Toll-like receptor 3 (TLR3) variant and NLRP12 mutation confer susceptibility to a complex clinical presentation

Tal, Yuval; Ribak, Yaarit; Khalaila, Aya; Shamriz, Oded; Marcus, Nir; Zinger, Adar; Meiner, Vardiella; Schuster, Ronen; Lewis, Eli C.; Nahum, Amit

doi:10.1016/j.clim.2019.108249

Cited by 8 publications

(5 citation statements)

References 25 publications

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“…Although IBD pathogenesis has been oftentimes attributed to the canonical NF−κB pathway, this work illuminates the involvement of the previously overlooked noncanonical NF-κB pathway. A recent case-study conducted in 2020 reported a homozygous p. Leu412Phe variant for the TLR3 gene and a frameshift-causing deletion in the NLRP12 gene that was predicted to contribute to this patient's presentation of concomitant HSV esophagitis and CD [ 59 ]. Likewise, miR-372 was found to be upregulated in blood samples and colonic mucosa collected from human UC patients [ 60 ].…”

Section: Nlrp12 – Holding the Immune System In Check During Colitis A...mentioning

confidence: 99%

Negative regulatory NLRs mitigate inflammation via NF-κB pathway signaling in inflammatory bowel disease

et al. 2023

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Section: Nlrp12 – Holding the Immune System In Check During Colitis A...mentioning

confidence: 99%

Negative regulatory NLRs mitigate inflammation via NF-κB pathway signaling in inflammatory bowel disease

et al. 2023

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“…Patients with TLR3 deficiencies or mutations are more susceptible to developing HSE, but the importance of TLR3 may be cell-type specific [ 111 , 112 , 113 ]. Fibroblasts and induced pluripotent stem cells derived from patients with TLR3 deficiencies are susceptible to HSV-1 infection and are unable to control viral replication; however, peripheral blood mononuclear cells and several leukocytes are able to amount a normal IFN response despite TLR3 deficiencies [ 111 , 112 , 114 ].…”

Section: Recognition Of Hsv-1 By the Innate Immune Systemmentioning

confidence: 99%

Herpes Simplex Virus Type 1 Interactions with the Interferon System

Danastas

Miranda-Saksena

Cunningham

2020

IJMS

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The interferon (IFN) system is one of the first lines of defense activated against invading viral pathogens. Upon secretion, IFNs activate a signaling cascade resulting in the production of several interferon stimulated genes (ISGs), which work to limit viral replication and establish an overall anti-viral state. Herpes simplex virus type 1 is a ubiquitous human pathogen that has evolved to downregulate the IFN response and establish lifelong latent infection in sensory neurons of the host. This review will focus on the mechanisms by which the host innate immune system detects invading HSV-1 virions, the subsequent IFN response generated to limit viral infection, and the evasion strategies developed by HSV-1 to evade the immune system and establish latency in the host.

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“…To date, only four NLRP12 variants been reported in patients with CD (Supplementary Table S1). Tal et al [36] described a patient with severe herpes simplex virus (HSV) esophagitis and CD. WES analysis revealed that he had two coinciding genetic mutations in toll-like receptor 3 (TLR3) and NLRP12.…”

Section: Discussionmentioning

confidence: 99%

Identification of a Novel NLRP12 Frameshift Mutation (Val730Glyfs $^{*}$ 41) by Whole-Exome Sequencing in Patients with Crohn’s Disease

Chen,

Huang,

Chen

et al. 2024

Human Mutation

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NLRP12 encodes the nucleotide-binding leucine-rich repeat-containing receptor 12 protein and has been linked to familial cold autoinflammatory syndrome 2 (FCAS2). Previous studies have reported that NLRP12 protein can dampen inflammatory responses in DSS-induced mice colitis. To date, only four alterations in the NLRP12 gene have been associated with Crohn’s disease (CD). Here, we reported a novel heterozygous NLRP12 frameshift mutation (c.2188dupG, p.Val730Glyfs∗41) identified by whole-exome sequencing in the proband with CD. The Sanger sequencing confirmed that his sister and father also carried this NLRP12 mutation, which cosegregated well with the CD phenotype. In silico analysis predicted this mutation to be disease-causing. Patients heterozygous for this mutation exhibited decreased NLRP12 protein levels in the peripheral blood and colon. Functional assays showed that mutant NLRP12 plasmid-transfected HEK293T cells exhibited significantly lower NLRP12 mRNA and protein levels than wild-type plasmid-transfected cells. The nonsense-mediated decay inhibitor NMDI14 significantly increased NLRP12 mRNA and protein levels in mutant plasmid-transfected cells. Overall, our results demonstrated that this heterozygous NLRP12 mutation (c.2188dupG) resulted in decreased NLRP12 expression, which might contribute to the mechanism underlying CD.

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Toll-like receptor 3 (TLR3) variant and NLRP12 mutation confer susceptibility to a complex clinical presentation

Cited by 8 publications

References 25 publications

Negative regulatory NLRs mitigate inflammation via NF-κB pathway signaling in inflammatory bowel disease

Negative regulatory NLRs mitigate inflammation via NF-κB pathway signaling in inflammatory bowel disease

Herpes Simplex Virus Type 1 Interactions with the Interferon System

Identification of a Novel NLRP12 Frameshift Mutation (Val730Glyfs $^{*}$ 41) by Whole-Exome Sequencing in Patients with Crohn’s Disease

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Toll-like receptor 3 (TLR3) variant and NLRP12 mutation confer susceptibility to a complex clinical presentation

Cited by 8 publications

References 25 publications

Negative regulatory NLRs mitigate inflammation via NF-κB pathway signaling in inflammatory bowel disease

Negative regulatory NLRs mitigate inflammation via NF-κB pathway signaling in inflammatory bowel disease

Herpes Simplex Virus Type 1 Interactions with the Interferon System

Identification of a Novel NLRP12 Frameshift Mutation (Val730Glyfs∗41) by Whole-Exome Sequencing in Patients with Crohn’s Disease

Contact Info

Product

Resources

About

Identification of a Novel NLRP12 Frameshift Mutation (Val730Glyfs $^{*}$ 41) by Whole-Exome Sequencing in Patients with Crohn’s Disease