Journal article
Gain-of-Function Mutations in RPA1 Cause a Syndrome with Short Telomeres and Somatic Genetic Rescue
Blood, Vol.139(7), pp.1039-1051
11/12/2021
DOI: 10.1182/blood.2021011980
PMCID: PMC8854676
PMID: 34767620
Abstract
Human telomere biology disorders (TBD)/short telomere syndromes (STS) are heterogeneous disorders caused by inherited loss-of-function mutations in telomere-associated genes. Here, we identify three germline heterozygous missense variants in RPA1 gene in four unrelated probands presenting with short telomeres and varying clinical features of TBD/STS including bone marrow failure, myelodysplastic syndrome, T- and B-cell lymphopenia, pulmonary fibrosis, or skin manifestations. All variants cluster to DNA binding domain A of RPA1 protein. RPA1 is a single-strand DNA-binding protein required for DNA replication and repair and involved in telomere maintenance. We showed that RPA1E240K and RPA1V227A proteins exhibit increased binding to single-strand and telomeric DNA, implying a gain in DNA-binding function while RPA1T270A has binding properties similar to wild type protein. To study the mutational effect in a cellular system, we used CRISPR/Cas9 to knock-in the RPA1E240K mutation into healthy inducible pluripotent stem cells. This resulted in severe telomere shortening and impaired hematopoietic differentiation. Furthermore, in patient with RPA1E240K, we discovered somatic genetic rescue (SGR) in hematopoietic cells due to an acquired truncating cis RPA1 mutation or a uniparental isodisomy 17p with loss of mutant allele, coinciding with stabilized blood counts. Using single-cell sequencing, the two SGR events were proven to be independently acquired in hematopoietic stem cells. In summary, we describe the first human disease caused by germline RPA1 variants in individuals with TBD/STS.
Details
- Title: Subtitle
- Gain-of-Function Mutations in RPA1 Cause a Syndrome with Short Telomeres and Somatic Genetic Rescue
- Creators
- Dmitri Churikov - Centre de Recherche en Cancérologie de MarseilleSandrine Hirschi - Université de StrasbourgVictor Pastor - St. Jude Children's Research HospitalMelanie Boerries - German Cancer Consortium (DKTK), Germany.Melchior Lauten - University Hospital Schleswig-HolsteinCharikleia Kelaidi - Children's Hospital Agia SophiaRicha Sharma - St. Jude Children's Research HospitalMarcin Wlodarski - University of FreiburgSushree Sahoo - St. Jude Children's Research HospitalMegan Anne Cooper - Washington University in St. LouisMasayoshi Honda - University of IowaSarah Nicholas - Baylor College of MedicineJill Rosenfeld - Baylor College of MedicineSophie Granger - University of IowaSophia Polychronopoulou - Children's Hospital Agia SophiaCharnise Goodings - St. Jude Children's Research HospitalCaroline Kannengiesser - Hôpital Xavier ArnozanLouis Sanchez - Sorbonne Université, GermanyAxel Künstner - University of LübeckCarole Saintome - Muséum national d'Histoire naturelleCharlotte Niemeyer - German Cancer Research CenterHauke Busch - University of Luebeck, Luebeck, Germany.Patrick Revy - Institut des Maladies Génétiques ImagineFabian Beier - University Hospital Aachen, Aachen, Germany.Shondra Pruett-Miller - St. Jude Children's Research HospitalMarc Wold - University of IowaMarcus Valentine - St. Jude Children's Research HospitalMaria Spies - University of IowaAlfonso Gonzalez Fernandez - St. Jude Children's Research HospitalMiriam Erlacher - German Cancer Research CenterStéphane Coulon - Aix-Marseille UniversitéTi-Cheng Chang - St. Jude Children's Research HospitalVincent Géli - Aix-Marseille UniversitéUndiagnosed Diseases Network
- Resource Type
- Journal article
- Publication Details
- Blood, Vol.139(7), pp.1039-1051
- DOI
- 10.1182/blood.2021011980
- PMID
- 34767620
- PMCID
- PMC8854676
- NLM abbreviation
- Blood
- ISSN
- 0006-4971
- eISSN
- 1528-0020
- Publisher
- American Society of Hematology
- Language
- English
- Date published
- 11/12/2021
- Academic Unit
- Radiation Oncology; Biochemistry and Molecular Biology
- Record Identifier
- 9984288727102771
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