{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T21:47:18Z","timestamp":1757540838003,"version":"3.41.2"},"reference-count":21,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2020,5,15]],"date-time":"2020-05-15T00:00:00Z","timestamp":1589500800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp; Gen Med"],"published-print":{"date-parts":[[2020,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>The Bosch\u2010Boonstra\u2010Schaaf optic atrophy syndrome (BBSOAS) is an autosomal\u2010dominant disorder (OMIM615722) mostly characterized by optic atrophy and\/or hypoplasia, mild intellectual disability, hypotonia, seizures\/infantile epilepsy. This disorder is caused by loss\u2010of\u2010function alterations of <jats:italic>NR2F1<\/jats:italic> (i.e., either whole gene deletions or single nucleotide variants) and, to date, 40 patients have been identified with deletions or mutations in this gene. Here we describe two monozygotic twins harboring a de novo missense variant in the DNA\u2010binding domain of <jats:italic>NR2F1<\/jats:italic> (c.313G&gt;A, p.Gly105Ser), with well\u2010characterized features associated to BBSOAS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Patients\u2019 DNA was analyzed by exome sequencing identifying the missense variant c.313G&gt;A in <jats:italic>NR2F1<\/jats:italic> (NM_005654.4). Furthermore, molecular modeling was performed to evaluate putative differences in DNA binding between wild\u2010type and mutated NR2F1.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The missense variant is predicted to be likely pathogenetic following the ACMG (American College of Medical Genetics and Genomics)\/AMP (Association for Molecular Pathology) guidelines. Indeed, dynamic simulation experiments highlighted that the Gly105Ser substitution let the formation of a hydrogen bond between the S105 side chain and R142 and a base (G5) of the DNA sequence, allowing us to hypothesize that the G105 residue might be evolutionary conserved due to the absence of a side chain, besides glycine conformational features. Therefore, the G105S variation seems to cause a stiffening and a possible deformation in the protein\u2010DNA complex due to the interaction of residues R142\u2010S105 and G5 on the DNA, compared to the wild\u2010type.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In summary, we described two monozygotic twins harboring a novel Gly105Ser mutation in NR2F1 DNA binding domain, displaying the classical phenotype of BBSOAS\u2010affected patients. Our computational data suggest a dominant negative effect of this newly characterized missense variant. To date, this is the first genetic report analyzing in silico structural consequences of NR2F1 Gly105Ser substitution.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.1278","type":"journal-article","created":{"date-parts":[[2020,5,16]],"date-time":"2020-05-16T05:33:52Z","timestamp":1589607232000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Missense <i>NR2F1<\/i> variant in monozygotic twins affected with the Bosch\u2013Boonstra\u2013Schaaf optic atrophy syndrome"],"prefix":"10.1002","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6245-8266","authenticated-orcid":false,"given":"Catia","family":"Mio","sequence":"first","affiliation":[{"name":"Department of Medicine (DAME) University of Udine Udine Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Federico","family":"Fogolari","sequence":"additional","affiliation":[{"name":"Department of Mathematics Computer Sciences and Physics (DMIF) University of Udine Udine Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Pezzoli","sequence":"additional","affiliation":[{"name":"Medical Genetics Laboratory Hospital Papa Giovanni XXIII Bergamo Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angela V.","family":"D\u2019Elia","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics ASUIUD University Hospital of Udine Udine Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Iascone","sequence":"additional","affiliation":[{"name":"Medical Genetics Laboratory Hospital Papa Giovanni XXIII Bergamo Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuseppe","family":"Damante","sequence":"additional","affiliation":[{"name":"Department of Medicine (DAME) University of Udine Udine Italy"},{"name":"Institute of Medical Genetics ASUIUD University Hospital of Udine Udine Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,5,15]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.35650"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn1958"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1159\/000489001"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2018.04.024"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.61409"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2014.01.002"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1004"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2016.18"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/gbb.12556"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/7480749"},{"issue":"6","key":"e_1_2_9_12_1","article-title":"Novel NR2F1 variants likely disrupt DNA binding: Molecular modeling in two cases, review of published cases, genotype\u2013phenotype correlation, and phenotypic expansion of the Bosch\u2013Boonstra\u2013Schaaf optic atrophy syndrome","volume":"3","author":"Kaiwar C.","year":"2017","journal-title":"Cold Spring Harbor Molecular Case Studies"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx1126"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s10038-017-0398-3"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv1189"},{"key":"e_1_2_9_16_1","first-page":"1","article-title":"Targeted panel sequencing identifies a novel NR2F1 mutations in a patient with Bosch\u2013Boonstra\u2013Schaaf optic atrophy syndrome","author":"Park S. 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