
      University, 34134, Vezneciler, Istanbul, Turkey.
AD  - Acibadem Fulya Hospital, Department of Obstetrics and Gynecology, IVF and 
      Endometriosis Center, 34349, Besiktas, Istanbul, Turkey.
FAU - Balci, Burcin Karamustafaoglu
AU  - Balci BK
AUID- ORCID: 0000-0001-5196-4502
AD  - Istanbul Faculty of Medicine, Department of Obstetrics and Gynecology, Division 
      of Reproductive Endocrinology and Infertility, Istanbul University, 34093, 
      Istanbul, Turkey.
FAU - Gunel, Tuba
AU  - Gunel T
AUID- ORCID: 0000-0003-3514-5210
AD  - Department of Molecular Biology and Genetics, Faculty of Science, Istanbul 
      University, 34134, Vezneciler, Istanbul, Turkey. gunel@istanbul.edu.tr.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220427
PL  - United States
TA  - Reprod Sci
JT  - Reproductive sciences (Thousand Oaks, Calif.)
JID - 101291249
RN  - 0 (DNA, Mitochondrial)
RN  - EC 3.1.- (Endodeoxyribonucleases)
RN  - EC 3.1.21.- (endonuclease G)
SB  - IM
EIN - Reprod Sci. 2022 May 4;:. PMID: 35508586
MH  - *DNA, Mitochondrial/genetics
MH  - *Endodeoxyribonucleases/genetics
MH  - Humans
MH  - In Situ Hybridization, Fluorescence
MH  - *Infertility, Male/genetics
MH  - Male
MH  - Mitochondria/genetics
MH  - Semen/metabolism
OTO - NOTNLM
OT  - ENDOG gene
OT  - Male infertility
OT  - Mitochondrial DNA
OT  - Mitochondrial endonuclease G
OT  - Paternal mitochondrial elimination
EDAT- 2022/04/29 06:00
MHDA- 2022/08/09 06:00
CRDT- 2022/04/28 05:30
PHST- 2021/10/29 00:00 [received]
PHST- 2022/04/15 00:00 [accepted]
PHST- 2022/04/29 06:00 [pubmed]
PHST- 2022/08/09 06:00 [medline]
PHST- 2022/04/28 05:30 [entrez]
AID - 10.1007/s43032-022-00953-8 [pii]
AID - 10.1007/s43032-022-00953-8 [doi]
PST - ppublish
SO  - Reprod Sci. 2022 Aug;29(8):2208-2222. doi: 10.1007/s43032-022-00953-8. Epub 2022 
      Apr 27.