TY - JOUR
T1 - Ligase-4 Deficiency Causes Distinctive Immune Abnormalities in Asymptomatic Individuals
AU - Felgentreff, Kerstin
AU - Baxi, Sachin N.
AU - Lee, Yu Nee
AU - Dobbs, Kerry
AU - Henderson, Lauren A.
AU - Csomos, Krisztian
AU - Tsitsikov, Erdyni N.
AU - Armanios, Mary
AU - Walter, Jolan E.
AU - Notarangelo, Luigi D.
N1 - Funding Information:
We thank all our patients and controls for participating in this study, and Dr. Frederick Alt for helpful comments and advice. This work was supported by a grant (5R01AI100887) from the National Institute of Allergy and Infectious Diseases – NIH to L.D.N.
Publisher Copyright:
© 2016, Springer Science+Business Media New York.
PY - 2016/5/1
Y1 - 2016/5/1
N2 - 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.
AB - 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.
KW - DNA repair
KW - Ligase 4 deficiency
KW - immune repertoire
KW - microhomology-mediated end-joining
KW - telomere length
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U2 - 10.1007/s10875-016-0266-5
DO - 10.1007/s10875-016-0266-5
M3 - Article
C2 - 27063650
AN - SCOPUS:84962838889
SN - 0271-9142
VL - 36
SP - 341
EP - 353
JO - Journal of Clinical Immunology
JF - Journal of Clinical Immunology
IS - 4
ER -