The following is a summary of “Autoimmunity and immunodeficiency associated with monoallelic LIG4 mutations via haploinsufficiency,” published in the AUGUST 2023 issue of Allergy & Immunology by Jauch, et al.
Biallelic mutations in the LIG4 gene, which encodes DNA-ligase 4, have been linked to a rare immunodeficiency syndrome characterized by severe infant-onset infections, skeletal anomalies, radiosensitivity, and neoplastic tendencies. DNA-ligase 4 is pivotal in DNA repair and the final step of V(D)J recombination. For a study, researchers sought to investigate the potential contribution of monoallelic missense mutations in LIG4 to immunodeficiency and autoimmunity with an autosomal dominant inheritance pattern.
Extensive flow-cytometric immune phenotyping was carried out, and rare variants of immune-related genes were analyzed through whole exome sequencing. DNA repair functionality and T-cell intrinsic DNA damage tolerance were assessed using a combination of in vitro and in silico techniques. Antigen-receptor diversity and autoimmune characteristics were elucidated using high-throughput sequencing and autoantibody arrays. Reconstitution experiments involving wild-type and mutant LIG4 were performed in LIG4 knockout Jurkat T cells, followed by the evaluation of DNA damage tolerance.
A novel heterozygous loss-of-function mutation (p.R580Q) in LIG4 was identified, associated with an autosomal dominant familial immune dysregulation syndrome. Clinical manifestations included autoimmune cytopenias, lymphoproliferation, agammaglobulinemia, and immune cell infiltration into nonlymphoid organs. Immunophenotyping revealed decreased naive CD4+ T cells and TCR-Vα7.2+ T cells, with minimal alterations in T-/B-cell receptor repertoires. Additional screening identified two unrelated patients with the monoallelic LIG4 mutation p.A842D, exhibiting similar clinical and immune-phenotypic dysregulations as observed in the index family. T-cell intrinsic DNA damage intolerance was observed in these patients. Reconstitution experiments and molecular dynamics simulations confirmed that both missense mutations resulted in loss of function and haploinsufficiency.
The study underscored the potential of specific monoallelic LIG4 mutations to contribute to human immune dysregulation through haploinsufficiency, providing insights into the intricate interplay between LIG4 mutations and immune dysfunction.