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      Genetics of severe combined immunodeficiency

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          Abstract

          Severe Combined Immunodeficiency (SCID) is an inherited group of rare, life-threatening disorders due to the defect in T cell development and function. Clinical manifestations are characterised by recurrent and severe bacterial, viral, and fungal opportunistic infections that start from early infancy period. Haematopoietic stem cell transplantation (HSCT) is the treatment of choice. The pattern of inheritance of SCID may be X-linked or autosomal recessive. Though the diagnosis of SCID is usually established by flow cytometry-based tests, genetic diagnosis is often needed for genetic counselling, prognostication, and modification of pre-transplant chemotherapeutic agents. This review aims to highlight the genetic aspects of SCID.

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          XLF interacts with the XRCC4-DNA ligase IV complex to promote DNA nonhomologous end-joining.

          Peter Ahnesorg, Philippa Smith, Stephen P. Jackson (2006)
          DNA nonhomologous end-joining (NHEJ) is a predominant pathway of DNA double-strand break repair in mammalian cells, and defects in it cause radiosensitivity at the cellular and whole-organism levels. Central to NHEJ is the protein complex containing DNA Ligase IV and XRCC4. By searching for additional XRCC4-interacting factors, we identified a previously uncharacterized 33 kDa protein, XRCC4-like factor (XLF, also named Cernunnos), that has weak sequence homology with XRCC4 and is predicted to display structural similarity to XRCC4. We show that XLF directly interacts with the XRCC4-Ligase IV complex in vitro and in vivo and that siRNA-mediated downregulation of XLF in human cell lines leads to radiosensitivity and impaired NHEJ. Furthermore, we establish that NHEJ-deficient 2BN cells derived from a radiosensitive and immune-deficient patient lack XLF due to an inactivating frameshift mutation in its gene, and that reintroduction of wild-type XLF into such cells corrects their radiosensitivity and NHEJ defects. XLF thus constitutes a novel core component of the mammalian NHEJ apparatus.
          Article 0 comments Cited 212 times – based on 0 reviews     Review now
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            V(D)J recombination: mechanisms of initiation.

            D Schatz, Gregory Swanson (2010)
            V(D)J recombination assembles immunoglobulin and T cell receptor genes during lymphocyte development through a series of carefully orchestrated DNA breakage and rejoining events. DNA cleavage requires a series of protein-DNA complexes containing the RAG1 and RAG2 proteins and recombination signals that flank the recombining gene segments. In this review, we discuss recent advances in our understanding of the function and domain organization of the RAG proteins, the composition and structure of RAG-DNA complexes, and the pathways that lead to the formation of these complexes. We also consider the functional significance of RAG-mediated histone recognition and ubiquitin ligase activities, and the role played by RAG in ensuring proper repair of DNA breaks made during V(D)J recombination. Finally, we propose a model for the formation of RAG-DNA complexes that involves anchoring of RAG1 at the recombination signal nonamer and RAG2-dependent surveillance of adjoining DNA for suitable spacer and heptamer sequences.
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              Artemis, a novel DNA double-strand break repair/V(D)J recombination protein, is mutated in human severe combined immune deficiency.

              F Deist, O Sanal, R Man … (2001)
              The V(D)J recombination process insures the somatic diversification of immunoglobulin and antigen T cell receptor encoding genes. This reaction is initiated by a DNA double-strand break (dsb), which is resolved by the ubiquitously expressed DNA repair machinery. Human T-B-severe combined immunodeficiency associated with increased cellular radiosensitivity (RS-SCID) is characterized by a defect in the V(D)J recombination leading to an early arrest of both B and T cell maturation. We previously mapped the disease-related locus to the short arm of chromosome 10. We herein describe the cloning of the gene encoding a novel protein involved in V(D)J recombination/DNA repair, Artemis, whose mutations cause human RS-SCID. Protein sequence analysis strongly suggests that Artemis belongs to the metallo-beta-lactamase superfamily.
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                Author and article information

                Contributors
                Pandiarajan Vignesh
                Journal
                Journal ID (nlm-ta): Genes Dis
                Journal ID (iso-abbrev): Genes Dis
                Title: Genes & Diseases
                Publisher: Chongqing Medical University
                ISSN (Print): 2352-4820
                ISSN (Electronic): 2352-3042
                Publication date PMC-release: 24 July 2019
                Publication date Collection: March 2020
                Publication date (Electronic): 24 July 2019
                Volume: 7
                Issue: 1
                Pages: 52-61
                Affiliations
                [1]Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
                Author notes
                [∗ ]Corresponding author. Pediatric Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical, Education and Research, Chandigarh 160012, India. Fax: +91 172 2744401. vigimmc@ 123456gmail.com
                Article
                Publisher ID: S2352-3042(19)30047-9
                DOI: 10.1016/j.gendis.2019.07.004
                PMC ID: 7063414
                PubMed ID: 32181275
                SO-VID: 6e16e176-25a4-49fe-ae04-4c0a8d7eb28c
                Copyright © © 2019 Chongqing Medical University. Production and hosting by Elsevier B.V.
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 10 April 2019
                Date revision received : 7 July 2019
                Date accepted : 9 July 2019
                Categories
                Subject: Article

                Keywords: adenosine deaminase,flow cytometry,genetics,newborn screening,severe combined immunodeficiency
                Data availability:
                Keywords: adenosine deaminase, flow cytometry, genetics, newborn screening, severe combined immunodeficiency

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