Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies
Patrick Maffucci, … , Jean-Laurent Casanova, Charlotte Cunningham-Rundles
Patrick Maffucci, … , Jean-Laurent Casanova, Charlotte Cunningham-Rundles
Published December 3, 2018; First published November 5, 2018
Citation Information: J Clin Invest. 2018;128(12):5489-5504. https://doi.org/10.1172/JCI99629.
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Research Article Genetics Immunology

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

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.

Authors

Patrick Maffucci, Jose Chavez, Thomas J. Jurkiw, Patrick J. O’Brien, Jordan K. Abbott, Paul R. Reynolds, Austen Worth, Luigi D. Notarangelo, Kerstin Felgentreff, Patricia Cortes, Bertrand Boisson, Lin Radigan, Aurélie Cobat, Chitra Dinakar, Mohammad Ehlayel, Tawfeg Ben-Omran, Erwin W. Gelfand, Jean-Laurent Casanova, Charlotte Cunningham-Rundles

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Figure 1

LIG1 mutations and functions.

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LIG1 mutations and functions. (A) Pedigrees for 3 kindreds with recessiv...
(A) Pedigrees for 3 kindreds with recessive mutations in LIG1. Patients 1 and 2 (P1 and P2) are from unrelated parents and both have the LIG1 mutations T415Mfs*10 and R641L. Patients 3 and 4 (P3 and P4) are brothers whose parents share grandmothers; patient 5 (P5) is a maternal cousin; these subjects have homozygous missense variants, P529L and R771W. The parents of P5 also share the same grandmother. (B) Sanger sequencing of P1 and a control, also P3 and a control. (Note that P2 has the same mutations as P1 and that P3 has the same genotype as P4 and P5.) (C) Schematic of LIG1 protein structure and approximate locations of all the identified mutations, in this and prior reports (16, 17). (D) Mechanism of LIG1-catalyzed DNA ligation. LIG1 consumes ATP and forms a covalent bond between AMP and K568. AMP is then transferred to the 5′-phosphate of a nicked DNA substrate. Attack by the 3′-hydroxyl seals the nick and releases AMP. All 3 chemical steps require Mg2+ as an essential cofactor.