{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T11:36:49Z","timestamp":1784806609854,"version":"3.55.0"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2020,12,18]],"date-time":"2020-12-18T00:00:00Z","timestamp":1608249600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Professor Christopher Chen Endowment Fund"},{"name":"University of Queensland and National Health and Medical Research Council","award":["Project Grants APP1078134, APP1103689 and APP1122484"],"award-info":[{"award-number":["Project Grants APP1078134, APP1103689 and APP1122484"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,2,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Premature loss of ovarian activity before 40\u2009years of age is known as primary ovarian insufficiency (POI) and occurs in \u223c1% of women. A more subtle decline in ovarian activity, known as premature ovarian ageing (POA), occurs in \u223c10% of women. Despite the high prevalence of POA, very little is known regarding its genetic causation. Senataxin (SETX) is an RNA\/DNA helicase involved in repair of oxidative stress-induced DNA damage. Homozygous mutation of SETX leads to the neurodegenerative disorder, ataxia oculomotor apraxia type 2 (AOA2). There have been reports of POI in AOA2 females suggesting a link between SETX and ovarian ageing. Here, we studied female mice lacking either one (Setx+\/\u2212) or both (Setx\u2212\/\u2212) copies of SETX over a 12- to 14-month period. We find that DNA damage is increased in oocytes from 8-month-old Setx+\/\u2212 and Setx\u2212\/\u2212 females compared with Setx+\/+ oocytes leading to a marked reduction in all classes of ovarian follicles at least 4\u2009months earlier than typically occurs in female mice. Furthermore, during a 12-month long mating trial, Setx+\/\u2212 and Setx\u2212\/\u2212 females produced significantly fewer pups than Setx+\/+ females from 7\u2009months of age onwards. These data show that SETX is critical for preventing POA in mice, likely by preserving DNA integrity in oocytes. Intriguingly, heterozygous Setx loss causes an equally severe impact on ovarian ageing as homozygous Setx loss. Because heterozygous SETX disruption is less likely to produce systemic effects, SETX compromise could underpin some cases of insidious POA.<\/jats:p>","DOI":"10.1093\/molehr\/gaaa080","type":"journal-article","created":{"date-parts":[[2020,11,28]],"date-time":"2020-11-28T12:10:30Z","timestamp":1606565430000},"source":"Crossref","is-referenced-by-count":15,"title":["Premature ovarian ageing following heterozygous loss of Senataxin"],"prefix":"10.1093","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2835-8464","authenticated-orcid":false,"given":"G N","family":"Subramanian","sequence":"first","affiliation":[{"name":"The Christopher Chen Oocyte Biology Research Laboratory, UQ Centre for Clinical Research, The University of Queensland, Herston, QLD, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Lavin","sequence":"additional","affiliation":[{"name":"Cancer and Neuroscience Laboratory, UQ Centre for Clinical Research, The University of Queensland, Herston, QLD, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3104-0449","authenticated-orcid":false,"given":"H A","family":"Homer","sequence":"additional","affiliation":[{"name":"The Christopher Chen Oocyte Biology Research Laboratory, UQ Centre for Clinical Research, The University of Queensland, Herston, QLD, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,12,18]]},"reference":[{"key":"2021020516054533800_gaaa080-B1","first-page":"4","article-title":"The presence of immature GV-stage oocytes during IVF\/ICSI is a marker of poor oocyte quality: a pilot study","volume":"8","author":"Astbury","year":"2020","journal-title":"Med Sci (Basel)"},{"key":"2021020516054533800_gaaa080-B2","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1007\/s12311-019-01012-w","article-title":"Disruption of spermatogenesis and infertility in ataxia with oculomotor apraxia type 2 (AOA2)","volume":"18","author":"Becherel","year":"2019","journal-title":"Cerebellum"},{"key":"2021020516054533800_gaaa080-B3","doi-asserted-by":"crossref","first-page":"e1003435","DOI":"10.1371\/journal.pgen.1003435","article-title":"Senataxin plays an essential role with DNA damage response proteins in meiotic recombination and gene silencing","volume":"9","author":"Becherel","year":"2013","journal-title":"PLoS Genet"},{"key":"2021020516054533800_gaaa080-B4","doi-asserted-by":"crossref","first-page":"R15","DOI":"10.1530\/REP-16-0069","article-title":"DNA damage responses in mammalian oocytes","volume":"152","author":"Collins","year":"2016","journal-title":"Reproduction"},{"key":"2021020516054533800_gaaa080-B5","doi-asserted-by":"crossref","first-page":"8553","DOI":"10.1038\/ncomms9553","article-title":"DNA damage induces a meiotic arrest in mouse oocytes mediated by the spindle assembly checkpoint","volume":"6","author":"Collins","year":"2015","journal-title":"Nat Commun"},{"key":"2021020516054533800_gaaa080-B6","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1093\/molehr\/gaw023","article-title":"Granulosa cell and oocyte mitochondrial abnormalities in a mouse model of fragile X premature ovarian insufficiency","volume":"22","author":"Dioguardi","year":"2016","journal-title":"Mol Hum Reprod"},{"key":"2021020516054533800_gaaa080-B7","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1002\/mus.21328","article-title":"Sensorimotor neuronopathy in ataxia with oculomotor apraxia type 2","volume":"40","author":"Gazulla","year":"2009","journal-title":"Muscle Nerve"},{"key":"2021020516054533800_gaaa080-B8","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/1477-7827-9-23","article-title":"Defining ovarian reserve to better understand ovarian aging","volume":"9","author":"Gleicher","year":"2011","journal-title":"Reprod Biol Endocrinol"},{"key":"2021020516054533800_gaaa080-B9","doi-asserted-by":"crossref","first-page":"2395","DOI":"10.1093\/humrep\/dep256","article-title":"Do etiologies of premature ovarian aging (POA) mimic those of premature ovarian failure (POF)?","volume":"24","author":"Gleicher","year":"2009","journal-title":"Hum Reprod"},{"key":"2021020516054533800_gaaa080-B10","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1093\/humupd\/dmx035","article-title":"Regulation of chromosome segregation in oocytes and the cellular basis for female meiotic errors","volume":"24","author":"Greaney","year":"2018","journal-title":"Hum Reprod Update"},{"key":"2021020516054533800_gaaa080-B11","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1093\/humrep\/dey358","article-title":"BRCA1\/2 gene mutations do not affect the capacity of oocytes from breast cancer candidates for fertility preservation to mature in vitro","volume":"34","author":"Grynberg","year":"2019","journal-title":"Hum Reprod"},{"key":"2021020516054533800_gaaa080-B12","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/j.fertnstert.2018.10.014","article-title":"BRCA carriers have similar reproductive potential at baseline to noncarriers: comparisons in cancer and cancer-free cohorts undergoing fertility preservation","volume":"111","author":"Gunnala","year":"2019","journal-title":"Fertil Steril"},{"key":"2021020516054533800_gaaa080-B13","doi-asserted-by":"crossref","first-page":"3548","DOI":"10.1210\/jc.2015-4279","article-title":"Excessive age-related decline in functional ovarian reserve in infertile women: prospective cohort of 15,500 women","volume":"101","author":"Iliodromiti","year":"2016","journal-title":"J Clin Endocrinol Metab"},{"key":"2021020516054533800_gaaa080-B14","doi-asserted-by":"crossref","first-page":"6641","DOI":"10.1096\/fj.202000153R","article-title":"Sirt3 is dispensable for oocyte quality and female fertility in lean and obese mice","volume":"34","author":"Iljas","year":"2020","journal-title":"FASEB J"},{"key":"2021020516054533800_gaaa080-B15","doi-asserted-by":"crossref","first-page":"e13204","DOI":"10.1111\/acel.13204","article-title":"Sirt1 sustains female fertility by slowing age-related decline in oocyte quality required for post-fertilization embryo development","volume":"19","author":"Iljas","year":"2020","journal-title":"Aging Cell"},{"key":"2021020516054533800_gaaa080-B16","doi-asserted-by":"crossref","first-page":"4576","DOI":"10.1073\/pnas.83.12.4576","article-title":"Promotion of the Whitten effect in female mice by synthetic analogs of male urinary constituents","volume":"83","author":"Jemiolo","year":"1986","journal-title":"Proc Natl Acad Sci USA"},{"key":"2021020516054533800_gaaa080-B17","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1016\/j.tem.2018.07.002","article-title":"Molecular genetics of premature ovarian insufficiency","volume":"29","author":"Jiao","year":"2018","journal-title":"Trends Endocrinol Metab"},{"key":"2021020516054533800_gaaa080-B18","doi-asserted-by":"crossref","first-page":"e25230","DOI":"10.4161\/rdis.25230","article-title":"Senataxin protects the genome: implications for neurodegeneration and other abnormalities","volume":"1","author":"Lavin","year":"2013","journal-title":"Rare Dis"},{"key":"2021020516054533800_gaaa080-B19","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1095\/biolreprod.110.088583","article-title":"Oxidative damage increases and antioxidant gene expression decreases with aging in the mouse ovary","volume":"84","author":"Lim","year":"2011","journal-title":"Biol Reprod"},{"key":"2021020516054533800_gaaa080-B20","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.1002\/ajmg.a.31816","article-title":"Ovarian failure in ataxia with oculomotor apraxia type 2","volume":"143a","author":"Lynch","year":"2007","journal-title":"Am J Med Genet"},{"key":"2021020516054533800_gaaa080-B21","doi-asserted-by":"crossref","first-page":"8706","DOI":"10.1038\/ncomms9706","article-title":"DNA damage-induced metaphase I arrest is mediated by the spindle assembly checkpoint and maternal age","volume":"6","author":"Marangos","year":"2015","journal-title":"Nat Commun"},{"key":"2021020516054533800_gaaa080-B22","first-page":"200","article-title":"Initial and cyclic recruitment of ovarian follicles","volume":"21","author":"McGee","year":"2000","journal-title":"Endocr Rev"},{"key":"2021020516054533800_gaaa080-B23","doi-asserted-by":"crossref","first-page":"1947","DOI":"10.1126\/science.1103974","article-title":"The GS-linked receptor GPR3 maintains meiotic arrest in mammalian oocytes","volume":"306","author":"Mehlmann","year":"2004","journal-title":"Science"},{"key":"2021020516054533800_gaaa080-B24","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1210\/mend.13.6.0306","article-title":"Targeted expression of Bcl-2 in mouse oocytes inhibits ovarian follicle atresia and prevents spontaneous and chemotherapy-induced oocyte apoptosis in vitro","volume":"13","author":"Morita","year":"1999","journal-title":"Mol Endocrinol"},{"key":"2021020516054533800_gaaa080-B25","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/j.ydbio.2008.01.048","article-title":"Age-associated increase in aneuploidy and changes in gene expression in mouse eggs","volume":"316","author":"Pan","year":"2008","journal-title":"Dev Biol"},{"key":"2021020516054533800_gaaa080-B26","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1093\/humrep\/den050","article-title":"Anti-Mullerian hormone indicates early ovarian decline in fragile X mental retardation (FMR1) premutation carriers: a preliminary study","volume":"23","author":"Rohr","year":"2008","journal-title":"Hum Reprod"},{"key":"2021020516054533800_gaaa080-B27","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1007\/s10815-020-01774-x","article-title":"An explanation of the mechanisms underlying fragile X-associated premature ovarian insufficiency","volume":"37","author":"Rose","year":"2020","journal-title":"J Assist Reprod Genet"},{"key":"2021020516054533800_gaaa080-B28","doi-asserted-by":"crossref","first-page":"e201907213","DOI":"10.1083\/jcb.201907213","article-title":"Oocytes mount a noncanonical DNA damage response involving APC-Cdh1-mediated proteolysis","volume":"219","author":"Subramanian","year":"2020","journal-title":"J Cell Biol"},{"key":"2021020516054533800_gaaa080-B29","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1038\/nature05337","article-title":"p63 protects the female germ line during meiotic arrest","volume":"444","author":"Suh","year":"2006","journal-title":"Nature"},{"key":"2021020516054533800_gaaa080-B30","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1083\/jcb.200701042","article-title":"Senataxin, defective in ataxia oculomotor apraxia type 2, is involved in the defense against oxidative DNA damage","volume":"177","author":"Suraweera","year":"2007","journal-title":"J Cell Biol"},{"key":"2021020516054533800_gaaa080-B31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/molehr\/gan069","article-title":"Chromatin configurations in the germinal vesicle of mammalian oocytes","volume":"15","author":"Tan","year":"2009","journal-title":"Mol Hum Reprod"},{"key":"2021020516054533800_gaaa080-B32","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/1477-7827-1-11","article-title":"Ovarian follicle counts\u2014not as simple as 1, 2, 3","volume":"1","author":"Tilly","year":"2003","journal-title":"Reprod Biol Endocrinol"},{"key":"2021020516054533800_gaaa080-B33","doi-asserted-by":"crossref","first-page":"172ra121","DOI":"10.1126\/scitranslmed.3004925","article-title":"Impairment of BRCA1-related DNA double-strand break repair leads to ovarian aging in mice and humans","volume":"5","author":"Titus","year":"2013","journal-title":"Sci Transl Med"},{"key":"2021020516054533800_gaaa080-B34","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1095\/biolreprod66.4.917","article-title":"Smad 3 may regulate follicular growth in the mouse ovary","volume":"66","author":"Tomic","year":"2002","journal-title":"Biol Reprod"},{"key":"2021020516054533800_gaaa080-B35","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1210\/er.2016-1047","article-title":"Premature ovarian insufficiency: new perspectives on genetic cause and phenotypic spectrum","volume":"37","author":"Tucker","year":"2016","journal-title":"Endocr Rev"},{"key":"2021020516054533800_gaaa080-B36","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1093\/humupd\/dmz043","article-title":"BRCA-related ATM-mediated DNA double-strand break repair and ovarian aging","volume":"26","author":"Turan","year":"2020","journal-title":"Hum Reprod Update"},{"key":"2021020516054533800_gaaa080-B37","doi-asserted-by":"crossref","first-page":"e8772","DOI":"10.1371\/journal.pone.0008772","article-title":"Human ovarian reserve from conception to the menopause","volume":"5","author":"Wallace","year":"2010","journal-title":"PLoS One"},{"key":"2021020516054533800_gaaa080-B38","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1093\/humrep\/dew027","article-title":"ESHRE Guideline: management of women with premature ovarian insufficiency","volume":"31","author":"Webber","year":"2016","journal-title":"Hum Reprod"},{"key":"2021020516054533800_gaaa080-B39","doi-asserted-by":"crossref","first-page":"3393","DOI":"10.1038\/s41467-020-17088-6","article-title":"Nampt-mediated spindle sizing secures a post-anaphase increase in spindle speed required for extreme asymmetry","volume":"11","author":"Wei","year":"2020","journal-title":"Nat Commun"},{"key":"2021020516054533800_gaaa080-B40","doi-asserted-by":"crossref","first-page":"4029","DOI":"10.1038\/s41467-018-06510-9","article-title":"Cdk1 inactivation induces post-anaphase-onset spindle migration and membrane protrusion required for extreme asymmetry in mouse oocytes","volume":"9","author":"Wei","year":"2018","journal-title":"Nat Commun"},{"key":"2021020516054533800_gaaa080-B41","doi-asserted-by":"crossref","first-page":"4569","DOI":"10.1210\/jc.2004-0347","article-title":"Evidence of early ovarian aging in fragile X premutation carriers","volume":"89","author":"Welt","year":"2004","journal-title":"J Clin Endocrinol Metab"},{"key":"2021020516054533800_gaaa080-B42","doi-asserted-by":"crossref","first-page":"jcs233379","DOI":"10.1242\/jcs.233379","article-title":"First meiotic anaphase requires Cep55-dependent inhibitory cyclin-dependent kinase 1 phosphorylation","volume":"132","author":"Zhou","year":"2019","journal-title":"J Cell Sci"}],"container-title":["Molecular Human Reproduction"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/molehr\/advance-article-pdf\/doi\/10.1093\/molehr\/gaaa080\/35102819\/gaaa080.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/molehr\/article-pdf\/27\/2\/gaaa080\/36200326\/gaaa080.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/molehr\/article-pdf\/27\/2\/gaaa080\/36200326\/gaaa080.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,2,8]],"date-time":"2021-02-08T14:08:16Z","timestamp":1612793296000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/molehr\/article\/doi\/10.1093\/molehr\/gaaa080\/6041621"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,18]]},"references-count":42,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2021,2,5]]}},"URL":"https:\/\/doi.org\/10.1093\/molehr\/gaaa080","relation":{},"ISSN":["1460-2407"],"issn-type":[{"value":"1460-2407","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,2,1]]},"published":{"date-parts":[[2020,12,18]]},"article-number":"gaaa080"}}