{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T16:00:59Z","timestamp":1753891259700,"version":"3.41.2"},"reference-count":29,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,7]],"date-time":"2022-07-07T00:00:00Z","timestamp":1657152000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100012542","name":"Sichuan Province Science and Technology Support Program","doi-asserted-by":"publisher","award":["19ZDYF1202 2020YFS0253 21ZDYF1891"],"award-info":[{"award-number":["19ZDYF1202 2020YFS0253 21ZDYF1891"]}],"id":[{"id":"10.13039\/100012542","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p>Telomere biology disorders (TBDs) induced by <jats:italic>TINF2<\/jats:italic> mutations manifest clinically with a spectrum of phenotypes, from silent carriers to a set of overlapping conditions. A rare <jats:italic>TINF2<\/jats:italic> frameshift mutation (c.591delG) encoding a truncated mutant TIN2 protein (p.W198fs) was identified in a 6-years-and-3-month-old Chinese girl with neuroblastoma (NB) by next generation sequencing and confirmed by Sanger sequencing. To explore the possible implications of <jats:italic>TINF2<\/jats:italic> mutations in TBDs development, the <jats:italic>TINF2<\/jats:italic> mutant was transfected into the human embryonic kidney (HEK) 293T cells, and mRNA expression of the shelterin complex components as well as the cellular distribution of mutant TIN2 were examined. The <jats:italic>TINF2<\/jats:italic> mutation was phenotypically associated with short stature in the proband, nail dystrophy and spotted hypopigmentation in her mother, and psoriasis in her older brother. I-TASSER modeling analysis revealed conformational changes of the mutant TIN2 protein and loss of pivotal domains downstream of the 198th amino acid. Additionally, mRNA expression of the shelterin components was downregulated, and TIN2 mutant protein expression was reduced in HEK293T cells transfected with mutant <jats:italic>TINF2<\/jats:italic>. Furthermore, instead of being restricted to the nucleus, the mutant TIN2 was identified in both the cytoplasm and the nucleus. The <jats:italic>TINF2<\/jats:italic> gene mutation might impair the function of the shelterin complex and the telomere maintenance mechanisms, both of which are involved in the development of TBDs. TBDs have been associated with increased cancer risk. To the best of our knowledge, this is the first report of NB in patients with TBDs. The relationship between the <jats:italic>TINF2<\/jats:italic> mutation and NB may need to further study.<\/jats:p>","DOI":"10.3389\/fgene.2022.913133","type":"journal-article","created":{"date-parts":[[2022,7,7]],"date-time":"2022-07-07T05:46:45Z","timestamp":1657172805000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["A Rare Heterozygous TINF2 Deletional Frameshift Mutation in a Chinese Pedigree With a Spectrum of TBDs Phenotypes"],"prefix":"10.3389","volume":"13","author":[{"given":"Hai-Long","family":"Ren","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying-Chun","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guo-Qian","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ju","family":"Gao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xia","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"6549","DOI":"10.1182\/blood-2008-12-192880","article-title":"Cancer in Dyskeratosis Congenita","volume":"113","author":"Alter","year":"2009","journal-title":"Blood"},{"key":"B2","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1007\/s10549-006-9204-1","article-title":"Telomere Content Correlates with Stage and Prognosis in Breast Cancer","volume":"99","author":"Fordyce","year":"2006","journal-title":"Breast Cancer Res. Treat."},{"key":"B3","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1101\/gad.233395.113","article-title":"A TIN2 Dyskeratosis Congenita Mutation Causes Telomerase-independent Telomere Shortening in Mice","volume":"28","author":"Frescas","year":"2014","journal-title":"Genes. Dev."},{"key":"B4","doi-asserted-by":"publisher","first-page":"100064","DOI":"10.1074\/jbc.REV120.014017","article-title":"Molecular Mechanisms of Telomere Biology Disorders","volume":"296","author":"Grill","year":"2021","journal-title":"J. Biol. Chem."},{"key":"B5","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1089\/thy.2019.0156","article-title":"A Truncating Germline Mutation of TINF2 in Individuals with Thyroid Cancer or Melanoma Results in Longer Telomeres","volume":"30","author":"He","year":"2020","journal-title":"Thyroid"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1471","DOI":"10.1002\/pros.21182","article-title":"Organ-wide Telomeric Status in Diseased and Disease-free Prostatic Tissues","volume":"70","author":"Heaphy","year":"2010","journal-title":"Prostate"},{"key":"B7","doi-asserted-by":"publisher","first-page":"959","DOI":"10.1126\/science.1230062","article-title":"TERT Promoter Mutations in Familial and Sporadic Melanoma","volume":"339","author":"Horn","year":"2013","journal-title":"Science"},{"key":"B8","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1038\/s41525-021-00198-5","article-title":"Telomere Biology Disorders","volume":"6","author":"Kam","year":"2021","journal-title":"npj Genom. Med."},{"key":"B9","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/70508","article-title":"TIN2, a New Regulator of Telomere Length in Human Cells","volume":"23","author":"Kim","year":"1999","journal-title":"Nat. Genet."},{"key":"B10","doi-asserted-by":"publisher","first-page":"3474","DOI":"10.1172\/JCI120851","article-title":"Long Telomeres and Cancer Risk: the Price of Cellular Immortality","volume":"129","author":"McNally","year":"2019","journal-title":"J. C Lin. Invest."},{"key":"B11","doi-asserted-by":"publisher","first-page":"368","DOI":"10.3390\/biom12030368","article-title":"Decrease in RNase HII and Accumulation of lncRNAs\/DNA Hybrids: A Causal Implication in Psoriasis?","volume":"12","author":"Mehmetbeyoglu","year":"2022","journal-title":"Biomolecules"},{"key":"B12","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1097\/NNR.0000000000000037","article-title":"Telomere Length","volume":"63","author":"Montpetit","year":"2014","journal-title":"Nurs. Res."},{"key":"B13","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1016\/s0304-3835(00)00521-8","article-title":"Correlation of Telomere Lengths in Normal and Cancers Tissue in the Large Bowel","volume":"158","author":"Nakamura","year":"2000","journal-title":"Caner Lett."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1807","DOI":"10.1182\/blood.2021013523","article-title":"Disease Progression and Clinical Outcomes in Telomere Biology Disorders","volume":"139","author":"Niewisch","year":"2022","journal-title":"Blood"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.1080\/17474086.2019.1662720","article-title":"An Update on the Biology and Management of Dyskeratosis Congenita and Related Telomere Biology Disorders","volume":"12","author":"Niewisch","year":"2019","journal-title":"Expert Rev. Hematol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"101080","DOI":"10.1016\/j.jbc.2021.101080","article-title":"Structure, Dynamics, and Regulation of TRF1-TIN2-Mediated Trans- and Cis-Interactions on Telomeric DNA","volume":"297","author":"Pan","year":"2021","journal-title":"J. Biol. Chem."},{"key":"B17","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and Guidelines for the Interpretation of Sequence Variants: a Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"B18","doi-asserted-by":"publisher","first-page":"478","DOI":"10.1038\/ng.2947","article-title":"POT1 Loss-Of-Function Variants Predispose to Familial Melanoma","volume":"46","author":"Robles-Espinoza","year":"2014","journal-title":"Nat. Genet."},{"key":"B19","doi-asserted-by":"publisher","first-page":"753","DOI":"10.1097\/GIM.0b013e3181f415b5","article-title":"The Genetics and Clinical Manifestations of Telomere Biology Disorders","volume":"12","author":"Savage","year":"2010","journal-title":"Genet. Med."},{"key":"B20","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1016\/j.ajhg.2007.10.004","article-title":"TINF2, a Component of the Shelterin Telomere Protection Complex, Is Mutated in Dyskeratosis Congenita","volume":"82","author":"Savage","year":"2008","journal-title":"Am. J. Hum. Genet."},{"key":"B21","doi-asserted-by":"publisher","first-page":"e61235","DOI":"10.7554\/eLife.61235","article-title":"TINF2 Is a Haploinsufficient Tumor Suppressor that Limits Telomere Length","volume":"9","author":"Schmutz","year":"2020","journal-title":"Elife"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1946","DOI":"10.1182\/blood.2019003264","article-title":"Cancer Spectrum and Outcomes in the Mendelian Short Telomere Syndromes","volume":"135","author":"Schratz","year":"2020","journal-title":"Blood"},{"key":"B23","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1038\/ng.2941","article-title":"Rare Missense Variants in POT1 Predispose to Familial Cutaneous Malignant Melanoma","volume":"46","author":"Shi","year":"2014","journal-title":"Nat. Genet."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.gde.2015.06.004","article-title":"The Short and Long Telomere Syndromes: Paired Paradigms for Molecular Medicine","volume":"33","author":"Stanley","year":"2015","journal-title":"Curr. Opin. Genet. Dev."},{"key":"B25","first-page":"437","article-title":"Telomeres, Telomerase and Cancer","volume-title":"Encyclopedia of Cancer","author":"Tomita","year":"2017"},{"key":"B26","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1111\/j.1399-0004.2010.01605.x","article-title":"Telomere Length Measurement Can Distinguish Pathogenic from Non\u2010pathogenic Variants in the Shelterin Component, TIN2","volume":"81","author":"Vulliamy","year":"2012","journal-title":"Clin. Genet."},{"key":"B27","doi-asserted-by":"publisher","first-page":"e24383","DOI":"10.1371\/journal.pone.0024383","article-title":"Differences in Disease Severity but Similar Telomere Lengths in Genetic Subgroups of Patients with Telomerase and Shelterin Mutations","volume":"6","author":"Vulliamy","year":"2011","journal-title":"PLoS ONE"},{"key":"B28","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1038\/ng1346","article-title":"Disease Anticipation Is Associated with Progressive Telomere Shortening in Families with Dyskeratosis Congenita Due to Mutations in TERC","volume":"36","author":"Vulliamy","year":"2004","journal-title":"Nat. Genet."},{"key":"B29","doi-asserted-by":"publisher","first-page":"23022","DOI":"10.1074\/jbc.M111.225870","article-title":"TIN2 Protein Dyskeratosis Congenita Missense Mutants Are Defective in Association with Telomerase","volume":"286","author":"Yang","year":"2011","journal-title":"J. Biol. Chem."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.913133\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,7]],"date-time":"2022-07-07T05:46:49Z","timestamp":1657172809000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.913133\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,7]]},"references-count":29,"alternative-id":["10.3389\/fgene.2022.913133"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2022.913133","relation":{},"ISSN":["1664-8021"],"issn-type":[{"type":"electronic","value":"1664-8021"}],"subject":[],"published":{"date-parts":[[2022,7,7]]},"article-number":"913133"}}