Impaired lymphocyte development and antibody class switching and increased malignancy in a murine model of DNA ligase IV syndrome.
Hypomorphic mutations in DNA ligase IV (LIG4) cause a human syndrome of immunodeficiency, radiosensitivity, and growth retardation due to defective DNA repair by the nonhomologous end-joining (NHEJ) pathway. Lig4-null mice are embryonic lethal, and better mouse models are needed to study human LigIV syndrome. We recently identified a viable mouse strain with a Y288C hypomorphic mutation in the Lig4 gene. Lig4Y288C mice exhibit a greater than 10-fold reduction of LigIV activity in vivo and recapitulate the immunodeficiency and growth retardation seen in human patients. Here, we have demonstrated that the Lig4Y288C mutation leads to multiple defects in lymphocyte development and function, including impaired V(D)J recombination, peripheral lymphocyte survival and proliferation, and B cell class switch recombination. We also highlight a high incidence of thymic tumors in the Lig4Y288C mice, suggesting that wild-type LigIV protects against malignant transformation. These findings provide explanations for the complex lymphoid phenotype of human LigIV syndrome.
Nijnik
Anastasia
A
Henry Wellcome Building of Molecular Physiology, Oxford University, Oxford, United Kingdom.
Dawson
Sara
S
Crockford
Tanya L
TL
Woodbine
Lisa
L
Visetnoi
Supawan
S
Bennett
Sophia
S
Jones
Margaret
M
Turner
Gareth D
GD
Jeggo
Penelope A
PA
Goodnow
Christopher C
CC
Cornall
Richard J
RJ
D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D002470:Cell Survival; D011088:DNA Ligases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D017578:Immunoglobulin Class Switching / Q000276:immunology*; D007132:Immunoglobulin Isotypes / Q000276:immunology*; D008214:Lymphocytes / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D013577:Syndrome; D013953:Thymus Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology
D007132:Immunoglobulin Isotypes; D011088:DNA Ligases