TLR4

protein-coding

toll like receptor 4, the group of CD molecules|Toll like receptors

Gene summary

The protein encoded by this gene is a member of the Toll-like receptor (TLR) family which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. In silico studies have found a particularly strong binding of surface TLR4 with the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus disease-2019 (COVID-19). This receptor has also been implicated in signal transduction events induced by lipopolysaccharide (LPS) found in most gram-negative bacteria. Mutations in this gene have been associated with differences in LPS responsiveness, and with susceptibility to age-related macular degeneration. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2020]

MANE transcript

NM_138554.5

Inheritance

ClinVar variants

U:93B:26

Top phenotype

TLR4-related disorder

gnomAD constraint

pLI —, LoF o/e 0.66

Max pathogenic AF

—

Genomic locus

chr9:117,704,175-117,724,735

External References & Databases

Ensembl (ENSG00000136869)

Transcript & Mutation Effects

hg38 • Region Span ~20.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

inflammatory bowel diseaseLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0005265

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TLR4 variants in ClinVar

7 Conditions Cataloged

not specifiedTotal: 89

not providedTotal: 18

TLR4-related disorderTotal: 7

Lung adenocarcinomaTotal: 2

Hereditary angioedema with normal C1InhTotal: 1

Primary ciliary dyskinesiaTotal: 1

Susceptibility to severe COVID-19Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_138554.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	9 clinvar	2 clinvar	12
missense			88 clinvar	13 clinvar	2 clinvar	103
nonsense			2 clinvar			2
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	0	93	22	4	119

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 9 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_138554.5	RefSeq	NP_612564.1	3	MANE Select
ENST00000355622.8	Ensembl	ENSP00000363089.5	3	MANE Select
NM_003266.4	RefSeq	NP_003257.1	2	Standard
NM_138557.3	RefSeq	NP_612567.1	1	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

PI3K-Akt signaling pathway - Homo sapiens (human)
Pertussis - Homo sapiens (human)
Salmonella infection - Homo sapiens (human)
Legionellosis - Homo sapiens (human)
HIF-1 signaling pathway - Homo sapiens (human)

Biological Process

activation of MAPK activity
toll-like receptor signaling pathway
B cell proliferation involved in immune response
nitric oxide production involved in inflammatory response
regulation of dendritic cell cytokine production

Molecular Function

lipopolysaccharide binding
amyloid-beta binding
lipopolysaccharide receptor activity
transmembrane signaling receptor activity
signaling receptor binding

Cellular Component

cytoplasm
early endosome
plasma membrane
integral component of plasma membrane
external side of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000355622
Coding exons: 3
Length: 12540
Individuals with no LoFs: 125454
Homozygous LoFs: 1
Heterozygous LoFs: 256
Defined: 125711
p: 0.00102

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.647	379	416	0.911	0.0000200	5553
Missense (PolyPhen)		115	159.35	0.72168		2264
Synonymous	0.381	158	164	0.962	0.00000792	1618
Loss of Function	1.59	17	25.7	0.661	0.00000137	328

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00084	0.00084	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.0012	0.0012	notable
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00019	0.00018	rare
South Asian	0.0058	0.0057	notable
Other	0.00098	0.00098	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Cooperates with LY96 and CD14 to mediate the innate immune response to bacterial lipopolysaccharide (LPS) (PubMed:27022195). Acts via MYD88, TIRAP and TRAF6, leading to NF- kappa-B activation, cytokine secretion and the inflammatory response (PubMed:9237759, PubMed:10835634, PubMed:27022195). Also involved in LPS-independent inflammatory responses triggered by free fatty acids, such as palmitate, and Ni(2+). Responses triggered by Ni(2+) require non-conserved histidines and are, therefore, species-specific (PubMed:20711192). Both M.tuberculosis HSP70 (dnaK) and HSP65 (groEL-2) act via this protein to stimulate NF-kappa-B expression (PubMed:15809303). In complex with TLR6, promotes sterile inflammation in monocytes/macrophages in response to oxidized low-density lipoprotein (oxLDL) or amyloid-beta 42. In this context, the initial signal is provided by oxLDL- or amyloid- beta 42-binding to CD36. This event induces the formation of a heterodimer of TLR4 and TLR6, which is rapidly internalized and triggers inflammatory response, leading to the NF-kappa-B- dependent production of CXCL1, CXCL2 and CCL9 cytokines, via MYD88 signaling pathway, and CCL5 cytokine, via TICAM1 signaling pathway, as well as IL1B secretion. Binds electronegative LDL (LDL(-)) and mediates the cytokine release induced by LDL(-) (PubMed:23880187). Stimulation of monocytes in vitro with M.tuberculosis PstS1 induces p38 MAPK and ERK1/2 activation primarily via TLR2, but also partially via this receptor (PubMed:16622205). {ECO:0000269|PubMed:10835634, ECO:0000269|PubMed:15809303, ECO:0000269|PubMed:16622205, ECO:0000269|PubMed:17478729, ECO:0000269|PubMed:20037584, ECO:0000269|PubMed:20711192, ECO:0000269|PubMed:23880187, ECO:0000269|PubMed:27022195, ECO:0000269|PubMed:9237759}.;

Recessive Scores

pRec: 0.920

Intolerance Scores

LoFtool: 0.846
RVIS EVS: -0.02
RVIS percentile EVS: 52.32

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 1.00

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium