Jauch, Annaïse JAnnaïse JJauchBignucolo, OlivierOlivierBignucoloSeki, SayuriSayuriSekiGhraichy, MarieMarieGhraichyDelmonte, Ottavia MOttavia MDelmontevon Niederhäusern, ValentinValentinvon NiederhäusernHiggins, RebeccaRebeccaHigginsGhosh, AdhidebAdhidebGhoshNishizawa, MasakoMasakoNishizawaTanaka, MarikoMarikoTanakaBaldrich, AdrianAdrianBaldrichKöppen, JuliusJuliusKöppenHirsiger, Julia RJulia RHirsigerHupfer, RobinRobinHupferEhl, StephanStephanEhlRensing-Ehl, AnneAnneRensing-EhlHopfer, HelmutHelmutHopferPrince, Spasenija SavicSpasenija SavicPrinceDaley, Stephen RStephen RDaleyMarquardsen, Florian AFlorian AMarquardsenMeyer, Benedikt JBenedikt JMeyerTamm, MichaelMichaelTammDaikeler, Thomas DThomas DDaikelerDiesch, TamaraTamaraDieschKühne, ThomasThomasKühneHelbling, ArthurArthurHelblingBerkemeier, CarolineCarolineBerkemeierHeijnen, IngmarIngmarHeijnenNavarini, Alexander AAlexander ANavariniTrück, JohannesJohannesTrückde Villartay, Jean-PierreJean-Pierrede VillartayOxenius, AnnetteAnnetteOxeniusBerger, Christoph TChristoph TBergerHess, ChristophChristophHessNotarangelo, Luigi DLuigi DNotarangeloYamamoto, HiroyukiHiroyukiYamamotoRecher, MikeMikeRecher2024-10-252024-10-252023-08https://boris-portal.unibe.ch/handle/20.500.12422/166199BACKGROUND Biallelic mutations in LIG4 encoding DNA-ligase 4 cause a rare immunodeficiency syndrome manifesting as infant-onset life-threatening and/or opportunistic infections, skeletal malformations, radiosensitivity and neoplasia. LIG4 is pivotal during DNA repair and during V(D)J recombination as it performs the final DNA-break sealing step. OBJECTIVE We explored whether monoallelic LIG4 missense mutations may underlie immunodeficiency and autoimmunity with autosomal dominant inheritance. METHODS Extensive flow-cytometric immune-phenotyping was performed. Rare variants of immune system genes were analyzed by whole exome sequencing. DNA repair functionality and T cell-intrinsic DNA damage tolerance was tested with an ensemble of in vitro and in silico tools. Antigen-receptor diversity and autoimmune features were characterized by high-throughput sequencing and autoantibody arrays. Reconstitution of wild-type vs. mutant LIG4 were performed in LIG4 knock-out Jurkat T cells and DNA damage tolerance was subsequently assessed. RESULTS A novel heterozygous LIG4 loss-of-function mutation (p.R580Q), associated with a dominantly inherited familial immune-dysregulation consisting of autoimmune cytopenias, and in the index patient with lymphoproliferation, agammaglobulinemia and adaptive immune cell infiltration into nonlymphoid organs. Immunophenotyping revealed reduced naïve CD4+ T cells and low TCR-Vα7.2+ T cells, while T/B-cell receptor repertoires showed only mild alterations. Cohort screening identified two other non-related patients with the monoallelic LIG4 mutation p.A842D recapitulating clinical and immune-phenotypic dysregulations observed in the index family and displaying T cell-intrinsic DNA damage intolerance. Reconstitution experiments and molecular dynamics simulations categorize both missense mutations as loss-of-function and haploinsufficient. CONCLUSION We provide evidence that certain monoallelic LIG4 mutations may cause human immune dysregulation via haploinsufficiency.enDNA damage DNA ligase 4 autoimmunity autosomal dominant haploinsufficiency immunodeficiency inborn errors of immunity primary immunodeficiency600 - Technology::610 - Medicine & healtharticle10.48350/1813973700474710.1016/j.jaci.2023.03.022