Chiara Bacchelli1, Federico A Moretti2, Marlene Carmo2, Stuart Adams3, Horia C Stanescu4, Kerra Pearce1, Manisha Madkaikar5, Kimberly C Gilmour6, Adeline K Nicholas7, C Geoffrey Woods7, Robert Kleta4, Phil L Beales1, Waseem Qasim6, H Bobby Gaspar8. 1. Genetics and Genomic Medicine, UCL Institute of Child Health, London, United Kingdom. 2. Infection, Immunity, Inflammation and Physiological Medicine, UCL Institute of Child Health, London, United Kingdom. 3. Bone Marrow Transplantation, Great Ormond Street Hospital NHS Trust, London, United Kingdom. 4. Centre for Nephrology, University College London Royal Free Hospital, London, United Kingdom. 5. Infection, Immunity, Inflammation and Physiological Medicine, UCL Institute of Child Health, London, United Kingdom; Department of Pediatric Immunology and Leukocyte Biology, National Institute of Immunohematology, ICMR, Mumbai, India. 6. Infection, Immunity, Inflammation and Physiological Medicine, UCL Institute of Child Health, London, United Kingdom; Department of Clinical Immunology, Great Ormond Street Hospital NHS Trust, London, United Kingdom. 7. Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom. 8. Infection, Immunity, Inflammation and Physiological Medicine, UCL Institute of Child Health, London, United Kingdom; Department of Clinical Immunology, Great Ormond Street Hospital NHS Trust, London, United Kingdom. Electronic address: h.gaspar@ucl.ac.uk.
Abstract
BACKGROUND: Signaling through the T-cell receptor (TCR) is critical for T-cell development and function. Linker for activation of T cells (LAT) is a transmembrane adaptor signaling molecule that is part of the TCR complex and essential for T-cell development, as demonstrated by LAT-deficient mice, which show a complete lack of peripheral T cells. OBJECTIVE: We describe a pedigree affected by a severe combined immunodeficiency phenotype with absent T cells and normal B-cell and natural killer cell numbers. A novel homozygous frameshift mutation in the gene encoding for LAT was identified in this kindred. METHODS: Genetic, molecular, and functional analyses were used to identify and characterize the LAT defect. Clinical and immunologic analysis of patients was also performed and reported. RESULTS: Homozygosity mapping was used to identify potential defective genes. Sanger sequencing of the LAT gene showed a mutation that resulted in a premature stop codon and protein truncation leading to complete loss of function and loss of expression of LAT in the affected family members. We also demonstrate loss of LAT expression and lack of TCR signaling restoration in LAT-deficient cell lines reconstituted with a synthetic LAT gene bearing this severe combined immunodeficiency mutation. CONCLUSION: For the first time, the results of this study show that inherited LAT deficiency should be considered in patients with combined immunodeficiency with T-cell abnormalities.
BACKGROUND: Signaling through the T-cell receptor (TCR) is critical for T-cell development and function. Linker for activation of T cells (LAT) is a transmembrane adaptor signaling molecule that is part of the TCR complex and essential for T-cell development, as demonstrated by LAT-deficient mice, which show a complete lack of peripheral T cells. OBJECTIVE: We describe a pedigree affected by a severe combined immunodeficiency phenotype with absent T cells and normal B-cell and natural killer cell numbers. A novel homozygous frameshift mutation in the gene encoding for LAT was identified in this kindred. METHODS: Genetic, molecular, and functional analyses were used to identify and characterize the LAT defect. Clinical and immunologic analysis of patients was also performed and reported. RESULTS: Homozygosity mapping was used to identify potential defective genes. Sanger sequencing of the LAT gene showed a mutation that resulted in a premature stop codon and protein truncation leading to complete loss of function and loss of expression of LAT in the affected family members. We also demonstrate loss of LAT expression and lack of TCR signaling restoration in LAT-deficient cell lines reconstituted with a synthetic LAT gene bearing this severe combined immunodeficiency mutation. CONCLUSION: For the first time, the results of this study show that inherited LAT deficiency should be considered in patients with combined immunodeficiency with T-cell abnormalities.
Keywords:
Severe combined immunodeficiency; T lymphopenia; T-cell receptor signaling; genetic defect; immunodeficiency; linker for activation of T cells
Authors: Manuel A R Ferreira; Judith M Vonk; Hansjörg Baurecht; Ingo Marenholz; Chao Tian; Joshua D Hoffman; Quinta Helmer; Annika Tillander; Vilhelmina Ullemar; Yi Lu; Franz Rüschendorf; David A Hinds; Norbert Hübner; Stephan Weidinger; Patrik K E Magnusson; Eric Jorgenson; Young-Ae Lee; Dorret I Boomsma; Robert Karlsson; Catarina Almqvist; Gerard H Koppelman; Lavinia Paternoster Journal: J Allergy Clin Immunol Date: 2018-04-19 Impact factor: 10.793