RGD Reference Report - Homozygous DNA ligase IV R278H mutation in mice leads to leaky SCID and represents a model for human LIG4 syndrome. - Rat Genome Database

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

Authors: Rucci, Francesca  Notarangelo, Luigi D  Fazeli, Alex  Patrizi, Laura  Hickernell, Thomas  Paganini, Tiziana  Coakley, Kristen M  Detre, Cynthia  Keszei, Marton  Walter, Jolan E  Feldman, Lauren  Cheng, Hwei-Ling  Poliani, Pietro Luigi  Wang, Jing H  Balter, Barbara B  Recher, Mike  Andersson, Emma-Maria  Zha, Shan  Giliani, Silvia  Terhorst, Cox  Alt, Frederick W  Yan, Catherine T 
Citation: Rucci F, etal., Proc Natl Acad Sci U S A. 2010 Feb 16;107(7):3024-9. doi: 10.1073/pnas.0914865107. Epub 2010 Feb 1.
RGD ID: 13204717
Pubmed: PMID:20133615   (View Abstract at PubMed)
PMCID: PMC2840307   (View Article at PubMed Central)
DOI: DOI:10.1073/pnas.0914865107   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
LIG4HumanDNA ligase IV deficiency  ISOLig4 (Mus musculus)DNA:missense mutation: :p.R278H (mouse)RGD 
Lig4RatDNA ligase IV deficiency  ISOLig4 (Mus musculus)DNA:missense mutation: :p.R278H (mouse)RGD 
Lig4MouseDNA ligase IV deficiency  IMP DNA:missense mutation: :p.R278H (mouse)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Lig4  (DNA ligase 4)

Genes (Mus musculus)
Lig4  (ligase IV, DNA, ATP-dependent)

Genes (Homo sapiens)
LIG4  (DNA ligase 4)


Additional Information