{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T10:56:58Z","timestamp":1790247418686,"version":"4.1.0"},"reference-count":20,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,1,24]],"date-time":"2020-01-24T00:00:00Z","timestamp":1579824000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,1,24]],"date-time":"2020-01-24T00:00:00Z","timestamp":1579824000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["17H06248"],"award-info":[{"award-number":["17H06248"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["17H03616"],"award-info":[{"award-number":["17H03616"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["18ek0109266h0002"],"award-info":[{"award-number":["18ek0109266h0002"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["18ek0109278h0002"],"award-info":[{"award-number":["18ek0109278h0002"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007786","name":"National Center for Child Health and Development","doi-asserted-by":"crossref","award":["2019-A1"],"award-info":[{"award-number":["2019-A1"]}],"id":[{"id":"10.13039\/100007786","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Cell Pediatr"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n<jats:title>Background<\/jats:title>\n<jats:p>X chromosome inactivation (XCI) is an indispensable process in the development of human female embryos. Reportedly, XCI occurs when a blastocyst contains 10\u201312 embryonic progenitor cells. To date, it remains unclear whether XCI ratios are normally preserved in Klinefelter syndrome (KS) patients with 47,XXY karyotype.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Methods<\/jats:title>\n<jats:p>We examined XCI ratios in 18 KS patients through DNA methylation analysis for the polymorphic trinucleotide locus in the <jats:italic>AR<\/jats:italic> gene. The results of the KS patients were compared to previous data from healthy young women.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Results<\/jats:title>\n<jats:p>XCI ratios in KS patients followed a normal distribution. Skewed XCI was observed in two patients, one of whom exhibited extremely skewed XCI. The frequencies of skewed and extremely skewed XCI in the KS cohort were comparable to those in healthy women.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Conclusion<\/jats:title>\n<jats:p>This study confirmed the rarity of skewed XCI in KS patients. These results indicate that the presence of a supernumerary X chromosome during the cleavage and early blastocyst stages does not affect the developmental tempo of embryos. Our data deserve further validation.<\/jats:p>\n<\/jats:sec>","DOI":"10.1186\/s40348-020-0093-x","type":"journal-article","created":{"date-parts":[[2020,1,24]],"date-time":"2020-01-24T00:05:35Z","timestamp":1579824335000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Random X chromosome inactivation in patients with Klinefelter syndrome"],"prefix":"10.1186","volume":"7","author":[{"given":"Kenichi","family":"Kinjo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoko","family":"Yoshida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshitomo","family":"Kobori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Okada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erina","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsutomu","family":"Ogata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mami","family":"Miyado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9971-4035","authenticated-orcid":false,"given":"Maki","family":"Fukami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,1,24]]},"reference":[{"issue":"6","key":"93_CR1","first-page":"1101","volume":"58","author":"JW Belmont","year":"1996","unstructured":"Belmont JW (1996) Genetic control of X inactivation and processes leading to X-inactivation skewing. Am J Hum Genet 58(6):1101\u20131108","journal-title":"Am J Hum Genet"},{"issue":"5","key":"93_CR2","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1034\/j.1399-0004.2000.580504.x","volume":"58","author":"CJ Brown","year":"2000","unstructured":"Brown CJ, Robinson WP (2000) The causes and consequences of random and non-random X chromosome inactivation in humans. Clin Genet 58(5):353\u2013363","journal-title":"Clin Genet"},{"issue":"451","key":"93_CR3","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1080\/08035320600618783","volume":"95","author":"KH \u00d8rstavik","year":"2006","unstructured":"\u00d8rstavik KH (2006) Skewed X inactivation in healthy individuals and in different diseases. Acta Paediatr Suppl 95(451):24\u201329","journal-title":"Acta Paediatr Suppl"},{"issue":"1","key":"93_CR4","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1182\/blood.V88.1.59.59","volume":"88","author":"L Busque","year":"1996","unstructured":"Busque L, Mio R, Mattioli J, Brais E, Blais N, Lalonde Y, Maragh M, Gilliland DG (1996) Nonrandom X-inactivation patterns in normal females: lyonization ratios vary with age. Blood 88(1):59\u201365","journal-title":"Blood"},{"issue":"5","key":"93_CR5","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1056\/NEJM199801293380611","volume":"338","author":"JM Puck","year":"1998","unstructured":"Puck JM, Willard HF (1998) X inactivation in females with X-linked disease. N Engl J Med 338(5):325\u2013328","journal-title":"N Engl J Med"},{"issue":"3","key":"93_CR6","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1086\/507565","volume":"79","author":"JM Amos-Landgraf","year":"2006","unstructured":"Amos-Landgraf JM, Cottle A, Plenge RM, Friez M, Schwartz CE, Longshore J, Willard HF (2006) X chromosome-inactivation patterns of 1,005 phenotypically unaffected females. Am J Hum Genet 79(3):493\u2013499","journal-title":"Am J Hum Genet"},{"issue":"9","key":"93_CR7","doi-asserted-by":"publisher","first-page":"1762","DOI":"10.1093\/humrep\/dez117","volume":"34","author":"T Yoshida","year":"2019","unstructured":"Yoshida T, Miyado M, Mikami M, Suzuki E, Kinjo K, Matsubara K, Ogata T, Akutsu H, Kagami M, Fukami M (2019) Aneuploid rescue precedes X-chromosome inactivation and increases the incidence of its skewness by reducing the size of the embryonic progenitor cell pool. Hum Reprod 34(9):1762\u20131769","journal-title":"Hum Reprod"},{"issue":"2","key":"93_CR8","first-page":"312","volume":"31","author":"DH Kort","year":"2016","unstructured":"Kort DH, Chia G, Treff NR, Tanaka AJ, Xing T, Vensand LB, Micucci S, Prosser R, Lobo RA, Sauer MV, Egli D (2016) Human embryos commonly form abnormal nuclei during development: a mechanism of DNA damage, embryonic aneuploidy, and developmental arrest. Hum Reprod 31(2):312\u2013323","journal-title":"Hum Reprod"},{"issue":"6","key":"93_CR9","doi-asserted-by":"publisher","first-page":"1353","DOI":"10.1086\/301651","volume":"61","author":"AW Lau","year":"1997","unstructured":"Lau AW, Brown CJ, Penaherrera M, Langlois S, Kalousek DK, Robinson WP (1997) Skewed X-chromosome inactivation is common in fetuses or newborns associated with confined placental mosaicism. Am J Hum Genet 61(6):1353\u20131361","journal-title":"Am J Hum Genet"},{"issue":"1","key":"93_CR10","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1210\/jc.2012-2382","volume":"98","author":"KA Groth","year":"2013","unstructured":"Groth KA, Skakkebaek A, Host C, Gravholt CH, Bojesen A (2013) Clinical review: Klinefelter syndrome--a clinical update. J Clin Endocrinol Metab 98(1):20\u201330","journal-title":"J Clin Endocrinol Metab"},{"issue":"6","key":"93_CR11","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1093\/molehr\/gaq019","volume":"16","author":"F Tuttelmann","year":"2010","unstructured":"Tuttelmann F, Gromoll J (2010) Novel genetic aspects of Klinefelter\u2019s syndrome. Mol Hum Reprod 16(6):386\u2013395","journal-title":"Mol Hum Reprod"},{"issue":"6 Pt 2","key":"93_CR12","doi-asserted-by":"publisher","first-page":"e642","DOI":"10.1111\/j.1365-2605.2011.01223.x","volume":"34","author":"A Bojesen","year":"2011","unstructured":"Bojesen A, Hertz JM, Gravholt CH (2011) Genotype and phenotype in Klinefelter syndrome - impact of androgen receptor polymorphism and skewed X inactivation. Int J Androl 34(6 Pt 2):e642\u2013e648","journal-title":"Int J Androl"},{"issue":"5","key":"93_CR13","doi-asserted-by":"publisher","first-page":"955","DOI":"10.2164\/jandrol.111.016030","volume":"33","author":"A Mehta","year":"2012","unstructured":"Mehta A, Malek-Jones M, Bolyakov A, Mielnik A, Schlegel PN, Paduch DA (2012) Methylation-specific PCR allows for fast diagnosis of X chromosome disomy and reveals skewed inactivation of the X chromosome in men with Klinefelter syndrome. J Androl 33(5):955\u2013962","journal-title":"J Androl"},{"issue":"8","key":"93_CR14","doi-asserted-by":"publisher","first-page":"1653","DOI":"10.1093\/humrep\/16.8.1653","volume":"16","author":"Y Suzuki","year":"2001","unstructured":"Suzuki Y, Sasagawa I, Tateno T, Ashida J, Nakada T, Muroya K, Ogata T (2001) Mutation screening and CAG repeat length analysis of the androgen receptor gene in Klinefelter\u2019s syndrome patients with and without spermatogenesis. Hum Reprod 16(8):1653\u20131656","journal-title":"Hum Reprod"},{"issue":"12","key":"93_CR15","doi-asserted-by":"publisher","first-page":"6208","DOI":"10.1210\/jc.2004-1424","volume":"89","author":"M Zitzmann","year":"2004","unstructured":"Zitzmann M, Depenbusch M, Gromoll J, Nieschlag E (2004) X-chromosome inactivation patterns and androgen receptor functionality influence phenotype and social characteristics as well as pharmacogenetics of testosterone therapy in Klinefelter patients. J Clin Endocrinol Metab 89(12):6208\u20136217","journal-title":"J Clin Endocrinol Metab"},{"issue":"9","key":"93_CR16","doi-asserted-by":"publisher","first-page":"5041","DOI":"10.1210\/jc.2005-0432","volume":"90","author":"AR Zinn","year":"2005","unstructured":"Zinn AR, Ramos P, Elder FF, Kowal K, Samango-Sprouse C, Ross JL (2005) Androgen receptor CAGn repeat length influences phenotype of 47,XXY (Klinefelter) syndrome. J Clin Endocrinol Metab 90(9):5041\u20135046","journal-title":"J Clin Endocrinol Metab"},{"issue":"13","key":"93_CR17","doi-asserted-by":"publisher","first-page":"e100","DOI":"10.1182\/blood-2011-11-390351","volume":"119","author":"SI Swierczek","year":"2012","unstructured":"Swierczek SI, Piterkova L, Jelinek J, Agarwal N, Hammoud S, Wilson A, Hickman K, Parker CJ, Cairns BR, Prchal JT (2012) Methylation of AR locus does not always reflect X chromosome inactivation state. Blood 119(13):e100\u2013e109","journal-title":"Blood"},{"issue":"6","key":"93_CR18","first-page":"1229","volume":"51","author":"RC Allen","year":"1992","unstructured":"Allen RC, Zoghbi HY, Moseley AB, Rosenblatt HM, Belmont JW (1992) Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. Am J Hum Genet 51(6):1229\u20131239","journal-title":"Am J Hum Genet"},{"issue":"4","key":"93_CR19","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1093\/humupd\/dmg028","volume":"9","author":"NS Thomas","year":"2003","unstructured":"Thomas NS, Hassold TJ (2003) Aberrant recombination and the origin of Klinefelter syndrome. Hum Reprod Update 9(4):309\u2013317","journal-title":"Hum Reprod Update"},{"issue":"6","key":"93_CR20","first-page":"855","volume":"45","author":"EB Hook","year":"1989","unstructured":"Hook EB, Topol BB, Cross PK (1989) The natural history of cytogenetically abnormal fetuses detected at midtrimester amniocentesis which are not terminated electively: new data and estimates of the excess and relative risk of late fetal death associated with 47,+21 and some other abnormal karyotypes. Am J Hum Genet 45(6):855\u2013861","journal-title":"Am J Hum Genet"}],"container-title":["Molecular and Cellular Pediatrics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s40348-020-0093-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s40348-020-0093-x\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s40348-020-0093-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,1,23]],"date-time":"2021-01-23T00:08:47Z","timestamp":1611360527000},"score":1,"resource":{"primary":{"URL":"https:\/\/molcellped.springeropen.com\/articles\/10.1186\/s40348-020-0093-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,24]]},"references-count":20,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,12]]}},"alternative-id":["93"],"URL":"https:\/\/doi.org\/10.1186\/s40348-020-0093-x","relation":{},"ISSN":["2194-7791"],"issn-type":[{"value":"2194-7791","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1,24]]},"assertion":[{"value":"3 October 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 January 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 January 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"This study was approved by the Institutional Review Board Committee at the National Center for Child Health and Development and performed after obtaining written informed consent from the participants.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"1"}}