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Homozygous DNA ligase IV R278H mutation in mice leads to leaky SCID and represents a model for human LIG4 syndrome.

DNA ligase IV (LIG4) is an essential component of the nonhomologous end-joining (NHEJ) repair pathway and plays a key role in V(D)J recombination. Hypomorphic LIG4 mutations in humans are associated with increased cellular radiosensitivity, microcephaly, facial dysmorphisms, growth retardation, developmental delay, and a variable degree of immunodeficiency. We have generated a knock-in mouse model with a homozygous Lig4 R278H mutation that corresponds to the first LIG4 mutation reported in humans. The phenotype of homozygous mutant mice Lig4(R278H/R278H) (Lig4(R/R)) includes growth retardation, a decreased life span, a severe cellular sensitivity to ionizing radiation, and a very severe, but incomplete block in T and B cell development. Peripheral T lymphocytes show an activated and anergic phenotype, reduced viability, and a restricted repertoire, reminiscent of human leaky SCID. Genomic instability is associated with a high rate of thymic tumor development. Finally, Lig4(R/R) mice spontaneously produce low-affinity antibodies that include autoreactive specificities, but are unable to mount high-affinity antibody responses. These findings highlight the importance of LIG4 in lymphocyte development and function, and in genomic stability maintenance, and provide a model for the complex phenotype of LIG4 syndrome in humans.

Pubmed ID: 20133615 RIS Download

Mesh terms: Abnormalities, Multiple | Animals | Antibody Formation | Apoptosis | Blotting, Southern | Child | DNA Ligase ATP | DNA Ligases | Developmental Disabilities | Disease Models, Animal | Flow Cytometry | Humans | Immunoglobulins | Immunophenotyping | Mice | Mutation, Missense | Severe Combined Immunodeficiency | Syndrome

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Associated grants

  • Agency: NIAID NIH HHS, Id: P01 AI076210-01A1
  • Agency: NIAID NIH HHS, Id: P01 AI076210-01A18140
  • Agency: NCI NIH HHS, Id: T32 CA009382
  • Agency: Howard Hughes Medical Institute, Id: CA 09382-26
  • Agency: NCI NIH HHS, Id: P01 AI076210
  • Agency: NIAID NIH HHS, Id:

Mouse Genome Informatics (Data, Gene Annotation)

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