title: Mutations in linker for activation of T cells (LAT) lead to a novel form of severe combined immunodeficiency.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors: Genetics and Genomic Medicine, UCL Institute of Child Health, London, United Kingdom.
authors: Chiara
authors: C
authors: Bacchelli
authors: Infection, Immunity, Inflammation and Physiological Medicine, UCL Institute of Child Health, London, United Kingdom.
authors: Federico A
authors: FA
authors: Moretti
authors: Infection, Immunity, Inflammation and Physiological Medicine, UCL Institute of Child Health, London, United Kingdom.
authors: Marlene
authors: M
authors: Carmo
authors: Bone Marrow Transplantation, Great Ormond Street Hospital NHS Trust, London, United Kingdom.
authors: Stuart
authors: S
authors: Adams
authors: Centre for Nephrology, University College London Royal Free Hospital, London, United Kingdom.
authors: Horia C
authors: HC
authors: Stanescu
authors: Genetics and Genomic Medicine, UCL Institute of Child Health, London, United Kingdom.
authors: Kerra
authors: K
authors: Pearce
authors: 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.
authors: Manisha
authors: M
authors: Madkaikar
authors: 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.
authors: Kimberly C
authors: KC
authors: Gilmour
authors: Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom.
authors: Adeline K
authors: AK
authors: Nicholas
authors: Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom.
authors: C Geoffrey
authors: CG
authors: Woods
authors: Centre for Nephrology, University College London Royal Free Hospital, London, United Kingdom.
authors: Robert
authors: R
authors: Kleta
authors: Genetics and Genomic Medicine, UCL Institute of Child Health, London, United Kingdom.
authors: Phil L
authors: PL
authors: Beales
authors: 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.
authors: Waseem
authors: W
authors: Qasim
authors: 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.
authors: H Bobby
authors: HB
authors: Gaspar
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D020013:Calcium Signaling / Q000235:genetics; D002454:Cell Differentiation; D003241:Consanguinity; D005260:Female; D005838:Genotype; D006720:Homozygote; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D010154:Pakistan; D010375:Pedigree; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D017384:Sequence Deletion / Q000235:genetics*; D016511:Severe Combined Immunodeficiency / Q000235:genetics*; D013601:T-Lymphocytes / Q000502:physiology*; D019076:Transgenes / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C110810:LAT protein, human; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell
keywords: Severe combined immunodeficiency; T lymphopenia; T-cell receptor signaling; genetic defect; immunodeficiency; linker for activation of T cells