Rare missense variant inMSH4associated with primary gonadal failure in both 46, XX and 46, XY individuals
| العنوان: | Rare missense variant inMSH4associated with primary gonadal failure in both 46, XX and 46, XY individuals |
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| المؤلفون: | Mehdi Totonchi, Mehri Mashayekhi, Ken McElreavey, Navid Almadani, Anu Bashambou, Arvand Akbari, Kimiya Padidar, Najmeh Salehi, Mohammad Ali Sadighi Gilani |
| المساهمون: | Royan Institute for Reproductive Biomedicine [Tehran, Iran], Academic Center for Education, Culture and Research (ACECR), University of Tehran, Génétique du Développement humain - Human developmental genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), This study was financially supported by Royan Institute, Tehran, Iran, and Institut Pasteur, Paris, France, We are sincerely thankful to the personnel of Royan Department of Genetics and the Human Developmental Genetics Unit of Institut Pasteur, Paris, France, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS) |
| المصدر: | Human Reproduction Human Reproduction, 2021, 36 (4), pp.1134-1145. ⟨10.1093/humrep/deaa362⟩ Human Reproduction, Oxford University Press (OUP), 2021, 36 (4), pp.1134-1145. ⟨10.1093/humrep/deaa362⟩ |
| بيانات النشر: | Oxford University Press (OUP), 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Male, Proband, 46, XX Disorders of Sex Development, [SDV]Life Sciences [q-bio], Cell Cycle Proteins, Iran, MESH: Mice, Knockout, Mice, non-obstructive azoospermia, Missense mutation, MESH: Animals, Exome sequencing, Mice, Knockout, Sanger sequencing, Genetics, 0303 health sciences, MESH: Paris, 030305 genetics & heredity, Rehabilitation, Obstetrics and Gynecology, oligozoospermia, DNA-Binding Proteins, symbols, Female, primary gonadal failure, France, Paris, dbSNP, familial exome sequencing, Biology, 03 medical and health sciences, symbols.namesake, MESH: Cell Cycle Proteins, Animals, Humans, MESH: Mice, Gene, Retrospective Studies, 030304 developmental biology, Disorder of Sex Development, 46,XY, MESH: Humans, MESH: Retrospective Studies, MSH4, MESH: Male, primary ovarian insufficiency, MESH: France, MSH5, Reproductive Medicine, MESH: Iran, MESH: Female, MESH: DNA-Binding Proteins |
| الوصف: | STUDY QUESTIONCan whole-exome sequencing (WES) reveal a shared pathogenic variant responsible for primary gonadal failure in both male and female patients from a consanguineous family?SUMMARY ANSWERPatients with primary ovarian insufficiency (POI) and non-obstructive azoospermia (NOA) were homozygous for the rare missense variant p. S754L located in the highly conserved MSH4 MutS signature motif of the ATPase domain. An oligozoospermic patient was heterozygous for the variant.WHAT IS KNOWN ALREADYMSH4 is a meiosis-specific protein expressed at a certain level in the testes and ovaries. Along with its heterodimer partner MSH5, it is responsible for double-strand Holliday junction recognition and stabilization, to ensure accurate chromosome segregation during meiosis. Knockout male and female mice for Msh4 and Msh5 are reportedly infertile due to meiotic arrest. In humans, MSH4 is associated with male and female gonadal failure, with distinct variations in the MutS domain V.STUDY DESIGN, SIZE, DURATIONThis was a retrospective genetics study of a consanguineous family with multiple cases of gonadal failure in both genders. The subject family was recruited in Iran, in 2018.PARTICIPANTS/MATERIALS, SETTING, METHODSThe proband who is affected by POI, an NOA brother, a fertile sister and their parents were subjected to WES. The discovered variant was validated in these individuals, and the rest of the family was also genotyped by Sanger sequencing. The variant was not detected in 800 healthy Iranian individuals from the Iranome database nor in 30 sporadic NOA and 30 sporadic POI patients. Suggested effect in aberrant splicing was studied by RT-PCR. Moreover, protein homology modeling was used to further investigate the amino acid substitution in silico.MAIN RESULTS AND THE ROLE OF CHANCEThe discovered variant is very rare and has never been reported in the homozygous state. It occurs in the ATPase domain at Serine 754, the first residue within the highly conserved MutS signature motif, substituting it with a Leucine. All variant effect prediction tools indicated this variant as deleterious. Since the substitution occurs immediately before the Walker B motif at position 755, further investigations based on protein homology were conducted. Considering the modeling results, the nature of the substituted amino acid residue and the distances between p. S754L variation and the residues of the Walker B motif suggested the possibility of conformational changes affecting the ATPase activity of the protein.LARGE SCALE DATAWe have submitted dbSNP entry rs377712900 to ClinVar under SCV001169709, SCV001169708 and SCV001142647 for oligozoospermia, NOA and POI, respectively.LIMITATIONS, REASONS FOR CAUTIONStudies in model organisms can shed more light on the role of this variant as our results were obtained by variant effect prediction tools and protein homology modeling.WIDER IMPLICATIONS OF THE FINDINGSIdentification of variants in meiotic genes should improve genetic counseling for both male and female infertility. Also, as two of our NOA patients underwent testicular sperm extraction (TESE) with no success, ruling out the existence of pathogenic variants in meiotic genes in such patients prior to TESE could prove useful.STUDY FUNDING/COMPETING INTEREST(S)This study was financially supported by Royan Institute in Tehran, Iran, and Institut Pasteur in Paris, France. The authors declare no competing interests.TRIAL REGISTRATION NUMBERN/A |
| تدمد: | 1460-2350 0268-1161 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7fbb6fadc8926a4bf1f45ebf363194abTest https://doi.org/10.1093/humrep/deaa362Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....7fbb6fadc8926a4bf1f45ebf363194ab |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602350 02681161 |
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