{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T21:42:26Z","timestamp":1785793346255,"version":"3.56.0"},"reference-count":52,"publisher":"American Society of Hematology","issue":"6","license":[{"start":{"date-parts":[[2022,4,14]],"date-time":"2022-04-14T00:00:00Z","timestamp":1649894400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/legalcode"}],"content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,8,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Mutations in the TINF2 gene, encoding the shelterin protein TIN2, cause telomere shortening and the inherited bone marrow (BM) failure syndrome dyskeratosis congenita (DC). A lack of suitable model systems limits the mechanistic understanding of telomere shortening in the stem cells and thus hinders the development of treatment options for BM failure. Here, we endogenously introduced TIN2-DC mutations in human embryonic stem cells (hESCs) and human hematopoietic stem and progenitor cells (HSPCs) to dissect the disease mechanism and identify a gene-editing strategy that rescued the disease phenotypes. The hESCs with the T284R disease mutation exhibited the short telomere phenotype observed in DC patients. Yet, telomeres in mutant hESCs did not trigger DNA damage responses at telomeres or show exacerbated telomere shortening when differentiated into telomerase-negative cells. Disruption of the mutant TINF2 allele by introducing a frameshift mutation in exon 2 restored telomere length in stem cells and the replicative potential of differentiated cells. Similarly, we introduced TIN2-DC disease variants in human HSPCs to assess the changes in telomere length and proliferative capacity. Lastly, we showed that editing at exon 2 of TINF2 that restored telomere length in hESCs could be generated in TINF2-DC patient HSPCs. Our study demonstrates a simple genetic intervention that rescues the TIN2-DC disease phenotype in stem cells and provides a versatile platform to assess the efficacy of potential therapeutic approaches in\u00a0vivo.<\/jats:p>","DOI":"10.1182\/blood.2021013750","type":"journal-article","created":{"date-parts":[[2022,4,14]],"date-time":"2022-04-14T20:52:37Z","timestamp":1649969557000},"page":"608-618","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":20,"title":["Editing <i>TINF2<\/i> as a potential therapeutic approach to restore telomere length in dyskeratosis congenita"],"prefix":"10.1182","volume":"140","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1646-610X","authenticated-orcid":false,"given":"Seunga","family":"Choo","sequence":"first","affiliation":[{"name":"1Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3152-6852","authenticated-orcid":false,"given":"Franziska K.","family":"Lorbeer","sequence":"additional","affiliation":[{"name":"1Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel G.","family":"Regalado","sequence":"additional","affiliation":[{"name":"1Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2319-6360","authenticated-orcid":false,"given":"Sarah B.","family":"Short","sequence":"additional","affiliation":[{"name":"1Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0809-9143","authenticated-orcid":false,"given":"Shannon","family":"Wu","sequence":"additional","affiliation":[{"name":"1Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabrielle","family":"Rieser","sequence":"additional","affiliation":[{"name":"1Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1864-8502","authenticated-orcid":false,"given":"Alison A.","family":"Bertuch","sequence":"additional","affiliation":[{"name":"2Department of Pediatrics, Baylor College of Medicine, Houston, TX;"},{"name":"3Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5598-5092","authenticated-orcid":false,"given":"Dirk","family":"Hockemeyer","sequence":"additional","affiliation":[{"name":"1Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA;"},{"name":"4Chan Zuckerberg Biohub, San Francisco, CA; and"},{"name":"5Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"issue":"2 Pt 1","key":"2022081115222953900_B1","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/0092-8674(85)90170-9","article-title":"Identification of a specific telomere terminal transferase activity in tetrahymena 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cells critically depends on the shelterin protein TPP1","volume":"31","author":"Boyle","year":"2020","journal-title":"Mol Biol Cell."},{"issue":"23","key":"2022081115222953900_B30","doi-asserted-by":"crossref","first-page":"5765","DOI":"10.1182\/blood-2009-01-198374","article-title":"Probing the mitotic history and developmental stage of hematopoietic cells using single telomere length analysis (STELA)","volume":"113","author":"Hills","year":"2009","journal-title":"Blood."},{"issue":"6","key":"2022081115222953900_B31","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1016\/j.stem.2020.03.016","article-title":"Small-molecule PAPD5 inhibitors restore telomerase activity in patient stem cells","volume":"26","author":"Nagpal","year":"2020","journal-title":"Cell Stem Cell."},{"issue":"1","key":"2022081115222953900_B32","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1111\/j.1399-0004.2010.01605.x","article-title":"Telomere length measurement can distinguish pathogenic from 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