Autoimmunity and immunodeficiency associated with monoallelic LIG4 mutations via haploinsufficiency.
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BORIS DOI
Date of Publication
August 2023
Publication Type
Article
Division/Institute
Author
Jauch, Annaïse J | |
Bignucolo, Olivier | |
Seki, Sayuri | |
Ghraichy, Marie | |
Delmonte, Ottavia M | |
von Niederhäusern, Valentin | |
Higgins, Rebecca | |
Ghosh, Adhideb | |
Nishizawa, Masako | |
Tanaka, Mariko | |
Baldrich, Adrian | |
Köppen, Julius | |
Hirsiger, Julia R | |
Hupfer, Robin | |
Ehl, Stephan | |
Rensing-Ehl, Anne | |
Hopfer, Helmut | |
Prince, Spasenija Savic | |
Daley, Stephen R | |
Marquardsen, Florian A | |
Meyer, Benedikt J | |
Tamm, Michael | |
Daikeler, Thomas D | |
Diesch, Tamara | |
Kühne, Thomas | |
Berkemeier, Caroline | |
Heijnen, Ingmar | |
Navarini, Alexander A | |
Trück, Johannes | |
de Villartay, Jean-Pierre | |
Oxenius, Annette | |
Berger, Christoph T | |
Hess, Christoph | |
Notarangelo, Luigi D | |
Yamamoto, Hiroyuki | |
Recher, Mike |
Subject(s)
Series
The Journal of allergy and clinical immunology
ISSN or ISBN (if monograph)
1097-6825
Publisher
Elsevier
Language
English
Publisher DOI
PubMed ID
37004747
Uncontrolled Keywords
Description
BACKGROUND
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.
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.
File(s)
| File | File Type | Format | Size | License | Publisher/Copright statement | Content | |
|---|---|---|---|---|---|---|---|
| 1-s2.0-S0091674923004220-main.pdf | text | Adobe PDF | 8.02 MB | Attribution (CC BY 4.0) | accepted |