{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T12:23:34Z","timestamp":1787660614853,"version":"build-2736575974"},"reference-count":23,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"vor","delay-in-days":12,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Dyskeratosis congenita (DKC) is typically characterized by the triad of abnormal cutaneous pigmentation, nail dystrophy, and oral mucosal leukoplakia. Progressive bone marrow failure develops in over 80% of cases and constitutes the leading cause of early mortality. Pathogenic variants in\n                      <jats:italic>DKC1<\/jats:italic>\n                      have been associated with a high risk of developing aplastic anemia, myelodysplastic syndrome, leukemia, and solid tumors. The\n                      <jats:italic>DKC1<\/jats:italic>\n                      missense variant, c.5C&gt;T, leading to p.(Ala2Val), has been reported in families affected with dyskeratosis congenita. However, due to lack of functional analysis, it remains a variant of uncertain significance (VUS). Here, we performed functional analysis of the\n                      <jats:italic>DKC1<\/jats:italic>\n                      gene product to investigate the pathophysiology of\n                      <jats:italic>DKC1<\/jats:italic>\n                      \u2010related dyskeratosis congenita.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed co\u2010localization studies of HEK293T cells transfected with GFP\u2010tagged constructs encoding either a wild\u2010type (WT) or p.(Ala2Val) human DKC1 protein, along with Liquid Chromatography Mass Spectrometry (LCMS) of immunoprecipitated (IP) WT or p.(Ala2Val) DKC1 protein to study post\u2010translation modification status.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We have shown that p.(Ala2Val) DKC1 leads to mis\u2010localization of the protein from the nucleolus to the nucleoplasm. Also, LCMS showed that N\u2010terminal methionine cleavage occurs for both, but N\u2010acetylation occurs for WT but not for p.(Ala2Val) DKC1.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The mis\u2010localization and altered post\u2010translational modification of p.(Ala2Val) DKC1 provides functional evidence to clinical laboratories to reclassify p.(Ala2Val) variant as \u201cpathogenic\u201d as per American College of Medical Genetics (ACMG) variant interpretation guidelines.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/mgg3.70273","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T10:55:11Z","timestamp":1786618511000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["N\u2010Terminal Variant p.\n                    <scp>Ala2Val<\/scp>\n                    in X\u2010Linked Dyskeratosis Congenita Gene (\n                    <i>DKC1<\/i>\n                    ) Disrupts Its Post\u2010Translational Modification and Nucleolar Localization"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8251-6574","authenticated-orcid":false,"given":"Taimoor I.","family":"Sheikh","sequence":"first","affiliation":[{"name":"Molecular Neuropsychiatry &amp; Development (MiND) Lab, Molecular Brain Science Research Department Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health  Toronto Ontario Canada"},{"name":"Department of Pathology Allegheny Health Network  Pittsburgh Pennsylvania USA"},{"name":"Department of Pathology and Laboratory Medicine Drexel University College of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0692-2519","authenticated-orcid":false,"given":"John B.","family":"Vincent","sequence":"additional","affiliation":[{"name":"Molecular Neuropsychiatry &amp; Development (MiND) Lab, Molecular Brain Science Research Department Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health  Toronto Ontario Canada"},{"name":"Institute of Medical Science, University of Toronto  Toronto Ontario Canada"},{"name":"Department of Psychiatry University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-02-075598"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2016.55"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-06-566810"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcmd.2012.05.008"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-020-01045-7"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/GIM.0b013e318197a49a"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1097\/HS9.0000000000000539"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1261\/rna.078953.121"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2006.09.009"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1006\/geno.1998.5600"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1205969"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng0598-32"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng985"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.09.003"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(04)15468-8"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.32412"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2018.215699"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1136\/thorax.56.11.891"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22730"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1097\/GIM.0b013e3181f415b5"},{"key":"e_1_2_11_22_1","volume-title":"GeneReviews","author":"Savage S. 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