* 601194
TOLL-LIKE RECEPTOR 1; TLR1
Alternative titles; symbols
TOLL/INTERLEUKIN 1 RECEPTOR-LIKE; TIL
HGNC Approved Gene Symbol: TLR1
Cytogenetic location: 4p14 Genomic coordinates (GRCh38) : 4:38,787,569-38,805,644 (from NCBI)
Gene-Phenotype Relationships
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4p14 | {Leprosy, protection against} | 613223 | 3 | |
| {Leprosy, susceptibility to, 5} | 613223 | 3 |
TEXT
Cloning and Expression
The Drosophila Toll gene is involved in establishing the dorsal/ventral axis in the developing fly embryo. Taguchi et al. (1996) stated that, when activated, Toll causes DNA binding by the dorsal gene product, a homolog of NF-kappa-B (see 164011). Toll encodes a membrane protein whose extracellular domains share sequence similarity with platelet glycoprotein 1b (see 231200) and other leucine-rich repeat-containing proteins but whose cytoplasmic region is related to interleukin-1 receptor (IL1R; 147810) (Gay and Keith, 1991). As with Toll, when the IL1 receptor is activated it causes DNA binding by NF-kappa-B. See TLR4 (603030). Nomura et al. (1994) identified a human cDNA, KIAA0012, which encodes a protein referred to as TIL (Toll/interleukin-1 receptor-like) by Taguchi et al. (1996) and which is characterized by extracellular leucine-rich repeats and an IL1 receptor-type cytoplasmic domain.
By searching an EST database for human Toll homologs, Rock et al. (1998) identified sequences from TIL, or TLR1, and 4 other genes that they designated Toll-like receptors (TLR) 2 to 5. See 603030. The predicted TLR1 protein is 786 amino acids long. Using Northern blot analysis, Rock et al. (1998) found that TLR1 is expressed ubiquitously and at higher levels than the other TLR genes. Transcripts of 3.0 and 8.0 were observed, suggesting that the TLR1 mRNA is alternatively spliced.
Using Northern blot analysis, Muzio et al. (2000) determined the differential expression pattern of the TLRs in leukocytes. TLR1 was expressed ubiquitously in leukocytes, and its expression was unchanged in response to lipopolysaccharide (LPS).
Using RT-PCR and ELISA analysis, Kadowaki et al. (2001) defined the differential expression of TLR1 through TLR10 and the pathogen-associated molecular pattern recognition profiles and cytokine production patterns of monocytes and dendritic cell precursors. They concluded that neither monocytes nor dendritic cell precursors can respond to all microbial antigens and that they have limited functional plasticity.
Mapping
Taguchi et al. (1996) mapped the TIL gene to 4p14 by fluorescence in situ hybridization.
Biochemical Features
TLRs and IL1Rs share a conserved cytoplasmic TIR domain. Mutations in this domain disrupt responses to LPS and to gram-positive bacteria, mediated by TLR4 and TLR2 (603028), respectively. By structural analysis, Xu et al. (2000) determined that the TIR domains of human TLR2 and TLR1, which are 50% identical at the amino acid level, contain a central 5-stranded parallel beta-sheet surrounded by 5 alpha helices on both sides. The structures have a large conserved surface patch, and mutational and functional analyses indicated that residues in the surface patch are crucial for receptor signaling. The authors concluded that instead of disturbing the structure of the TIR domain, mutations may abolish signaling by disrupting the recruitment of the MYD88 (602170) adaptor molecule.
Gene Function
Alexopoulou et al. (2002) reported that a small percentage of individuals who receive a vaccination series with the OspA antigen of Borrelia burgdorferi, the causative spirochete agent of Lyme disease, have very low antibody responses to the vaccine. They studied 7 of these 'low responders.' Macrophages from the low responders produced lower levels of the proinflammatory cytokines tumor necrosis factor (TNF; 191160) and IL6 (147620), while production of the antiinflammatory cytokine IL10 (124092) was similar to that of normal responders. Mutation analysis did not identify any defects in the TLR2 gene in the low responders. However, Tlr2-deficient mice produced lower levels of antibody and IL6 in response to OspA in the absence of complete Freund adjuvant (CFA), but not to intact B. burgdorferi. Apart from a higher spirochete burden early in the course of the disease, Tlr2 -/- mice resolved the infection in a manner similar to wildtype mice. Tlr1-deficient mice had a similar pattern of responses, except that these mice were capable of producing IL6 in response to peptidoglycan and were also capable of making IL10 in response to OspA. The human low antibody responders had no mutations in the TLR1 gene. However, flow cytometric analysis demonstrated undetectable cell-surface expression of TLR1, but not of TLR2, in all but 1 of the low responders. Alexopoulou et al. (2002) concluded that although TLR1 expression is critical for antibody responses to OspA, the presence of other TLRs in the host that presumably recognize other B. burgdorferi antigens results in no greater susceptibility to infection and disease in these hosts.
Using homologous recombination, Takeuchi et al. (2002) generated mice deficient in Tlr1, but not Tlr2. Macrophages from Tlr1-deficient mice stimulated with mycobacteria or with a mycobacterial 19-kD lipoprotein had impaired production of TNFA and IL6. Responses to mycoplasmal diacylated lipoproteins, but not to bacterial triacylated lipoproteins, was normal in Tlr1-deficient macrophages. Immunoprecipitation analysis indicated that TLR1 and TLR2 associated in a ligand-independent manner in human embryonic kidney cells. Takeuchi et al. (2002) concluded that TLR1 is involved in the recognition of triacylated lipoproteins and mycobacterial products, and that TLR2 pairs with TLR1 or TLR6 (605403) to recognize different pathogen-associated molecular patterns, or PAMPs.
Krutzik et al. (2003) showed that TLR2-TLR1 heterodimers mediated the strongest cell activation by killed Mycobacterium leprae. Human cell lines transiently expressing homodimers of any of the 10 TLRs except TLR2 did not mediate responsiveness. A genomewide scan of M. leprae detected 31 putative lipoproteins. Synthetic lipopeptides representing the 19- and 33-kD lipoproteins activated both monocytes and dendritic cells, as measured by IL12B (161561) release. This activation and TLR1 expression could be enhanced by type 1 cytokines, such as IFNG (147570) or GMCSF (CSF2; 138960), whereas type 2 cytokines, such as IL4 (147780), inhibited activation and downregulated TLR2 expression on both monocytes and dendritic cells. Both TLR2 and TLR1 were more strongly expressed in lesions from patients with the resistant tuberculoid form of the disease (see 246300), which is associated with type 1 cytokine expression and low numbers of mycobacteria. In contrast, in lesions from patients with the lepromatous form, which is characterized by disseminated leprosy bacilli and weak specific cell-mediated immunity with type 2 cytokines, there was reduced TLR2 and TLR1 expression. However, peripheral blood monocytes and dendritic cells from both patient groups were responsive to the 19-kD lipoprotein in the presence or absence of IFNG. Krutzik et al. (2003) concluded that the local expression and activation of TLRs contribute to the host response against pathogens, but they may also be implicated in inflammation-induced nerve injury in tuberculoid leprosy.
West et al. (2011) demonstrated that engagement of a subset of Toll-like receptors (TLR1, TLR2, and TLR4) results in the recruitment of mitochondria to macrophage phagosomes and augments mitochondrial reactive oxygen species (mROS) production. This response involves translocation of a TLR signaling adaptor, TRAF6 (602355), to mitochondria, where it engages the protein ECSIT (608388), which is implicated in mitochondrial respiratory chain assembly. Interaction with TRAF6 leads to ECSIT ubiquitination and enrichment at the mitochondrial periphery, resulting in increased mitochondrial and cellular ROS generation. ECSIT- and TRAF6-depleted macrophages have decreased levels of TLR-induced ROS and are significantly impaired in their ability to kill intracellular bacteria. Additionally, reducing macrophage mROS levels by expressing catalase (115500) in mitochondria results in defective bacterial killing, confirming the role of mROS in bactericidal activity. West et al. (2011) concluded that their results revealed a novel pathway linking innate immune signaling to mitochondria, implicated mROS as an important component of antibacterial responses, and further established mitochondria as hubs for innate immune signaling.
Molecular Genetics
Johnson et al. (2007) identified a common SNP in TLR1, rs5743618, that results in an ile602-to-ser (I602S; 601194.0001) substitution at the junction of the transmembrane and intracellular domains of TLR1. Using flow cytometric analysis, they demonstrated that individuals homozygous for the 602S allele lacked cell surface, but not intracellular, expression of TLR1. TLR2 and TLR6 expression and LPS responsiveness were normal in these individuals. TLR1 602S homozygotes also released less TNF in response to a synthetic triacylated lipopeptide than individuals with at least 1 TLR1 602I allele. Expression in transfected cells confirmed lack of surface expression of the TLR1 602S variant, and Western blot analysis showed no lack of total TLR1. The 602S allele was more frequent in 66 Europeans (75% allele frequency) than in 27 Africans (26%) or in 21 East Asians, all of whom were homozygous for 602I. Johnson et al. (2007) found that the 602S allele was significantly underrepresented in 57 Turkish leprosy patients compared with 90 controls, suggesting that 602S plays a protective role in the context of clinical leprosy (see 246300).
Omueti et al. (2007) noted that the extracellular domains of human TLRs contain 19 to 25 predicted leucine-rich repeat (LRR) motifs, and that LRR motifs 9 to 12 of TLR1 are required for sensing bacterial lipopeptides. They found that TLR1 containing a nonsynonymous SNP (rs5743613) resulting in a pro315-to-leu (P315L) change in the loop of LRR motif 11 was impaired in mediating responses to a variety of bacterial lipopeptide agonists and in binding to an anti-TLR1 antibody, although it was expressed normally on the cell surface. Phylogenetic and SNP database analysis indicated that P315 is highly conserved in a variety of other mammals, and that the P315L polymorphism is relatively rare in human populations, predominantly occurring in individuals of African descent. Omueti et al. (2007) proposed that the P315L polymorphism may predispose certain individuals to infectious diseases in which TLR1 sensing is critical to innate immune defense.
Schuring et al. (2009) studied association of an asn248-to-ser (N248S; 601194.0002) SNP in the TLR1 gene and leprosy (LPRS5; 613223) in a Bangladeshi population consisting of 842 patients and 543 controls. Homozygosity for S248 was significantly associated with leprosy per se (OR = 1.34), whereas heterozygosity was found to be protective against leprosy (OR = 0.78). In contrast, the homozygous N248 genotype was equally distributed among patients and controls. Schuring et al. (2009) noted that amino acid 248 of TLR1 is located in the external ligand-binding site of the receptor, and that Omueti et al. (2007) had shown that the S248 variant enabled normal function, whereas the N248 variant diminished the response of TLR1 to bacterial agonists.
ALLELIC VARIANTS 2 Selected Examples):
.0001 LEPROSY, PROTECTION AGAINST
SNP: rs5743618, gnomAD: rs5743618, ClinVar: RCV000008865, RCV002291545, RCV003974810
Protection Against Leprosy
Johnson et al. (2007) identified a nonsynonymous SNP in TLR1, 1805T-G (rs5743618), that results in an ile602-to-ser (I602S) substitution at the junction of the transmembrane and intracellular domains of TLR1. They found that 602S was associated with aberrant trafficking of TLR1 to the cell surface and diminished responses of blood monocytes to bacterial agonists. The 602S allele was more frequent in 66 Europeans (75% allele frequency) than in 27 Africans (26%) or in 21 East Asians, all of whom were homozygous for 602I. Johnson et al. (2007) found that the 602S allele was significantly underrepresented in 57 Turkish leprosy patients compared with 90 controls (odds ratio of 0.48). Leprosy patients were more frequently homozygous for 602I, whereas control subjects were more likely to be homozygous for 602S. The results suggested that TLR1 602S plays a protective role in the context of clinical leprosy (see 613223).
Using luciferase reporter analysis, Misch et al. (2008) observed reduced NFKB (see 164011) activity in embryonic kidney cells transfected with the 1805G TLR1 variant following stimulation with extracts of M. leprae compared with cells transfected with the 1805T TLR1 variant. Peripheral blood mononuclear cells from individuals homozygous for 1805G had significantly reduced proinflammatory cytokine responses following stimulation with whole M. leprae or cell wall extracts. In 933 Nepalese leprosy patients, including 238 with the inflammatory reversal reaction, the 1805G allele was associated with protection from reversal reaction (OR of 0.51). Misch et al. (2008) proposed that TLR1 may be associated with a Th1 response and that TLR1 deficiency due to 1805G influences adaptive immunity during leprosy infection and may affect clinical manifestations, such as nerve damage and disability.
Using flow cytometric analysis, Hart and Tapping (2012) demonstrated that monocytes and macrophages from individuals homozygous for 602S were resistant to downregulation of MHC class II, CD64 (see 146760), and IFNG (147570) responses when stimulated with a synthetic TLR1 agonist or mycobacterial membrane components compared with individuals carrying 602I. In addition, macrophages from individuals homozygous for 602S failed to upregulate expression of ARG1 (608313) when challenged with mycobacterial agonists. However, when cells expressing either variant were stimulated with whole mycobacteria, production of TNF and IL6 was similar, as was expression of MHC class II and ARG1. Hart and Tapping (2012) proposed that the TLR1 602S variant protects against mycobacterial disease by preventing soluble mycobacterial products, possibly released from granulomas, from disarming myeloid cells prior to encountering whole mycobacteria.
Association with Neutrophil Priming
Using agonists to TLR2 (603028)/TLR1 or TLR2/TLR6 (605403) heterodimers to stimulate polymorphonuclear leukocytes (PMNs) Whitmore et al. (2016) observed that all donors responded to TLR2/TLR6 priming, whereas only a subset responded to TLR2/TLR1 priming. Genotype analysis revealed that PMN responsiveness to TLR2/TLR1 priming was enhanced by the presence of the 1805G-T SNP in TLR1, which results in a ser602 to ile change. Surface expression of TLR1 was higher in high TLR2/TLR1 primers compared with low primers, and high primers showed an enhanced association of TLR1 with the endoplasmic reticulum chaperone GP96 (HSP90B1; 191175). Neutrophil priming responses in vitro did not differ between 1805GT heterozygotes and 1805TT homozygotes. Whitmore et al. (2016) concluded that the TLR1 1805G-T SNP leads to excessive PMN priming in response to cell stimulation.
.0002 LEPROSY, SUSCEPTIBILITY TO, 5
SNP: rs4833095, gnomAD: rs4833095, ClinVar: RCV000008866, RCV003974811
Schuring et al. (2009) studied association of an asn248-to-ser (N248S) SNP in the TLR1 gene and leprosy (LPRS5; 613223) in a Bangladeshi population consisting of 842 patients and 543 controls. They found that the S allele was slightly more frequent among patients than controls (54% vs 51%; OR = 1.12). Homozygosity for S248 was significantly associated with leprosy per se (OR = 1.34), whereas heterozygosity was found to be protective against leprosy (OR = 0.78). In contrast, the homozygous N248 genotype was equally distributed among patients and controls. No difference in allele frequency or genotype was associated with leprosy classification or serologic status. However, patients who experienced erythema nodosum leprosum reactions were more likely to have the N248 allele (68%) than were patients who had no reactions (46%). Schuring et al. (2009) noted that amino acid 248 of TLR1 is located in the external ligand-binding site of the receptor, and that Omueti et al. (2007) had shown that the S248 variant enabled normal function, whereas the N248 variant diminished the response of TLR1 to bacterial agonists.
REFERENCES
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Johnson, C. M., Lyle, E. A., Omueti, K. O., Stepensky, V. A., Yegin, O., Alpsoy, E., Hamann, L., Schumann, R. R., Tapping, R. I. Cutting edge: a common polymorphism impairs cell surface trafficking and functional responses of TLR1 but protects against leprosy. J. Immun. 178: 7520-7524, 2007. [PubMed: 17548585] [Full Text: https://doi.org/10.4049/jimmunol.178.12.7520]
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Omueti, K. O., Mazur, D. J., Thompson, K. S., Lyle, E. A., Tapping, R. I. The polymorphism P315L of human Toll-like receptor 1 impairs innate immune sensing of microbial cell wall components. J. Immun. 178: 6387-6394, 2007. [PubMed: 17475868] [Full Text: https://doi.org/10.4049/jimmunol.178.10.6387]
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Schuring, R. P., Hamann, L., Faber, W. R., Pahan, D., Richardus, J. H., Schumann, R. R., Oskam, L. Polymorphism N248S in the human Toll-like receptor 1 gene is related to leprosy and leprosy reactions. J. Infect. Dis. 199: 1816-1819, 2009. [PubMed: 19456232] [Full Text: https://doi.org/10.1086/599121]
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Paul J. Converse - updated : 7/1/2013
Ada Hamosh - updated : 6/21/2011
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Paul J. Converse - updated : 10/22/2008
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