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Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies.
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.
Afiliación
  • Maffucci P; Division of Clinical Immunology, Departments of Medicine and Pediatrics, and.
  • Chavez J; Graduate School of Biomedical Sciences, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
  • Jurkiw TJ; Division of Clinical Immunology, Departments of Medicine and Pediatrics, and.
  • O'Brien PJ; Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan, USA.
  • Abbott JK; Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan, USA.
  • Reynolds PR; Immunodeficiency Diagnosis and Treatment Program, Department of Pediatrics, National Jewish Health, Denver, Colorado, USA.
  • Worth A; Immunodeficiency Diagnosis and Treatment Program, Department of Pediatrics, National Jewish Health, Denver, Colorado, USA.
  • Notarangelo LD; Department of Pediatric Medicine, Great Ormond Street Hospital for Children, London, United Kingdom.
  • Felgentreff K; Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
  • Cortes P; Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.
  • Boisson B; Department of Molecular, Cellular and Biomedical Science, CUNY School of Medicine, City College of New York, New York, New York, USA.
  • Radigan L; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, USA.
  • Cobat A; Paris Descartes University, Imagine Institute, Paris, France.
  • Dinakar C; Division of Clinical Immunology, Departments of Medicine and Pediatrics, and.
  • Ehlayel M; Paris Descartes University, Imagine Institute, Paris, France.
  • Ben-Omran T; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.
  • Gelfand EW; Allergy, Asthma & Immunodeficiency, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Stanford University, Stanford, California, USA.
  • Casanova JL; Section of Pediatric Allergy-Immunology, Department of Pediatrics, Weill Cornell Medical College, Hamad Medical Corporation, Doha, Qatar.
  • Cunningham-Rundles C; Department of Clinical and Metabolic Genetics, Department of Pediatrics, Weill Cornell Medical College, Hamad Medical Corporation, Doha, Qatar.
J Clin Invest ; 128(12): 5489-5504, 2018 12 03.
Article en En | MEDLINE | ID: mdl-30395541
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Alelos / ADN Ligasa (ATP) / Síndromes de Inmunodeficiencia / Mutación Límite: Humans Idioma: En Revista: J Clin Invest Año: 2018 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Alelos / ADN Ligasa (ATP) / Síndromes de Inmunodeficiencia / Mutación Límite: Humans Idioma: En Revista: J Clin Invest Año: 2018 Tipo del documento: Article Pais de publicación: Estados Unidos