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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

Authors

  • Rucci F
  • Notarangelo LD
  • Fazeli A
  • Patrizi L
  • Hickernell T
  • Paganini T
  • Coakley KM
  • Detre C
  • Keszei M
  • Walter JE
  • Feldman L
  • Cheng HL
  • Poliani PL
  • Wang JH
  • Balter BB
  • Recher M
  • Andersson EM
  • Zha S
  • Giliani S
  • Terhorst C
  • Alt FW
  • Yan CT

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

February 16, 2010

Associated Grants

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

Mesh Terms

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