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Telomere attrition and dysfunction: a potential trigger of the progeroid phenotype in nijmegen breakage syndrome

R. Habib, R. Kim, H. Neitzel, I. Demuth, K. Chrzanowska, E. Seemanova, R. Faber, M. Digweed, R. Voss, K. Jäger, K. Sperling, M. Walter

. 2020 ; 12 (12) : 12342-12375. [pub] 20200620

Language English Country United States

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc21012460

BACKGROUND: Nibrin, as part of the NBN/MRE11/RAD50 complex, is mutated in Nijmegen breakage syndrome (NBS), which leads to impaired DNA damage response and lymphoid malignancy. RESULTS: Telomere length (TL) was markedly reduced in homozygous patients (and comparably so in all chromosomes) by ~40% (qPCR) and was slightly reduced in NBS heterozygotes older than 30 years (~25% in qPCR), in accordance with the respective cancer rates. Humanized cancer-free NBS mice had normal TL. Telomere elongation was inducible by telomerase and/or alternative telomere lengthening but was associated with abnormal expression of telomeric genes involved in aging and/or cell growth. Lymphoblastoid cells from NBS patients with long survival times (>12 years) displayed the shortest telomeres and low caspase 7 activity. CONCLUSIONS: NBS is a secondary telomeropathy. The two-edged sword of telomere attrition enhances the cancer-prone situation in NBS but can also lead to a relatively stable cellular phenotype in tumor survivors. Results suggest a modular model for progeroid syndromes with abnormal expression of telomeric genes as a molecular basis. METHODS: We studied TL and function in 38 homozygous individuals, 27 heterozygotes, one homozygous fetus, six NBS lymphoblastoid cell lines, and humanized NBS mice, all with the same founder NBN mutation: c.657_661del5.

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$a Habib, Raneem $u Department of Human Genetics, Ruhr-University Bochum, Bochum, Germany ; Institute of Medical and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany
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$a BACKGROUND: Nibrin, as part of the NBN/MRE11/RAD50 complex, is mutated in Nijmegen breakage syndrome (NBS), which leads to impaired DNA damage response and lymphoid malignancy. RESULTS: Telomere length (TL) was markedly reduced in homozygous patients (and comparably so in all chromosomes) by ~40% (qPCR) and was slightly reduced in NBS heterozygotes older than 30 years (~25% in qPCR), in accordance with the respective cancer rates. Humanized cancer-free NBS mice had normal TL. Telomere elongation was inducible by telomerase and/or alternative telomere lengthening but was associated with abnormal expression of telomeric genes involved in aging and/or cell growth. Lymphoblastoid cells from NBS patients with long survival times (>12 years) displayed the shortest telomeres and low caspase 7 activity. CONCLUSIONS: NBS is a secondary telomeropathy. The two-edged sword of telomere attrition enhances the cancer-prone situation in NBS but can also lead to a relatively stable cellular phenotype in tumor survivors. Results suggest a modular model for progeroid syndromes with abnormal expression of telomeric genes as a molecular basis. METHODS: We studied TL and function in 38 homozygous individuals, 27 heterozygotes, one homozygous fetus, six NBS lymphoblastoid cell lines, and humanized NBS mice, all with the same founder NBN mutation: c.657_661del5.
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$a Kim, Ryong $u Institute of Medical and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany ; Institute of Clinical Chemistry, Red-Cross General Hospital, Pyongyang, Democratic People's Republic of Korea
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$a Neitzel, Heidemarie $u Institute of Medical and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany
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$a Demuth, Ilja $u Department of Endocrinology and Metabolism, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Germany ; Charité - Universitätsmedizin Berlin, BCRT - Berlin Institute of Health Center for Regenerative Therapies, Berlin, Germany
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$a Chrzanowska, Krystyna $u Department of Medical Genetics, The Children's Memorial Health Institute, Warsaw, Poland
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$a Seemanova, Eva $u Department of Clinical Genetics, Institute of Biology and Medical Genetics, Second Medical School, Charles University, Prague, Czech Republic
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$a Faber, Renaldo $u Center for Prenatal Medicine, Leipzig, Germany
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$a Digweed, Martin $u Institute of Medical and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany
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$a Voss, Reinhard $u Integrated Functional Genomics, Interdisciplinary Center for Clinical Research, University of Münster, Münster, Germany
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$a Jäger, Kathrin $u Institute of Clinical Chemistry and Laboratory Medicine, University of Rostock, Rostock, Germany ; Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Germany
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$a Sperling, Karl $u Institute of Medical and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany
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$a Walter, Michael $u Institute of Clinical Chemistry and Laboratory Medicine, University of Rostock, Rostock, Germany ; Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Germany
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