TY - JOUR AU - Maffucci, Patrick AU - Chavez, Jose AU - Jurkiw, Thomas J. AU - O’Brien, Patrick J. AU - Abbott, Jordan K. AU - Reynolds, Paul R. AU - Worth, Austen AU - Notarangelo, Luigi D. AU - Felgentreff, Kerstin AU - Cortes, Patricia AU - Boisson, Bertrand AU - Radigan, Lin AU - Cobat, Aurélie AU - Dinakar, Chitra AU - Ehlayel, Mohammad AU - Ben-Omran, Tawfeg AU - Gelfand, Erwin W. AU - Casanova, Jean-Laurent AU - Cunningham-Rundles, Charlotte T1 - Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies PY - 2018/12/03/ AB - 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. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI99629 VL - 128 IS - 12 UR - https://doi.org/10.1172/JCI99629 SP - 5489 EP - 5504 PB - The American Society for Clinical Investigation ER -