Hearing Loss as the Main Clinical Presentation in NLRP3-Associated Autoinflammatory Disease

Oziębło, Dominika; Leja, Marcin L.; Jeznach, Aldona; Orzechowska, Magdalena; Skirecki, Tomasz; Więsik-Szewczyk, Ewa; Furmanek, Mariusz; Bałdyga, Natalia; Skarżyński, Henryk; Ołdak, Monika

doi:10.3389/fimmu.2022.904632

Cited by 9 publications

(13 citation statements)

References 27 publications

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“…21 In addition, based on previous reports of cochlear autoinflammation and hearing loss in affected individuals harboring NLRP3 missense mutations (p.Ser624Arg and p.Arg918Gln), the p.Gly571Val mutation could be associated with the early onset hearing loss in the individual who we report. 22,23 NLRP3 mutations lead to unregulated activation of the NLRP3 inflammasome, resulting in overproduction of inflammatory signals, such as interleukin-1. 9 Subsequent corneal inflammation may lead to corneal stromal opacification and scarring.…”

Section: Discussionmentioning

confidence: 99%

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Keratitis Fugax Hereditaria Associated With a Novel NLRP3 Mutation in a Non-Finnish Patient

Jatavallabhula,

Onyia,

Chung

et al. 2023

Cornea

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Purpose: The aim of this study was to report a novel heterozygous variant c.1712G>T (p.Gly571Val) in the nucleotide-binding domain, leucine-rich repeat family, pyrin domain–containing 3 gene (NLRP3) in a previously unreported non-Finnish individual with keratitis fugax hereditaria (KFH). Methods: Ophthalmologic examination of the proband was performed with slit-lamp biomicroscopy and anterior segment optical coherence tomography. Saliva was collected as a source of DNA, after which targeted exome sequencing of candidate genes was performed using a commercially available panel. Identified presumed pathogenic variants were confirmed by Sanger sequencing. Results: Slit-lamp examination of the 52-year-old female proband revealed peripheral arcus-like degeneration and bilateral central corneal opacification, observed on anterior segment optical coherence tomography to involve the anterior half of the corneal stroma. Examination of the proband's parents revealed clear corneas in each eye. Genetic testing of the proband identified the presence of a novel heterozygous NLRP3 missense mutation (c.1712G>T, p.Gly571Val), which was confirmed by Sanger sequencing. This mutation was absent in the proband's parents. Conclusions: Although KFH has been reported only in individuals of Finnish descent and only in association with a missense mutation in exon 1 of NLRP3, we report an individual of non-Finnish descent with KFH associated with a novel heterozygous variant in exon 2 of NLRP3. Thus, ophthalmologists should be aware of the ethnic and genetic heterogeneity associated with KFH.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Keratitis Fugax Hereditaria Associated With a Novel NLRP3 Mutation in a Non-Finnish Patient

Jatavallabhula,

Onyia,

Chung

et al. 2023

Cornea

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“…[54,55] In addition, hereditary hearing loss has recently been associated with inflammation. [56][57][58] While the pathogenesis of SNHL is unclear and incomplete, inflammation is a critical component in the pathogenesis of many SNHLs. Understanding the role of inflammatory factors and their associated pathways in the pathologic activity of inner ear diseases is critical for studying their disease mechanisms.…”

Section: Other Snhlsmentioning

confidence: 99%

“…Studies have shown that NF‐κB is activated by cochlear radiation and reaches its maximum activation state after 2–6 h. Tetramethylpyridine has anti‐inflammatory and anticoagulant effects that protect against radiation‐induced ototoxicity [54,55] . In addition, hereditary hearing loss has recently been associated with inflammation [56–58] …”

Section: Snhl and Inflammationmentioning

confidence: 99%

“…CD19 expression disappears when B cells eventually differentiate into antibody-secreting plasma cells. [58] The frequency of cochlear-specific interferon (IFN)γ production is increased in patients with SNHL. [62] T cell receptor gene therapy for pheochromocytoma primarily targets perivascular macrophage-like melanocytes (PVM/Ms) in the stria vascularis, which leads to SNHL, possibly due to the disruption of the BLB and endolymphatic potentials and/or sterile inflammation of the stria vascularis.…”

Section: Immune Cells In the Cochleamentioning

confidence: 99%

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Understanding the role of inflammation in sensorineural hearing loss: Current goals and future prospects

Li,

Chen,

Lin

et al. 2023

Brain-X

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Sensorineural hearing loss (SNHL) is a common otologic condition caused by damage to hair cells and spiral ganglion neurons that affects transmission pathways. Most of these cells cannot be regenerated, and there has been no breakthrough in regeneration techniques for inner ear cells. SNHL has a high incidence rate and can cause a variety of clinical symptoms, greatly impacting people's daily lives. With limited clinical treatments, the search for critical targets is urgent. Studies have shown that inflammation is prevalent in the pathogenesis of SNHL and plays a significant role in it. Inflammation is a normal body defense response, and a systemic anti‐inflammatory approach is undesirable. It is crucial for us to identify potential targets of inflammation in SNHL and take measures specifically targeting those targets with minimal systemic impact. This paper firstly describes the role of inflammation in various types of SNHL and then provides an overview of the interactions between inflammation and cochlear immunity, cochlear microcirculation, vascular spasm, and glutamate metabolism and finally comprehensively examines the feasibility of targets in these interactions. This paper is expected to facilitate the development of targeted anti‐inflammation for SNHL and provide strategies and approaches for treating clinical SNHL.

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A rare case of uncharacterized autoinflammatory disease: Patient carrying variations in NLRP3 and TNFRSF1A genes

Kilinc,

Gayibova,

Onen

et al. 2024

American J of Med Genetics Pt A

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Tumor necrosis factor type 1A receptor‐associated periodic syndrome (TRAPS) and cryopyrin‐associated autoinflammatory syndrome (CAPS) are rare monogenic autoinflammatory diseases (AIDs) mainly caused by pathogenic variations in the TNFRSF1A and NLRP3 genes, respectively. Here, we describe a unique patient presenting with symptoms overlapping both TRAPS and CAPS, without known pathogenic variants in the respective genes. The patient harbored the p.Val200Met variation in NLRP3 and the p.Ser226Cys variation in TNFRSF1A, prompting us to delve deeper into the functional analysis due to conflicting or inconclusive pathogenicity interpretations of the variants across various databases. Molecular dynamics analysis of the p.Val200Met variation in NLRP3 revealed a rigid conformation in the helical domain 2 subdomain of the NACHT domain. This increased rigidity suggests a potential mechanism by which this variation supports the assembly of the NLRP3 inflammasome. Notably, the patient's peripheral mononuclear blood cells demonstrated an elevated IL‐1β response upon lipopolysaccharides (LPS) induction. Subsequent initiation of anti‐IL‐1β therapy resulted in a significant alleviation of the patient's symptoms, further supporting our hypothesis. We interpret these findings as suggestive of a potential pathophysiological role for the NLPR3 p.Val200Met variation in shaping the patient's clinical phenotype, which was also supported by clinical and genetic analysis of the family. This case underscores the complexity of the genetic landscape in AIDs and highlights the value of combining family genetic and functional data to refine the understanding and management of such challenging cases.

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Hearing Loss as the Main Clinical Presentation in NLRP3-Associated Autoinflammatory Disease

Cited by 9 publications

References 27 publications

Keratitis Fugax Hereditaria Associated With a Novel NLRP3 Mutation in a Non-Finnish Patient

Keratitis Fugax Hereditaria Associated With a Novel NLRP3 Mutation in a Non-Finnish Patient

Understanding the role of inflammation in sensorineural hearing loss: Current goals and future prospects

A rare case of uncharacterized autoinflammatory disease: Patient carrying variations in NLRP3 and TNFRSF1A genes

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