Aging; DNA damage and repair; Mitotic errors; Rothmund-Thomson syndrome; Senescence; Hydroxyurea; CRIPT protein, human; Adaptor Proteins, Signal Transducing; Humans; Cellular Senescence/genetics; DNA Damage; Hydroxyurea/metabolism; Fibroblasts; Mutation; Adaptor Proteins, Signal Transducing/metabolism; Rothmund-Thomson Syndrome/genetics; Rothmund-Thomson Syndrome/diagnosis; Rothmund-Thomson Syndrome/pathology; Cellular Senescence; Genetics (clinical)
Abstract :
[en] [en] PURPOSE: Rothmund-Thomson syndrome (RTS) is characterized by poikiloderma, sparse hair, small stature, skeletal defects, cancer, and cataracts, resembling features of premature aging. RECQL4 and ANAPC1 are the 2 known disease genes associated with RTS in >70% of cases. We describe RTS-like features in 5 individuals with biallelic variants in CRIPT (OMIM 615789).
METHODS: Two newly identified and 4 published individuals with CRIPT variants were systematically compared with those with RTS using clinical data, computational analysis of photographs, histologic analysis of skin, and cellular studies on fibroblasts.
RESULTS: All CRIPT individuals fulfilled the diagnostic criteria for RTS and additionally had neurodevelopmental delay and seizures. Using computational gestalt analysis, CRIPT individuals showed greatest facial similarity with individuals with RTS. Skin biopsies revealed a high expression of senescence markers (p53/p16/p21) and the senescence-associated ß-galactosidase activity was elevated in CRIPT-deficient fibroblasts. RECQL4- and CRIPT-deficient fibroblasts showed an unremarkable mitotic progression and unremarkable number of mitotic errors and no or only mild sensitivity to genotoxic stress by ionizing radiation, mitomycin C, hydroxyurea, etoposide, and potassium bromate.
CONCLUSION: CRIPT causes an RTS-like syndrome associated with neurodevelopmental delay and epilepsy. At the cellular level, RECQL4- and CRIPT-deficient cells display increased senescence, suggesting shared molecular mechanisms leading to the clinical phenotypes.
Disciplines :
Pediatrics
Author, co-author :
Averdunk, Luisa ; Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany. Electronic address: luisasusan.averdunk@med.uni-duesseldorf.de
Huetzen, Maxim A; Max Planck Research Group Mechanisms of DNA Repair, Max Planck Institute for Biology of Ageing, Cologne, Germany, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne and Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany, Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
Moreno-Andrés, Daniel; Institute of Biochemistry and Molecular Cell Biology, Medical School, RWTH Aachen University, Aachen, Germany
Kalb, Reinhard; Institute for Human Genetics, Biocenter, University of Würzburg, Würzburg, Germany
McKee, Shane; Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast HSC Trust, Belfast, United Kingdom
Hsieh, Tzung-Chien; Institute of Genomic Statistics and Bioinformatics, University of Bonn, Bonn, Germany
Seibt, Annette; Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany
Schouwink, Marten; Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany
Lalani, Seema; Department of Molecular Genetics, Baylor College of Medicine, Houston, TX
Faqeih, Eissa Ali; Division of Medical Genetics, Children's Specialized Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
Brunet, Theresa; Technical University of Munich, School of Medicine, Institute of Human Genetics, Munich, Germany, Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany
Boor, Peter; Institute of Pathology and Electron Microscopy Facility, Medical Faculty, RWTH Aachen University, Aachen, Germany
Neveling, Kornelia; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
Hoischen, Alexander; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
Hildebrandt, Barbara; Institute of Human Genetics, University Hospital Düsseldorf, Heinrich-Heine-Universität, Düsseldorf, Germany
Graf, Elisabeth; Technical University of Munich, School of Medicine, Institute of Human Genetics, Munich, Germany
Lu, Linchao; Division of Hematology/Oncology, Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX
Jin, Weidong; Division of Hematology/Oncology, Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX
Schaper, Joerg; Center of Rare Diseases, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
Omer, Jamal A; Department of General Pediatrics, Children's Specialized Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
Demaret, Tanguy ; Université de Liège - ULiège > Faculté de Médecine > Mast. spéc. gén. clin. ; Centre de Génétique Humaine, Institut de Pathologie et Génétique, Gosselies, Belgium
Fleischer, Nicole; FDNA Inc., Boston, MA
Schindler, Detlev; Institute for Human Genetics, Biocenter, University of Würzburg, Würzburg, Germany
Krawitz, Peter; Institute of Genomic Statistics and Bioinformatics, University of Bonn, Bonn, Germany
Mayatepek, Ertan; Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany
Wieczorek, Dagmar; Institute of Human Genetics, University Hospital Düsseldorf, Heinrich-Heine-Universität, Düsseldorf, Germany
Wang, Lisa L; Division of Hematology/Oncology, Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX
Antonin, Wolfram; Institute of Biochemistry and Molecular Cell Biology, Medical School, RWTH Aachen University, Aachen, Germany
Jachimowicz, Ron D; Max Planck Research Group Mechanisms of DNA Repair, Max Planck Institute for Biology of Ageing, Cologne, Germany, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne and Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany, Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
von Felbert, Verena; Department of Dermatology and Allergology, Medical Faculty, RWTH Aachen University, Aachen, Germany
Distelmaier, Felix; Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany. Electronic address: felix.distelmaier@med.uni-duesseldorf.de
EONR - European Organization for Nuclear Research ERC - European Research Council DFG - Deutsche Forschungsgemeinschaft BMBF - Bundesministerium für Bildung und Forschung
Funding text :
We thank the individuals and their families for participating in our research study. We acknowledge the FACS and Imaging Core Facility at the Max Planck Institute for Biology of Ageing for providing technical support, and the Bioinformatics Core Facility at the Max Planck Institute for Biology of Ageing for providing data analysis support. We thank the colleagues from the Department of Translational Genomics of King Faisal Specialist Hospital and Research Centre for sharing the fibroblast cell line of CRIPT individual #3. We also thank Dr. Xi Luo (Department of Molecular and Human Genetics at Baylor College of Medicine) who annotated the sequence variants of the published RECQL4 cell lines in compliance with Human Genome Variation Society recommendations. Maxim A. Huetzen is a member of the Cologne Graduate School of Ageing Research. L.A. was supported by the Elterninitiative Kinderkrebsklinik e.V. F.D. was supported by a grant of the German Research Foundation/Deutsche Forschungsgemeinschaft (DI 1731/2-2) and by a grant from the “Elterninitiative Kinderkrebsklinik e.V.” (Düsseldorf; #701900167). P.B. was supported by the German Research Foundation/DFG, Project-IDs 454024652 and 445703531), the European Research Council (Consolidator Grant No 101001791), and the Federal Ministry of Education and Research (STOP-FSGS-01GM1901A). R.K. and D.S. were supported by the Federal Ministry of Education and Research (ADDRess - 01GM1909B). Conceptualization: L.A. F.D.; Data Curation (clinical data): L.A. S.M. E.A.F. S.L. P.B. J.A.O.; Formal Analysis (clinical data): L.A. S.M. E.A.F. S.L. T.D. T.-C.H. J.A.O. T.B. J.S. D.W. L.L.W. F.D.; Funding Acquisition: P.K. E.M. W.A. R.D.J. V.v.F. F.D.; Investigation (functional data): L.A. M.A.H. D.M.-A. A.S. K.N. A.H. P.B. B.H. W.A. R.D.J. V.v.F. M.S. E.G. L.L. W.J. D.S. R.K.; Methodology: L.A. D.M.-A. T.-C.H. K.N. P.B. P.K. W.A. R.D.J. D.S. R.K. F.D.; Project Administration: L.A. F.D.; Resources: P.K. E.M. W.A. R.D.J. V.v.F. F.D.; Software: D.M.-A. A.H. N.F. P.K. R.D.J.; Supervision: W.A. R.D.J. L.L.W. F.D.; Validation: L.L.W. F.D.; Visualization: L.A. M.A.H. D.M.-A. T.-C.H. A.S. B.H. N.F. V.v.F.; Writing-original draft: L.A. M.A.H.; Writing-review and editing: L.A. D.M.-A. T.B. J.S. T.D. L.L.W. W.A. E.M. D.S. D.W. F.D. The study was performed according to the Declaration of Helsinki and was approved by the institutional ethical review board (Heinrich-Heine-University, Düsseldorf, vote 2021-1340-LA/FD). The legal guardians provided written informed consent to participate in the study and gave their explicit permission for the publication of photographs. The authors attest that the research included in this report was conducted in a manner consistent with the principles of research ethics, such as those described in the Declaration of Helsinki and/or the Belmont Report. In particular, this research was conducted with the voluntary, informed consent of any research participants, free of coercion or coercive circumstances, and received institutional review board or research ethics committee approval consistent with the principles of research ethics and the legal requirements of the lead authors’ jurisdiction(s). The authors declare no conflicts of interest.L.A. was supported by the Elterninitiative Kinderkrebsklinik e.V. F.D. was supported by a grant of the German Research Foundation/ Deutsche Forschungsgemeinschaft (DI 1731/2-2) and by a grant from the “Elterninitiative Kinderkrebsklinik e.V.” (Düsseldorf; #701900167). P.B. was supported by the German Research Foundation/ DFG , Project-IDs 454024652 and 445703531), the European Research Council (Consolidator Grant No 101001791), and the Federal Ministry of Education and Research (STOP-FSGS-01GM1901A). R.K. and D.S. were supported by the Federal Ministry of Education and Research (ADDRess - 01GM1909B).
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