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LINKER FOR ACTIVATION OF T CELLS; LAT

LINKER FOR ACTIVATION OF T CELLS; LAT

HGNC Approved Gene Symbol: LATCytogenetic location: 16p11.2 Genomic coordinates (GRCh38): 16:28,984,802-28,990,783 (from NCBI)▼ DescriptionThe LAT gene encod...

HGNC Approved Gene Symbol: LAT

Cytogenetic location: 16p11.2 Genomic coordinates (GRCh38): 16:28,984,802-28,990,783 (from NCBI)

▼ Description
The LAT gene encodes a transmembrane adaptor molecule that functions as a linker protein important for T-cell receptor (TCR) signaling by acting as a scaffolding protein that couples the TCR to downstream signaling pathways through enzyme activation and second messengers (summary by Keller et al., 2016 and Bacchelli et al., 2017).

▼ Cloning and Expression
T-cell antigen receptor (TCR) triggers complex cascades of biochemical events leading to enhanced gene transcription, cellular proliferation and differentiation. The earliest signaling events coupled to the TCR are the activation of several protein tyrosine kinases (PTKs). Zhang et al. (1998) cloned the cDNA encoding a highly tyrosine phosphorylated 36- to 38-kD protein that may play an important role as a molecule downstream of PTKs. The deduced 233-amino acid sequence identifies an integral membrane protein containing multiple potential tyrosine phosphorylation sites. Zhang et al. (1998) named this protein LAT (linker for activation of T cells).

▼ Gene Structure
Windpassinger et al. (2002) determined that the LAT gene contains 11 exons and spans 5.7 kb.

▼ Mapping
By FISH, Windpassinger et al. (2002) mapped the LAT gene to chromosome 16p11.2.

▼ Gene Function
Zhang et al. (1998) showed that LAT was phosphorylated by ZAP-70/Syk (600085) protein tyrosine kinases, leading to recruitment of multiple signaling molecules. Its function was demonstrated by inhibition of T-cell activation following overexpression of a mutant form lacking critical tyrosine residues.

Zeyda et al. (2002) showed that treatment of human T lymphocytes with polyunsaturated fatty acids (PUFAs) interfered with signal transduction by blocking tyrosine phosphorylation of LAT and PLCG1 (172420). PUFA treatment caused displacement of LAT and other signaling proteins from lipid rafts, and retention of LAT in rafts restored PLCG1 signaling in PUFA-treated T-cell lines. Zeyda et al. (2002) concluded that displacement of LAT from lipid rafts is a mechanism through which PUFAs inhibit T-cell signaling and that LAT localization in rafts is critical for T-cell activation.

Using immunoprecipitation and immunoblot analysis, Hundt et al. (2006) showed that Lat was hypophosphorylated in anergic mouse T cells upon restimulation with anti-Cd3 (see 186740)/Cd28 (186760). Signaling events upstream of Lat, such as phosphorylation of Cd3z (CD247; 186780) and Zap70, were not impaired, whereas downstream signaling events, such as association of Lat with p85 (see PIK3R1; 171833), were reduced. Recruitment of Lat to the immunologic synapse and its localization in detergent-resistant membranes were also reduced in anergic T cells due to defective Lat palmitoylation. Hundt et al. (2006) proposed that regulation of the amount of LAT in the immunologic synapse and in detergent-resistant membranes by posttranslational palmitoylation contributes to induction of T-cell anergy.

▼ Molecular Genetics
In 3 sibs, born of consanguineous Arab parents, with immunodeficiency-52 (IMD52; 617514) manifest as immune deficiency and autoimmune disorders, Keller et al. (2016) identified a homozygous truncating mutation in exon 5 of the LAT gene (602354.0001), resulting in a protein with an intact extracellular and transmembrane region, but a shortened intracellular region eliminating several major phosphorylation sites. The mutation was found by exome analysis and confirmed by Sanger sequencing. Western blot analysis of cells transfected with the mutation showed presence of a truncated protein. In vitro functional studies showed that the mutant protein lost some LAT signaling properties, including phosphorylation of some downstream proteins, calcium mobilization, and upregulation of CD69 (107273) after stimulation. However, primary T cells derived from 1 of the patients showed normal calcium mobilization and sustained T-cell differentiation, suggesting that the mutant protein retained some function in vivo.

In 5 members of a highly consanguineous Pakistani family with IMD52 manifest as severe combined immunodeficiency, Bacchelli et al. (2017) identified a homozygous frameshift mutation in exon 1 of the LAT gene (602354.0002). The mutation, which was found by haplotype analysis and homozygosity mapping followed by candidate gene sequencing, segregated with the disorder in the family. Western blot analysis of patient lymphocytes showed no LAT protein, consistent with a complete loss of protein. In vitro functional expression studies in TCR-signaling cells transfected with the mutation showed disrupted downstream signaling, including failure of CD69 upregulation and absence of calcium flux induction upon stimulation, as well as absence of downstream tyrosine phosphorylation, which could be rescued by expression of wildtype LAT. Absence of LAT also resulted in decreased apoptosis of T cells compared to controls.

▼ Animal Model
By targeted disruption, Zhang et al. (1999) generated Lat-deficient mice. In contrast to mice deficient in other adaptor proteins, such as Slp76 (601603) or Syk, the healthy-looking Lat-deficient mice exhibited no bleeding disorders and had no platelet defects. Likewise, natural killer (NK) cell activity was normal and there were normal levels of B cells. However, as observed in other mice lacking lymphocyte-signaling molecules, mature alpha/beta and gamma/delta T cells were absent, thymi were small, comparable to thymi in Rag2 (179616)-deficient mice, and there was an arrest in thymocyte development at the CD25 (147730)-positive/CD44 (107269)-negative stage of the CD4 (186940)/CD8 (see 186910) double-negative population. In contrast to Rag2-deficient mice, injection of anti-CD3 antibody failed to induce either proliferation or progression of thymocytes from the double-negative to the double-positive stage. Zhang et al. (1999) concluded that LAT is critical for coupling the pre-TCR surface complexes to intracellular signaling pathways in the developmental response. The authors cautioned, however, against extrapolation of normal NK cell activity from mouse to human, given the expression of LAT in NK as well as T cells and that the signaling pathways may be different in the 2 species.

Aguado et al. (2002) generated mice that were homozygous for a tyr136-to-phe (Y136F) mutation (tyr136 is the mouse equivalent of human tyr132). Although normal at birth, the spleen and lymph nodes of these mice started to enlarge such that by 7 weeks of age they had five-fold greater cellularity than wildtype mice. The thymus, on the other hand, had only 10% of the cells of wildtype mice, with progressively reduced numbers of double-positive CD4-positive/CD8-positive cells. Double-negative and gamma/delta T-cell populations were normal, indicating that Y136F results in a severe but partial impairment of alpha/beta T-cell development. Analysis of cytokine expression revealed high levels of Th2-type cytokines (e.g., IL4; 147780) that were detectable even before activation, whereas wildtype cells expressed gamma-interferon (IFNG; 147570) after activation and could only be polarized to Th2 cytokine production after prolonged antigenic stimulation in the presence of IL4. Th2 cytokine expression was accompanied by high levels of eosinophils, B cells, serum IgG1 and IgE, and kappa (IGKC; 147200) and lambda (IGLC; 147220) light chains, all of which was most likely secondary to the presence of a high frequency of Th2 effector cells. Aguado et al. (2002) proposed that Y136F activates both a positive feedback loop that is dominant during T-cell development and a negative feedback loop that is active in CD4 T cells, leading somehow to Th2 differentiation. They also noted that the phenotype of the Y136F mutant mice resembled the phenotype of mice deficient in Nfatc2 (600490) and Nfatc3 (602698) transcription factors.

Sommers et al. (2002) also characterized mice with the Y136F mutation. Their results confirmed the early block in T-cell maturation and the subsequent polyclonal lymphoproliferative disorder with possible signs of autoimmune disease. TCR-induced activation of Plcg1, Nfatc1 (600489), and Nfatc2; calcium influx; IL2 (147680) production; and cell death were reduced or abrogated in T cells from mutant mice. Sommers et al. (2002) concluded that the PLCG1-calcium signaling pathway has an important role in early T-cell development.

Nunez-Cruz et al. (2003) generated mice in which the 3 C-terminal tyrosine residues of Lat, tyr175, tyr195, and tyr235, were replaced by phenylalanine. These mice had a block in alpha-beta T-cell development and a partial impairment of gamma-delta T-cell development. The accumulation of gamma-delta cells in enlarged spleen and lymph nodes of older mice chronically produced large amounts of Th2 cytokines, inducing maturation of plasma cells secreting IgE and IgG1. Nunez-Cruz et al. (2003) concluded that LAT is an essential regulator of T-cell homeostasis and terminal differentiation.

Mingueneau et al. (2009) generated mice with T cells heterozygous for the Lat Y136F mutation and found that 1 wildtype Lat molecule was sufficient for normal function. However, depletion of the wildtype allele triggered a Th2 lymphoproliferative disorder that resembled the immunopathology seen in mice homozygous for Lat Y136F. This pathologic conversion required MHC class II and Cd28. Generation of Lat-deficient peripheral T cells also resulted in the Th2 lymphoproliferative disorder, suggesting that Lat-independent TCR signals are involved in the pathologic conversion. Mingueneau et al. (2009) concluded that LAT is a key negative regulator of the module involved in T-cell triggering.

▼ ALLELIC VARIANTS ( 2 Selected Examples):

.0001 IMMUNODEFICIENCY 52
LAT, 2-BP DEL, 268GG
In 3 sibs, born of consanguineous Arab parents, with immunodeficiency-52 (IMD52; 617514), Keller et al. (2016) identified a homozygous 2-bp deletion (c.268_269delGG, NM_001014987.1) in exon 5 of the LAT gene, resulting in a frameshift and premature termination. The truncated protein was predicted to have an intact extracellular and transmembrane region, but a shortened intracellular region eliminating several major phosphorylation sites. The mutation, which was found by exome analysis and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the ExAC database. Western blot analysis of cells transfected with the mutation showed presence of a truncated protein. In vitro functional studies showed that the mutant protein lost some LAT signaling properties.

.0002 IMMUNODEFICIENCY 52
LAT, 1-BP INS, 44T
In 5 members of a highly consanguineous Pakistani family with immunodeficiency-52 (IMD52; 617514), Bacchelli et al. (2017) identified a homozygous 1-bp insertion (c.44_45insT) in exon 1 of the LAT gene, resulting in a frameshift and premature termination (Leu16AlafsTer28). The mutation, which was found by haplotype analysis and homozygosity mapping followed by candidate gene sequencing, segregated with the disorder in the family. It was not found in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases, or in 300 control Pakistani chromosomes. Western blot analysis of patient lymphocytes showed no LAT protein, suggesting that the mutation resulted in nonsense-mediated mRNA decay and a complete loss of protein expression. In vitro functional expression studies in TCR-signaling cells transfected with the mutation showed that it resulted in impaired downstream TCR signaling.

Tags: 16p11.2