{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T05:47:15Z","timestamp":1789451235667,"version":"build-2803163510"},"reference-count":34,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2018,7,11]],"date-time":"2018-07-11T00:00:00Z","timestamp":1531267200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["320030_160334"],"award-info":[{"award-number":["320030_160334"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp; Gen Med"],"published-print":{"date-parts":[[2018,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>One of the defining moments of human life occurs early during embryonic development, when individuals sexually differentiate into either male or female. Perturbation of this process can lead to disorders\/differences of sex development (<jats:styled-content style=\"fixed-case\">DSD<\/jats:styled-content>). Chromobox protein homolog 2 (<jats:italic><jats:styled-content style=\"fixed-case\">CBX<\/jats:styled-content>2<\/jats:italic>) has two distinct isoforms, <jats:styled-content style=\"fixed-case\">CBX<\/jats:styled-content>2.1 and <jats:styled-content style=\"fixed-case\">CBX<\/jats:styled-content>2.2: the role of <jats:styled-content style=\"fixed-case\">CBX<\/jats:styled-content>2.1 in <jats:styled-content style=\"fixed-case\">DSD<\/jats:styled-content> has been previously established, yet to date the function of the smaller isoform <jats:styled-content style=\"fixed-case\">CBX<\/jats:styled-content>2.2 remains unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The genomic <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> of two 46,<jats:styled-content style=\"fixed-case\">XY DSD<\/jats:styled-content> patients was analysed using whole exome sequencing. Furthermore, protein\/<jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> interaction studies were performed using <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> adenine methyltransferase identification (Dam<jats:styled-content style=\"fixed-case\">ID<\/jats:styled-content>) to identify putative binding partners of <jats:styled-content style=\"fixed-case\">CBX<\/jats:styled-content>2. Finally, in\u00a0vitro functional studies were used to elucidate the effect of wild\u2010type and variant <jats:styled-content style=\"fixed-case\">CBX<\/jats:styled-content>2.2 on selected downstream targets.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Here, we describe two patients with features of <jats:styled-content style=\"fixed-case\">DSD<\/jats:styled-content> i.e. atypical external genitalia, perineal hypospadias and no palpable gonads, each patient carrying a distinct <jats:styled-content style=\"fixed-case\">CBX<\/jats:styled-content>2.2 variant, p.Cys132Arg (c.394T&gt;C) and p.Cys154fs (c.460delT). We show that both <jats:styled-content style=\"fixed-case\">CBX<\/jats:styled-content>2.2 variants fail to regulate the expression of genes essential for sexual development, leading to a severe 46,<jats:styled-content style=\"fixed-case\">XY DSD<\/jats:styled-content> defect, likely because of a defective expression of <jats:styled-content style=\"fixed-case\">EMX<\/jats:styled-content>2 in the developing gonad.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our study indicates a distinct function of the shorter form of <jats:styled-content style=\"fixed-case\">CBX<\/jats:styled-content>2 and by identifying several of its unique targets, can advance our understanding of <jats:styled-content style=\"fixed-case\">DSD<\/jats:styled-content> pathogenesis and ultimately <jats:styled-content style=\"fixed-case\">DSD<\/jats:styled-content> diagnosis and management.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.445","type":"journal-article","created":{"date-parts":[[2018,7,12]],"date-time":"2018-07-12T02:54:39Z","timestamp":1531364079000},"page":"785-795","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Assembling the jigsaw puzzle: <scp>CBX<\/scp>2 isoform 2 and its targets in disorders\/differences of sex development"],"prefix":"10.1002","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5968-2307","authenticated-orcid":false,"given":"Patrick","family":"Sproll","sequence":"first","affiliation":[{"name":"Division of Endocrinology University of Fribourg Fribourg Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wassim","family":"Eid","sequence":"additional","affiliation":[{"name":"Division of Endocrinology University of Fribourg Fribourg Switzerland"},{"name":"Department of Biochemistry Medical Research Institute University of Alexandria Alexandria Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camila R.","family":"Gomes","sequence":"additional","affiliation":[{"name":"Medical School University of Sao Paulo Sao Paulo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Berenice B.","family":"Mendonca","sequence":"additional","affiliation":[{"name":"Medical School University of Sao Paulo Sao Paulo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalia L.","family":"Gomes","sequence":"additional","affiliation":[{"name":"Medical School University of Sao Paulo Sao Paulo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine M.\u2010F.","family":"Costa","sequence":"additional","affiliation":[{"name":"Medical School University of Sao Paulo Sao Paulo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Biason\u2010Lauber","sequence":"additional","affiliation":[{"name":"Division of Endocrinology University of Fribourg Fribourg Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,7,11]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2016.118"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2010.245"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2009.03.016"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2003-031389"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1210\/me.2014-1339"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/embor.2010.157"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.129.7.1633"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0925-4773(01)00546-9"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.48.5.1403"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1006\/mcne.2001.1046"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1136\/adc.2006.098319"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq418"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2011-1055"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-08-3367"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/31482"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1159\/000100033"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2010-0915"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.juro.2007.01.017"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.10.5.2261"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.124.9.1653"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.00530"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng0297-179"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2007.10.010"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1159\/000108930"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.36662"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1093\/jb\/mvi086"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.1239303"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2009.322"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1992.tb05319.x"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.129.13.3045"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.23.1.1-13.2003"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.5391806"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2007.148"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.220102"}],"container-title":["Molecular Genetics &amp; Genomic Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fmgg3.445","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mgg3.445","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,18]],"date-time":"2023-09-18T06:32:14Z","timestamp":1695018734000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/mgg3.445"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,7,11]]},"references-count":34,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2018,9]]}},"alternative-id":["10.1002\/mgg3.445"],"URL":"https:\/\/doi.org\/10.1002\/mgg3.445","archive":["Portico"],"relation":{},"ISSN":["2324-9269","2324-9269"],"issn-type":[{"value":"2324-9269","type":"print"},{"value":"2324-9269","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,7,11]]},"assertion":[{"value":"2018-06-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-06-13","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-07-11","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}