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.
Rucci
Francesca
F
Division of Immunology and Manton Center for Orphan Disease Research, Children's Hospital Boston, Boston, MA 02115, USA.
Notarangelo
Luigi D
LD
Fazeli
Alex
A
Patrizi
Laura
L
Hickernell
Thomas
T
Paganini
Tiziana
T
Coakley
Kristen M
KM
Detre
Cynthia
C
Keszei
Marton
M
Walter
Jolan E
JE
Feldman
Lauren
L
Cheng
Hwei-Ling
HL
Poliani
Pietro Luigi
PL
Wang
Jing H
JH
Balter
Barbara B
BB
Recher
Mike
M
Andersson
Emma-Maria
EM
Zha
Shan
S
Giliani
Silvia
S
Terhorst
Cox
C
Alt
Frederick W
FW
Yan
Catherine T
CT
D000015:Abnormalities, Multiple / Q000235:genetics*; D000818:Animals; D000917:Antibody Formation / Q000235:genetics*; D017209:Apoptosis / Q000276:immunology; D015139:Blotting, Southern; D002648:Child; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000235:genetics* / Q000276:immunology; D002658:Developmental Disabilities / Q000235:genetics*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006801:Humans; D007136:Immunoglobulins / Q000097:blood; D016130:Immunophenotyping; D051379:Mice; D020125:Mutation, Missense / Q000235:genetics* / Q000276:immunology; D016511:Severe Combined Immunodeficiency / Q000235:genetics*; D013577:Syndrome
D007136:Immunoglobulins; C000607893:LIG4 protein, human; D011088:DNA Ligases; D000072481:DNA Ligase ATP