Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies

• Published in: The Journal of clinical investigation Vol. 128; no. 12; pp. 5489 - 5504
• Main Authors: Maffucci, Patrick, Chavez, Jose, Jurkiw, Thomas J, O'Brien, Patrick J, Abbott, Jordan K, Reynolds, Paul R, Worth, Austen, Notarangelo, Luigi D, Felgentreff, Kerstin, Cortes, Patricia, Boisson, Bertrand, Radigan, Lin, Cobat, Aurélie, Dinakar, Chitra, Ehlayel, Mohammad, Ben-Omran, Tawfeg, Gelfand, Erwin W, Casanova, Jean-Laurent, Cunningham-Rundles, Charlotte
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.12.2018
• Subjects: Alleles; Anemia; Binding sites; Biomedical research; Cancer; Cell lines; Deoxyribonucleic acid; DNA; DNA damage; DNA Ligase ATP - genetics; DNA Ligase ATP - immunology; DNA repair; Enzymatic activity; Gene expression; Gene mutation; Genetic aspects; Genomes; Genotypes; Haplotypes; HEK293 Cells; Hematopoietic stem cells; Humans; Hypogammaglobulinemia; Immunodeficiency; Immunologic Deficiency Syndromes - genetics; Immunologic Deficiency Syndromes - immunology; Immunologic diseases; Immunology; LIG1 gene; Lymphocytes; Lymphopenia; Mutation; Patients; Phenotypes; Spectroscopy; Stem cell transplantation; T cell receptors; T cell development; Genetics; Immunology; B cells; Genetic diseases
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci99629

We report the molecular, cellular, and clinical features of 5 patients from 3 kindreds with biallelic mutations in the autosomal LIG1 gene encoding DNA ligase 1. The patients exhibited hypogammaglobulinemia, lymphopenia, increased proportions of circulating γδT cells, and erythrocyte macrocytosis. Clinical severity ranged from a mild antibody deficiency to a combined immunodeficiency requiring hematopoietic stem cell transplantation. Using engineered LIG1-deficient cell lines, we demonstrated chemical and radiation defects associated with the mutant alleles, which variably impaired the DNA repair pathway. We further showed that these LIG1 mutant alleles are amorphic or hypomorphic, and exhibited variably decreased enzymatic activities, which lead to premature release of unligated adenylated DNA. The variability of the LIG1 genotypes in the patients was consistent with that of their immunological and clinical phenotypes. These data suggest that different forms of autosomal recessive, partial DNA ligase 1 deficiency underlie an immunodeficiency of variable severity.