ArticleThe Journal of biological chemistry2010
A naturally occurring variant in human TLR9, P99L, is associated with loss of CpG oligonucleotide responsiveness.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 29 citations in OpenAlex.
- Mutated Toll-like receptor 9 increases Alzheimer's disease risk by compromising innate immunity protection.Molecular psychiatry · 2023Article
- TLR4 and TLR9 polymorphism: Probable role in susceptibility among the population of Bihar for Indian visceral leishmaniasis.Innate immunity · 2021Article
- TLR9 in MAFLD and NASH: At the Intersection of Inflammation and Metabolism.Frontiers in endocrinology · 2020Review
- Association of TLR4 and TLR9 gene polymorphisms and haplotypes with cervicitis susceptibility.PloS one · 2019Article
- Absence of toll-like receptor 9 Pro99Leu polymorphism in cervical cancer.F1000Research · 2018Article
- Lower frequency of TLR9 variant associated with protection from breast cancer among African Americans.PloS one · 2017Article
- Single nucleotide polymorphisms of Toll-like receptors and susceptibility to infectious diseases.Clinical and experimental immunology · 2015Review
- Article
- Genetic variants of innate immune receptors and infections after liver transplantation.World journal of gastroenterology · 2014Review
- RNA and imidazoquinolines are sensed by distinct TLR7/8 ectodomain sites resulting in functionally disparate signaling events.Journal of immunology (Baltimore, Md. : 1950) · 2014Article
- Toll-like receptor 9 interaction with CpG ODN--an in silico analysis approach.Theoretical biology & medical modelling · 2013Article
- Article
- Toll-like receptors and human disease: lessons from single nucleotide polymorphisms.Current genomics · 2012Article
- Leucine-rich repeat 11 of Toll-like receptor 9 can tightly bind to CpG-containing oligodeoxynucleotides, and the positively charged residues are critical for the high affinity.The Journal of biological chemistry · 2012Article
- Heterozygous carriage of a dysfunctional Toll-like receptor 9 allele affects CpG oligonucleotide responses in B cells.The Journal of biological chemistry · 2012Article
- DNA methylation as clinically useful biomarkers-light at the end of the tunnel.Pharmaceuticals (Basel, Switzerland) · 2012Article
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
Abstract
The innate immune system employs Toll-like receptors (TLRs) for the detection of invading microorganisms based on distinct molecular patterns. For example, TLR9 is activated by microbial DNA and also by short therapeutic CpG-containing oligonucleotides (CpG-ODN). TLR9 activation leads to the production of interferons and the priming of humoral adaptive immune responses. Unfortunately, the principles of ligand recognition by TLR9 are poorly understood, and genetic variants of TLR9, which may affect its function, have not been characterized systematically on the molecular level. We therefore sought to functionally characterize reported single nucleotide polymorphisms of TLR9 in the HEK293 model system. We discovered that two variants, P99L and M400I, are associated with altered receptor function regarding NF-κB activation and cytokine induction. Our investigations show that for the most functionally impaired variant, P99L, the ability to respond to physiological and therapeutic TLR9 ligands is severely compromised. However, CpG-ODN binding is normal. CpG-ODN recognition by TLR9 thus appears to involve two separate events, CpG-ODN binding and sensing. Our studies highlight Pro-99 as a residue important for the latter process. In genotyping studies, we confirmed that both M400I (rs41308230) and P99L (rs5743844) are relatively rare variants of TLR9. Our data add rs41308230 and rs5743844 to the list of functionally important TLR variants and warrant further research into their relevance for infectious disease susceptibility or responsiveness to CpG-ODN-based therapies.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.