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

Abstract

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.

• Authors: Francesca Rucci, Luigi D Notarangelo, Alex Fazeli, Laura Patrizi, Thomas Hickernell, Tiziana Paganini, Kristen M Coakley, Cynthia Detre, Marton Keszei, Jolan E Walter, Lauren Feldman, Hwei-Ling Cheng, Pietro Luigi Poliani, Jing H Wang, Barbara B Balter, Mike Recher, Emma-Maria Andersson, Shan Zha, Silvia Giliani, Cox Terhorst, Frederick W Alt, Catherine T Yan
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 107 Issue 7 Pg. 3024-9 (Feb 16 2010) ISSN: 1091-6490 [Electronic] United States
• PMID: 20133615 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Immunoglobulins
• LIG4 protein, human
• DNA Ligases
• DNA Ligase ATP

Topics

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