Update on DNA-Double Strand Break Repair Defects in Combined Primary Immunodeficiency
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IMMUNE DEFICIENCY AND DYSREGULATION (C KUO, SECTION EDITOR)
Update on DNA-Double Strand Break Repair Defects in Combined Primary Immunodeficiency Mary A. Slatter 1,2 & Andrew R. Gennery 1,2
# The Author(s) 2020
Abstract Purpose of Review The most serious DNA damage, DNA double strand breaks (DNA-dsb), leads to mutagenesis, carcinogenesis or apoptosis if left unrepaired. Non-homologous end joining (NHEJ) is the principle repair pathway employed by mammalian cells to repair DNA-dsb. Several proteins are involved in this pathway, defects in which can lead to human disease. This review updates on the most recent information available for the specific diseases associated with the pathway. Recent Findings A new member of the NHEJ pathway, PAXX, has been identified, although no human disease has been associated with it. The clinical phenotypes of Artemis, DNA ligase 4, Cernunnos-XLF and DNA-PKcs deficiency have been extended. The role of haematopoietic stem cell transplantation, following reduced intensity conditioning chemotherapy, for many of these diseases is being advanced. Summary In the era of newborn screening, urgent genetic diagnosis is necessary to correctly target appropriate treatment for patients with DNA-dsb repair disorders. Keywords Ataxia-telangiectasia . Nijmegen breakage syndrome . DNA-PK . DNA ligase 4 . Cernunnos-XLF . Radiosensitivity
Introduction There are a number of recognized immunodeficiency syndromes due to defects in genes important for DNA-dsb repair and variable, diversity and joining (VDJ) recombination during T- and B lymphocyte formation. This review aims to provide an update on the known disorders including the molecular pathways that are involved, the clinical features and the importance of diagnosis. The immunodeficiency associated with these disorders may be amenable to treatment by haematopoietic stem cell transplantation (HSCT) although features out with the haematopoietic system will remain
This article is part of the Topical Collection on Immune Deficiency and Dysregulation * Andrew R. Gennery [email protected] 1
Paediatric Immunology and Haematopoietic Stem Cell Transplantation, Great North Children’s Hospital, Clinical Resource Building, Floor 4, Block 2, Newcastle upon Tyne, UK
2
Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
unchanged. Due to sensitivity to DNA damaging chemotherapeutic agents, specific approaches to transplant are required.
Case Report A female infant presented at the age of 12 weeks with skin rash and failure to thrive. She had no dysmorphic features and had a normal head circumference. She was lymphocytopenic and a diagnosis of severe combined immunodeficiency (SCID) was made. Her lymphocyte subsets were as follows: CD3+ 474, CD19+ 8, CD4+ 187, CD8+ 137, NK 269 (all cells/μl) with absent naïve T-lymphocytes. She had absent IgM and IgA. Genetic studies to define the underlying disorder were arranged, but in the interim at 8 months of age, in the absence of a matched family donor or well matched unre
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