Autoimmunity and immunodeficiency associated with monoallelic LIG4 mutations via haploinsufficiency.

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; ... (2023). Autoimmunity and immunodeficiency associated with monoallelic LIG4 mutations via haploinsufficiency. The Journal of allergy and clinical immunology, 152(2), pp. 500-516. Elsevier 10.1016/j.jaci.2023.03.022

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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.

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