NeMO mutations: a rare cause of monogenic Behçet-like disease

Baldini, Letizia; Sabatino, Fabiana Di; Bodrero, Enrico; Dellepiane, Marta; Covizzi, Carlotta; Selva, Roberta La; Montin, Davide; Licciardi, Francesco

doi:10.1093/rheumatology/keaa505

Cited by 4 publications

(1 citation statement)

References 14 publications

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“…The phosphorylation of IKKα/β activates kinase activity that catalyzes the downstream phosphorylation cascade of NEMO, IκBα, and RelA to trigger RelA-dependent gene transcription (4). Failure of K63-linked polyubiquitination and phosphorylation of NEMO prevents the formation of the IKKα/IKKβ/NEMO heterotrimer, disrupts RelA activation, and increases the occurrence of recurrent bacterial infections that are associated with NF-κB-linked genetic diseases (7)(8)(9)(10), such as Familial incontinentia pigmenti (IP) and anhidrotic ectodermal dysplasia associated with immunode ciency (EDA-ID) (11,12), immunode ciency without ectodermal dysplasia (ID without EDA) (13), recurrent invasive pneumococcal disease (IPD) (14), and Behcet-like disease (15). These diseases are associated with NEMO mutations in functional domains or intron sequences (16, 17); however, the loss of function of exclusive NEMO B mutations has not been reported to date.…”

Section: Introductionmentioning

confidence: 99%

An Exclusive NEMO B Mutation Leads to NF-κB-linked Recurrent Pneumonia by Disrupting the NEMO/IKK Complex

Li¹,

Xu²,

Guo³

et al. 2022

Preprint

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Purpose A number of NEMO mutations in the shared sequences of NEMO isoform A and B have been associated with NF-κB-linked diseases. Here, we first report an exclusive NEMO B mutation as the genetic etiology of a male case with recurrent bacterial pneumonia and explore the underlying mechanism. Methods The genomic protein-coding regions of genes were analyzed using the whole exome sequencing (WES) technique, and the rare gene variant was confirmed by Sanger sequence analysis; activation of NF-kB signaling pathway was assessed by co-immunoprecipitation, western blotting, and single-cell RNA-seq analysis; glycolytic changes of peripheral immune cells were evaluated by extracellular acidification rate assay; protein-protein binding affinity and stability were estimated by structure modeling and molecular docking analysis. Results A c.20T > C mutation in exon 1 of the IKBKG germline sequence (NM_001099856.2) resulted in a Val7Ala replacement in the exclusive N-terminal sequence of NEMO B. This mutation significantly decreased the binding affinity and stability of NEMO B with IKKα/β, leading to the failure to form functional NEMO/IKK complex and the subsequent inhibition of RelA phosphorylation and nuclear translocation to initiate pro-inflammatory TNF-α and IL-1β gene transcription and metabolic support by glycolysis in response to the TLR4 agonist LPS. Single-cell sequencing analysis revealed abnormalities in monocyte and T-lymphocyte function and B-cell hyperplasia. Conclusions The exclusive N-terminal sequence of NEMO B is essential for a functional NEMO/IKKa/IKKb complex to activate NF-κB-dependent antibacterial immunity.

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Section: Introductionmentioning

confidence: 99%

An Exclusive NEMO B Mutation Leads to NF-κB-linked Recurrent Pneumonia by Disrupting the NEMO/IKK Complex

Li¹,

Xu²,

Guo³

et al. 2022

Preprint

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Genetic testing of Behçet’s disease using next-generation sequencing to identify monogenic mimics and HLA-B*51

Burleigh,

Omoyinmi,

Papadopoulou

et al. 2023

Rheumatology

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Objective Several monogenic autoinflammatory disorders and primary immunodeficiencies can present early in life with features that may be mistaken for Behçet’s disease (BD). We aimed to develop a genetic analysis workflow to identify rare monogenic BD-like diseases and establish the contribution of HLA haplotype in a cohort of patients from the UK. Methods Patients with clinically suspected BD were recruited from four BD specialist care centres in the UK. All participants underwent whole-exome sequencing (WES), and genetic analysis thereafter by (i) examining genes known to cause monogenic immunodeficiency, autoinflammation or vasculitis by virtual panel application; (ii) scrutiny of variants prioritized by Exomiser using Human Phenotype Ontology (HPO); (iii) identification of copy number variants using ExomeDepth; and (iv) HLA-typing using OptiType. Results Thirty-one patients were recruited: median age 15 (4–52), and median disease onset age 5 (0–20). Nine/31 (29%) patients had monogenic disease mimicking BD: five cases of Haploinsufficiency of A20 with novel TNFAIP3 variants (p.T76I, p. M112Tfs*8, p. S548Dfs*128, p. C657Vfs*14, p. E661Nfs*36); one case of ISG15 deficiency with a novel nonsense variant (ISG15: p.Q16X) and 1p36.33 microdeletion; one case of common variable immune deficiency (TNFRSF13B: p.A181E); and two cases of TNF receptor-associated periodic syndrome (TNFRSF1A: p.R92Q). Of the remaining 22 patients, eight (36%) were HLA-B*51 positive. Conclusion We describe a novel genetic workflow for BD, which can efficiently detect known and potentially novel monogenic forms of BD, whilst additionally providing HLA-typing. Our results highlight the importance of genetic testing before BD diagnosis, as this has an impact on choice of therapy, prognosis and genetic counselling.

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NF-kappa-B essential modulator (NEMO) gene polymorphism in an adult woman with systemic lupus erythematosus and recurrent non-tuberculous mycobacterial disseminated infections

et al. 2023

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Infections are among the most serious complications in patients with systemic lupus erythematosus (SLE), with bacterial and viral infections being the most common. Non-tuberculous mycobacterial (NTM) infections are quite rare and are typically seen in older patients with SLE with longstanding disease duration treated with corticosteroids. Here, we describe a 39-year-old woman with SLE and an unusual pattern of recurrent NTM disseminated infections. After excluding the presence of autoantibodies against interferon-γ, whole exome sequencing revealed a homozygous polymorphism in the NF-kappa-B essential modulator (NEMO) gene. Primary immunodeficiencies should be included in the differential diagnosis of patients with recurrent opportunistic infections, even in those with iatrogenic immunosuppression.

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NeMO mutations: a rare cause of monogenic Behçet-like disease

Cited by 4 publications

References 14 publications

An Exclusive NEMO B Mutation Leads to NF-κB-linked Recurrent Pneumonia by Disrupting the NEMO/IKK Complex

An Exclusive NEMO B Mutation Leads to NF-κB-linked Recurrent Pneumonia by Disrupting the NEMO/IKK Complex

Genetic testing of Behçet’s disease using next-generation sequencing to identify monogenic mimics and HLA-B*51

NF-kappa-B essential modulator (NEMO) gene polymorphism in an adult woman with systemic lupus erythematosus and recurrent non-tuberculous mycobacterial disseminated infections

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