RGD Reference Report - Ligase-4 Deficiency Causes Distinctive Immune Abnormalities in Asymptomatic Individuals. - Rat Genome Database

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Ligase-4 Deficiency Causes Distinctive Immune Abnormalities in Asymptomatic Individuals.

Authors: Felgentreff, Kerstin  Baxi, Sachin N  Lee, Yu Nee  Dobbs, Kerry  Henderson, Lauren A  Csomos, Krisztian  Tsitsikov, Erdyni N  Armanios, Mary  Walter, Jolan E  Notarangelo, Luigi D 
Citation: Felgentreff K, etal., J Clin Immunol. 2016 May;36(4):341-53. doi: 10.1007/s10875-016-0266-5. Epub 2016 Apr 11.
RGD ID: 13204707
Pubmed: PMID:27063650   (View Abstract at PubMed)
PMCID: PMC4842108   (View Article at PubMed Central)
DOI: DOI:10.1007/s10875-016-0266-5   (Journal Full-text)


PURPOSE: DNA Ligase 4 (LIG4) is a key factor in the non-homologous end-joining (NHEJ) DNA double-strand break repair pathway needed for V(D)J recombination and the generation of the T cell receptor and immunoglobulin molecules. Defects in LIG4 result in a variable syndrome of growth retardation, pancytopenia, combined immunodeficiency, cellular radiosensitivity, and developmental delay.
METHODS: We diagnosed a patient with LIG4 syndrome by radiosensitivity testing on peripheral blood cells, and established that two of her four healthy siblings carried the same compound heterozygous LIG4 mutations. An extensive analysis of the immune phenotype, cellular radiosensitivity, telomere length, and T and B cell antigen receptor repertoire was performed in all siblings.
RESULTS: In the three genotypically affected individuals, variable severities of radiosensitivity, alterations of T and B cell counts with an increased percentage of memory cells, and hypogammaglobulinemia, were noticed. Analysis of T and B cell antigen receptor repertoires demonstrated increased usage of alternative microhomology-mediated end-joining (MHMEJ) repair, leading to diminished N nucleotide addition and shorter CDR3 length. However, overall repertoire diversity was preserved.
CONCLUSIONS: We demonstrate that LIG4 syndrome presents with high clinical variability even within the same family, and that distinctive immunologic abnormalities may be observed also in yet asymptomatic individuals.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
LIG4HumanDNA ligase IV deficiency  IAGP DNA:missense mutation and nonsense mutation: :p.K449Q (c.1345A>C), p.R814* (c.2440C>T) (human)RGD 
Lig4RatDNA ligase IV deficiency  ISOLIG4 (Homo sapiens)DNA:missense mutation and nonsense mutation: :p.K449Q (c.1345A>C), p.R814* (c.2440C>T) (human)RGD 
Lig4MouseDNA ligase IV deficiency  ISOLIG4 (Homo sapiens)DNA:missense mutation and nonsense mutation: :p.K449Q (c.1345A>C), p.R814* (c.2440C>T) (human)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