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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

Masayoshi Honda
Charnise Goodings
Melanie Boerries
Marcin Wlodarski
Megan Anne Cooper
Jill Rosenfeld
Carole Saintome
Maria Spies

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 RPA1 E240K and RPA1 V227A proteins exhibit increased binding to single-strand and telomeric DNA, implying a gain in DNA-binding function while RPA1 T270A 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 RPA1 E240K mutation into healthy inducible pluripotent stem cells. This resulted in severe telomere shortening and impaired hematopoietic differentiation. Furthermore, in patient with RPA1 E240K , 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.
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Dates et versions

hal-03451935 , version 1 (26-11-2021)

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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-03451935⟩
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