title: Ligase-4 Deficiency Causes Distinctive Immune Abnormalities in Asymptomatic Individuals.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.|Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Felgentreff
authors.affiliation: Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Sachin N
authors.initials: SN
authors.lastname: Baxi
authors.affiliation: Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Yu Nee
authors.initials: YN
authors.lastname: Lee
authors.affiliation: Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Kerry
authors.initials: K
authors.lastname: Dobbs
authors.affiliation: Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Henderson
authors.affiliation: Pediatric Allergy and Immunology and the Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Krisztian
authors.initials: K
authors.lastname: Csomos
authors.affiliation: Department of Laboratory Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Erdyni N
authors.initials: EN
authors.lastname: Tsitsikov
authors.affiliation: Departments of Oncology, Pathology and McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Armanios
authors.affiliation: Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.|Pediatric Allergy and Immunology and the Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Jolan E
authors.initials: JE
authors.lastname: Walter
authors.affiliation: Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. luigi.notarangelo@childrens.harvard.edu.|Harvard Stem Cell Institute, Harvard University, Boston, MA, USA. luigi.notarangelo@childrens.harvard.edu.
authors.forename: Luigi D
authors.initials: LD
authors.lastname: Notarangelo
mesh_terms: D000293:Adolescent; D000328:Adult; D000361:Agammaglobulinemia / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D002648:Child; D000072481:DNA Ligase ATP / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000528:radiation effects; D006098:Granulocytes / Q000528:radiation effects; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000166:cytology; D018655:Lymphocyte Count; D016131:Lymphocyte Subsets / Q000276:immunology; D008297:Male; D009154:Mutation; D011839:Radiation, Ionizing; D055815:Young Adult
chemical_list: C000607893:LIG4 protein, human; D000072481:DNA Ligase ATP
keywords: DNA repair; Ligase 4 deficiency; immune repertoire; microhomology-mediated end-joining; telomere length