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Article Dans Une Revue Blood Année : 2021

Gain-of-Function Mutations in RPA1 Cause a Syndrome with Short Telomeres and Somatic Genetic Rescue

Sushree Sahoo
  • Fonction : Auteur
Masayoshi Honda
Sophie Granger
  • Fonction : Auteur
Charnise Goodings
Louis Sanchez
  • Fonction : Auteur
Axel Künstner
Fabian Beier
  • Fonction : Auteur
Shondra Pruett-Miller
Marcus Valentine
  • Fonction : Auteur
Alfonso Gonzalez Fernandez
  • Fonction : Auteur
Ti-Cheng Chang
  • Fonction : Auteur
Vincent Géli
Dmitri Churikov
Sandrine Hirschi
  • Fonction : Auteur
Victor Pastor
  • Fonction : Auteur
Melanie Boerries
Melchior Lauten
Charikleia Kelaidi
  • Fonction : Auteur
Marcin Wlodarski
Megan Anne Cooper
Sarah Nicholas
  • Fonction : Auteur
Jill Rosenfeld
Sophia Polychronopoulou
Caroline Kannengiesser
  • Fonction : Auteur
Carole Saintome
Charlotte Niemeyer
Patrick Revy
Marc Wold
  • Fonction : Auteur
Maria Spies
Miriam Erlacher
  • Fonction : Auteur
Stéphane Coulon

Résumé

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.

Dates et versions

hal-03431979 , version 1 (17-11-2021)

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Citer

Richa Sharma, Sushree Sahoo, Masayoshi Honda, Sophie Granger, Charnise Goodings, et al.. Gain-of-Function Mutations in RPA1 Cause a Syndrome with Short Telomeres and Somatic Genetic Rescue. Blood, 2021, ⟨10.1182/blood.2021011980⟩. ⟨hal-03431979⟩
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