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 Tcells (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 Tcells. We describe a pedigree affected by a severe combined immunodeficiency phenotype with absent Tcells and normal B-cell and natural killer cell numbers. Anovel 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 withcombined immunodeficiency with T-cell abnormalities.