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

Abstract

Polyclonal T cell response Oligoclonal CD8 + T Cell response A human immunodeficiency-causing POLD1 mutation disrupts the Polδ δ complex and severely restricts polyclonal CD8 + T cell responses T cells PCNA: Proliferating Cell Nuclear Antigen Polδ: DNA polymerase delta POLD1: DNA polymerase delta 1 catalytic subunit POLD1 : POLD1 R1060C RFC: Replication Factor C Pan T cell lymphopenia Recurrent viral infections Background: 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 d1 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 d (Pold) 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 Pold complex, leading to ineffective recruitment of replication factor C to initiate DNA replication. Molecular dynamics simulation revealed that the R1060C mutation

Determinants of neurological syndromes caused by varicella zoster virus (VZV)

“…The central role exerted by T cells in anti-VZV immunity is further demonstrated by the occurrence of severe varicella, pneumonia, or chronic VZV infection described in conditions involving the T cell surface molecules CD27 (Alkhairy et al 2015 ) and CD70 (Abolhassani et al 2017 ) as well STIM1 (Picard et al 2009 ). Recently, a defect in DNA polymerase delta1 causing a combined immunodeficiency particularly affecting naïve T cells was described in three children with recurrent infections, including one with encephalitis during primary varicella (Cui et al 2020 ). Hemorrhagic varicella, zoster, and keratitis were documented in STAT5B deficiency (Bezrodnik et al 2015 ) and DOCK2 deficiency affecting T cells and NK cells with impaired IFNα responses (Dobbs et al 2015 ).…”

“…infection Fischer et al ( 2015 ) CORO1A T and B cells Diss. infection, pneumonitis, meningitis Yee et al ( 2016 ) WAS All leukocytes Severe recurrent zoster Albert et al ( 2011 ) CARMIL2 T and B cell Recurrent varicella Schober et al ( 2017 ) MAGT1 T and NK cells Severe varicella, recurrent zoster Ravell et al ( 2020 ) STK4 T and B cells Recurrent severe zoster Abdollahpour et al ( 2012 ) CXCR4 T and B cells, neutrophils Recurrent zoster Heusinkveld et al ( 2017 ) CD27 T cells Severe varicella Alkhairy et al ( 2015 ) CD70 T cells Severe varicella Abolhassani et al ( 2017 ) STIM1 T cells Severe varicella, cellulitis Picard et al ( 2009 ) POL D1 T cells Severe recurrent varicella, encephalitis Cui et al ( 2020 ) STAT5B T and NK cells Hemorrhagic varicella, zoster, keratitis Bezrodnik et al ( 2015 ) DOCK2 T and NK cells Hemorrhagic varicella, pneumonitis Dobbs et al ( 2015 ) DOCK8 T, B, and NK cells Diss. VZV, CNS vasculopathy Zhang et al ( 2009 ); Sabry et al ( 2014 ) GATA2 Monocytes, NK, B cells Diss.…”

Underappreciated Roles of DNA Polymerase δ in Replication Stress Survival

“…In humans, the situation may be slightly different: an artificial mutational disruption of the human POLD1 CysB by the C1076F substitution seemed to affect POLD2 and POLD4 interaction only mildly and had no overt effect on POLD3 binding [46]. Still, samples from syndromic immunodeficiency patients harboring POLD1 R1060C and R1074W mutations in the CysB domain showed a substantial loss of interaction with POLD2 and POLD3 [77,78]. The attenuation of CysB mutations in humans may be due to stabilizing effects of PCNA through the fourth Pol δ subunit, POLD4, which is missing in yeast [39,46].…”

Congenital Diseases of DNA Replication: Clinical Phenotypes and Molecular Mechanisms

“…Pathogenic variants in pol δ disrupting POLD1 and POLD2 have also been linked to immunodeficiency, similar to diseases seen with defects in other polymerase subunits ( Figure 10 ) [ 90 , 93 , 94 , 96 , 97 ]. Affected individuals had severe lymphopenia of NK cells and CD4 + T cells, reduced CD8+ T cells, agammaglobulinemia, abnormal distribution of progenitor cells in the bone marrow or B cell lymphopenia [ 108 , 109 , 110 ]. Studies with patient-derived cells demonstrated impaired T cell development and proliferation [ 108 , 109 , 110 ].…”

“…Affected individuals had severe lymphopenia of NK cells and CD4 + T cells, reduced CD8+ T cells, agammaglobulinemia, abnormal distribution of progenitor cells in the bone marrow or B cell lymphopenia [ 108 , 109 , 110 ]. Studies with patient-derived cells demonstrated impaired T cell development and proliferation [ 108 , 109 , 110 ]. T and NK cells exhibited increased spontaneous DNA damage and NK cells were defective in their response to X-ray irradiation [ 109 ].…”