RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1

Bassam Abu-Libdeh, Satpal Jhujh, Srijita Dhar, Joshua A. Sommers, Arindam Datta, Gabriel M. C. Longo, Laura J. Grange, John Reynolds, Sophie Cooke, Gavin McNee, Robert Hollingworth, Beth Woodward, Anil N. Ganesh, Stephen Smerdon, Claudia M. Nicolae, Karina Durlacher-Bezer, Vered Molho-Pessach, Abdulsalam Abu-Libdeh, Vardiella Meiner, George-Lucian MoldovanVassilis Roukos, Tamar Harel, Robert M. Brosh Jr., Grant S. Stewart

Research output: Contribution to journalArticlepeer-review

Abstract

Despite being the first homolog of the bacterial RecQ helicase to be identified in humans, the function of RECQL1 remains poorly characterized. Furthermore, unlike other members of the human RECQ family of helicases, mutations in RECQL1 have not been associated with a genetic disease. Here, we identify 2 families with a genome instability disorder that we have named RECON (RECql ONe) syndrome, caused by biallelic mutations in the RECQL gene. The affected individuals had short stature, progeroid facial features, a hypoplastic nose, xeroderma, and skin photosensitivity and were homozygous for the same missense mutation in RECQL1 (p.Ala459Ser), located within its zinc binding domain. Biochemical analysis of the mutant RECQL1 protein revealed that the p.A459S missense mutation compromised its ATPase, helicase, and fork restoration activity, while its capacity to promote single-strand DNA annealing was largely unaffected. At the cellular level, this mutation in RECQL1 gave rise to a defect in the ability to repair DNA damage induced by exposure to topoisomerase poisons and a failure of DNA replication to progress efficiently in the presence of abortive topoisomerase lesions. Taken together, RECQL1 is the fourth member of the RecQ family of helicases to be associated with a human genome instability disorder.

Original languageEnglish
Article numbere147301
JournalJournal of Clinical Investigation
Volume132
Issue number5
Early online date13 Jan 2022
DOIs
Publication statusPublished - 1 Mar 2022

Bibliographical note

Funding Information:
We would like to thank the parents and patients from the 2 families for taking part in this study and generously donating tissue samples. We would also like to thank Fay Stewart for help with statistical analysis. GSS, RH, GSM, SLC, AG are funded by a CR-UK Programme grant (C17183/A23303). SSJ is supported by a project grant funded by the Great Ormond Street Hospital Children’s Charity and Sparks (V5019). LJG is supported by a joint funded University of Birmingham and CR-UK PhD studentship (C17422/A25154). BLW is supported by a CR-UK Clinical Academic Training Programme award (C11497/A31309). The VR laboratory is supported by funding from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, project IDs 393547839-SFB 1361 and 402733153-SPP 2202) and the DFG Major Research Instrumentation Programme (INST 247/845-1 FUGG). JJR is supported by the University of Birmingham. SD, JAS, AD, and RMB are supported in part by the NIH Intramural Research Program of the National Institute on Aging (1Z1AAG000741-19). A collaboration to study the identified RECQL variant was established via GeneMatcher (46).

Keywords

  • Breast Neoplasms
  • DNA Replication
  • Female
  • Genetic Predisposition to Disease
  • Genomic Instability
  • Humans
  • Mutation
  • RecQ Helicases/genetics

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