2. Academic Validation
  3. Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies

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

  • J Clin Invest. 2018 Dec 3;128(12):5489-5504. doi: 10.1172/JCI99629.
Patrick Maffucci 1 2,  Jose Chavez 1,  Thomas J Jurkiw 3,  Patrick J O'Brien 3,  Jordan K Abbott 4,  Paul R Reynolds 4,  Austen Worth 5,  Luigi D Notarangelo 6,  Kerstin Felgentreff 7,  Patricia Cortes 8,  Bertrand Boisson 9 10,  Lin Radigan 1,  Aurélie Cobat 10 11,  Chitra Dinakar 12,  Mohammad Ehlayel 13,  Tawfeg Ben-Omran 14,  Erwin W Gelfand 4,  Jean-Laurent Casanova 9 10 11 15 16,  Charlotte Cunningham-Rundles 1 2
Affiliations

Affiliations

  • 1 Division of Clinical Immunology, Departments of Medicine and Pediatrics, and.
  • 2 Graduate School of Biomedical Sciences, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
  • 3 Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan, USA.
  • 4 Immunodeficiency Diagnosis and Treatment Program, Department of Pediatrics, National Jewish Health, Denver, Colorado, USA.
  • 5 Department of Pediatric Medicine, Great Ormond Street Hospital for Children, London, United Kingdom.
  • 6 Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
  • 7 Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.
  • 8 Department of Molecular, Cellular and Biomedical Science, CUNY School of Medicine, City College of New York, New York, New York, USA.
  • 9 St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, USA.
  • 10 Paris Descartes University, Imagine Institute, Paris, France.
  • 11 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.
  • 12 Allergy, Asthma & Immunodeficiency, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Stanford University, Stanford, California, USA.
  • 13 Section of Pediatric Allergy-Immunology, Department of Pediatrics, Weill Cornell Medical College, Hamad Medical Corporation, Doha, Qatar.
  • 14 Department of Clinical and Metabolic Genetics, Department of Pediatrics, Weill Cornell Medical College, Hamad Medical Corporation, Doha, Qatar.
  • 15 Howard Hughes Medical Institute, New York, New York, USA.
  • 16 Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, Paris, France.
PMID: 30395541 DOI: 10.1172/JCI99629
Abstract

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.

Keywords

B cells; Genetic diseases; Genetics; Immunology; T cell development.

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