Biallelic variants in CRIPT cause a Rothmund-Thomson-like syndrome with increased cellular senescence

Luisa Averdunk; Maxim A Huetzen; Daniel Moreno-Andrés; Reinhard Kalb; Shane McKee; Tzung-Chien Hsieh; Annette Seibt; Marten Schouwink; Seema Lalani; Eissa Ali Faqeih; Theresa Brunet; Peter Boor; Kornelia Neveling; Alexander Hoischen; Barbara Hildebrandt; Elisabeth Graf; Linchao Lu; Weidong Jin; Joerg Schaper; Jamal A Omer; Tanguy Demaret; Nicole Fleischer; Detlev Schindler; Peter Krawitz; Ertan Mayatepek; Dagmar Wieczorek; Lisa L Wang; Wolfram Antonin; Ron D Jachimowicz; Verena von Felbert; Felix Distelmaier

doi:10.1016/j.gim.2023.100836

Biallelic variants in CRIPT cause a Rothmund-Thomson-like syndrome with increased cellular senescence

Genet Med. 2023 Jul;25(7):100836. doi: 10.1016/j.gim.2023.100836. Epub 2023 Mar 31.

Authors

Luisa Averdunk¹, Maxim A Huetzen², Daniel Moreno-Andrés³, Reinhard Kalb⁴, Shane McKee⁵, Tzung-Chien Hsieh⁶, Annette Seibt⁷, Marten Schouwink⁷, Seema Lalani⁸, Eissa Ali Faqeih⁹, Theresa Brunet¹⁰, Peter Boor¹¹, Kornelia Neveling¹², Alexander Hoischen¹², Barbara Hildebrandt¹³, Elisabeth Graf¹⁴, Linchao Lu¹⁵, Weidong Jin¹⁵, Joerg Schaper¹⁶, Jamal A Omer¹⁷, Tanguy Demaret¹⁸, Nicole Fleischer¹⁹, Detlev Schindler⁴, Peter Krawitz⁶, Ertan Mayatepek⁷, Dagmar Wieczorek¹³, Lisa L Wang¹⁵, Wolfram Antonin³, Ron D Jachimowicz², Verena von Felbert²⁰, Felix Distelmaier²¹

Affiliations

¹ Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany. Electronic address: [email protected].
² 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.
³ Institute of Biochemistry and Molecular Cell Biology, Medical School, RWTH Aachen University, Aachen, Germany.
⁴ Institute for Human Genetics, Biocenter, University of Würzburg, Würzburg, Germany.
⁵ Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast HSC Trust, Belfast, United Kingdom.
⁶ Institute of Genomic Statistics and Bioinformatics, University of Bonn, Bonn, Germany.
⁷ Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany.
⁸ Department of Molecular Genetics, Baylor College of Medicine, Houston, TX.
⁹ Division of Medical Genetics, Children's Specialized Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.
¹⁰ Technical University of Munich, School of Medicine, Institute of Human Genetics, Munich, Germany; Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany.
¹¹ Institute of Pathology and Electron Microscopy Facility, Medical Faculty, RWTH Aachen University, Aachen, Germany.
¹² Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
¹³ Institute of Human Genetics, University Hospital Düsseldorf, Heinrich-Heine-Universität, Düsseldorf, Germany.
¹⁴ Technical University of Munich, School of Medicine, Institute of Human Genetics, Munich, Germany.
¹⁵ Division of Hematology/Oncology, Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX.
¹⁶ Center of Rare Diseases, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
¹⁷ Department of General Pediatrics, Children's Specialized Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.
¹⁸ Centre de Génétique Humaine, Institut de Pathologie et Génétique, Gosselies, Belgium.
¹⁹ FDNA Inc., Boston, MA.
²⁰ Department of Dermatology and Allergology, Medical Faculty, RWTH Aachen University, Aachen, Germany.
²¹ Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany. Electronic address: [email protected].

PMID: 37013901
DOI: 10.1016/j.gim.2023.100836

Abstract

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.

Keywords: Aging; DNA damage and repair; Mitotic errors; Rothmund-Thomson syndrome; Senescence.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / metabolism
Cellular Senescence / genetics
DNA Damage
Fibroblasts
Humans
Hydroxyurea / metabolism
Mutation
Rothmund-Thomson Syndrome* / diagnosis
Rothmund-Thomson Syndrome* / genetics
Rothmund-Thomson Syndrome* / pathology

Substances

Hydroxyurea
CRIPT protein, human
Adaptor Proteins, Signal Transducing