Combined immunodeficiency caused by a loss-of-function mutation in DNA polymerase delta 1

Basit Öğe Kaydı
dc.contributor.authorCui, Ye
dc.contributor.authorKeles, Sevgi
dc.contributor.authorCharbonnier, Louis-Marie
dc.contributor.authorJule, Amelie M.
dc.contributor.authorHenderson, Lauren
dc.contributor.authorCelik, Seyma Celikbilek
dc.contributor.authorReisli, Ismail
dc.date.accessioned2024-02-23T14:12:30Z
dc.date.available2024-02-23T14:12:30Z
dc.date.issued2020
dc.departmentNEÜen_US
dc.description.abstractBackground: Mutations affecting DNA polymerases have been implicated in genomic instability and cancer development, but the mechanisms by which they can affect the immune system remain largely unexplored. Objective: We sought to establish the role of DNA polymerase M catalytic subunit (POLD1) as the cause of a primary immunodeficiency in an extended kindred. Methods: We performed whole-exome and targeted gene sequencing, lymphocyte characterization, molecular and functional analyses of the DNA polymerase delta (Pol delta) complex, and T- and B-cell antigen receptor repertoire analysis. Results: We identified a missense mutation (c. 3178C>T; p.R1060C) in POLD1 in 3 related subjects who presented with recurrent, especially herpetic, infections and T-cell lymphopenia with impaired T-cell but not B-cell proliferation. The mutation destabilizes the Pol delta complex, leading to ineffective recruitment of replication factor C to initiate DNA replication. Molecular dynamics simulation revealed that the R1060C mutation disrupts the intramolecular interaction between the POLD1 CysB motif and the catalytic domain and also between POLD1 and the Pol delta subunit POLD2. The patients exhibited decreased numbers of naive CD4 and especially CD8 T cells in favor of effector memory subpopulations. This skewing was associated with oligoclonality and restricted T-cell receptor beta-chain V-J pairing in CD8(+) but not CD4(+) T cells, suggesting that POLDR1060C differentially affects peripheral CD8(+) T-cell expansion and possibly thymic selection. Conclusion: These results identify gene defects in POLD1 as a novel cause of T-cell immunodeficiency.en_US
dc.description.sponsorshipNational Institutes of Health [5R01AI085090, 5R01AI128976]en_US
dc.description.sponsorshipThis work was supported by National Institutes of Health grants 5R01AI085090 and 5R01AI128976 (to T.A.C.).en_US
dc.identifier.doi10.1016/j.jaci.2019.10.004
dc.identifier.endpage+en_US
dc.identifier.issn0091-6749
dc.identifier.issn1097-6825
dc.identifier.issue1en_US
dc.identifier.pmid31629014en_US
dc.identifier.scopus2-s2.0-85075398067en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage391en_US
dc.identifier.urihttps://doi.org/10.1016/j.jaci.2019.10.004
dc.identifier.urihttps://hdl.handle.net/20.500.12452/12084
dc.identifier.volume145en_US
dc.identifier.wosWOS:000505590800042en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherMosby-Elsevieren_US
dc.relation.ispartofJournal Of Allergy And Clinical Immunologyen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectDna Polymerase Delta 1en_US
dc.subjectDna Polymerase Delta 1 Catalytic Subuniten_US
dc.subjectReplication Factor Cen_US
dc.subjectPold1en_US
dc.subjectPrimary Immunodeficiencywhole-Exome Sequencingen_US
dc.titleCombined immunodeficiency caused by a loss-of-function mutation in DNA polymerase delta 1en_US
dc.typeArticleen_US

Dosyalar

Koleksiyon

WoS İndeksli Yayınlar Koleksiyonu
PubMed İndeksli Yayın Koleksiyonu
Scopus İndeksli Yayınlar Koleksiyonu