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Averdunk, L.* ; Huetzen, M.A.* ; Moreno-Andrés, D.* ; Kalb, R.* ; McKee, S.* ; Hsieh, T.C.* ; Seibt, A.* ; Schouwink, M.* ; Lalani, S.* ; Faqeih, E.A.* ; Brunet, T. ; Boor, P.* ; Neveling, K.* ; Hoischen, A.* ; Hildebrandt, B.* ; Graf, E.* ; Lu, L.* ; Jin, W.* ; Schaper, J.* ; Omer, J.A.* ; Demaret, T.* ; Fleischer, N.* ; Schindler, D.* ; Krawitz, P.* ; Mayatepek, E.* ; Wieczorek, D.* ; Wang, L.L.* ; Antonin, W.* ; Jachimowicz, R.D.* ; von Felbert, V.* ; Distelmaier, F.*

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

Genet. Med. 25:100836 (2023)
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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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Aging ; Dna Damage And Repair ; Mitotic Errors ; Rothmund-thomson Syndrome ; Senescence; Recql4; Protein; Fibroblasts; Repair; Abnormalities; Retardation; Mutation; Mitosis; Kinase; Cancer
Language english
Publication Year 2023
HGF-reported in Year 2023
ISSN (print) / ISBN 1530-0366
e-ISSN 1098-3600
Journal Genetics in Medicine
Quellenangaben Volume: 25, Issue: 7, Pages: , Article Number: 100836 Supplement: ,
Publisher Lippincott Williams & Wilkins
Publishing Place Baltimore, Md.
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
POF-Topic(s) 30205 - Bioengineering and Digital Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-503292-001
Grants European Research Council (ERC)
Federal Ministry of Education and Research
European Research Council
German Research Foundation/DFG
"Elterninitiative Kinderkrebsklinik e.V." (Dusseldorf)
German Research Foundation/Deutsche Forschungsgemeinschaft
Elterninitiative Kinderkrebsklinik e.V.
DOI 10.1016/j.gim.2023.100836
WOS ID 001033634500001
Scopus ID 85161357983
PubMed ID 37013901
Erfassungsdatum 2023-10-06
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