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

Abu-Libdeh, Bassam
; 
Jhujh, Satpal S.
; 
Dhar, Srijita
; 
Sommers, Joshua A.
; 
Datta, Arindam
; 
Longo, Gabriel M.C.
; 
Grange, Laura J.
; 
Reynolds, John J.
; 
Cooke, Sophie L.
; 
McNee, Gavin
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Authors
Abu-Libdeh, Bassam
 Jhujh, Satpal S.
 Dhar, Srijita
 Sommers, Joshua A.
 Datta, Arindam
 Longo, Gabriel M.C.
 Grange, Laura J.
 Reynolds, John J.
 Cooke, Sophie L.
 McNee, Gavin
 Hollingworth, Robert
 Woodward, Beth L.
 Ganesh, Anil N.
 Smerdon, Stephen J.
 Nicolae, Claudia M.
 Durlacher-Betzer, Karina
 Molho-Pessach, Vered
 Abu-Libdeh, Abdulsalam
 Meiner, Vardiella
 Moldovan, George-Lucian
 Roukos, Vassilis
 Harel, Tamar
 Brosh, Robert M.
 Stewart, Grant S.
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Affiliation
Epub Date
Issue Date
2022-01-13
Submitted date
Subjects
RecQ helicase
 RECQL1
 genetic disease
 genome instability disorder
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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.
Citation
Publisher
American Society for Clinical Investigation
Journal
The Journal of Clinical Investigation
Research Unit
URI
https://wlv.openrepository.com/handle/2436/625887
DOI
10.1172/jci147301
PubMed ID
35025765 (pubmed)
PubMed Central ID
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https://doi.org/10.1172/jci147301
Type
Journal article
Language
en
Description
©2022 The Authors. Published by the American Society for Clinical Investigation. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link: https://doi.org/10.1172/JCI147301
Series/Report no.
ISSN
0021-9738
EISSN
1558-8238
ISBN
ISMN
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Sponsors
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).
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Licence for published version: Creative Commons Attribution 4.0 International
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