ANALYSIS OF B LYMPHOCYTES IN MOUSE MODEL LIGASE IV WITH HYPOMORPHIC MUTATION IN VDJ RECOMBINATION ASSOCIATED WITH GROWTH DEFECT

The major mechanism for the repair of DNA doublestrand breaks (DSBs) in mammalian cells is non-homologous end-joining (NHEJ), a process that involves the DNA-dependent protein kinase , XRCC4 and DNA ligase IV. Rodent cells and mice defective in these components are radiation-sensitive and defective in V(D)J-recombination, showing that NHEJ also functions to rejoin DSBs introduced during lymphocyte development. We have generated a knock-in mouse model with a homozygous Lig4 arginine to histidine (R278H) mutation that corresponds to the mutation identified in the first LIG4-deficient patient, who developed T cell leukemia associated with increased cellular radiosensitivity. The clinical presentation of the syndrome is complex and heterogeneous and may include varying degrees of lymphopenia, growth retardation and microcephaly. The phenotypic effects of the impaired repair of non programmed DNA damage are more diverse and difficult to study. Although such defects in cell survival and proliferation are likely to have an impact on the immune system, their contribution to the immunodeficiency of the LigIV syndrome remains unknown.