Familial exudative vitreoretinopathy (FEVR) is an inherited blinding disorder characterized by the abnormal development of the retinal vasculature. The majority of mutations identified in FEVR are found within four genes that encode the receptor complex (FZD4, LRP5, and TSPAN12) and ligand (NDP) of a molecular pathway that controls angiogenesis, the Norrin-b-catenin signaling pathway. However, half of all FEVR-affected case subjects do not harbor mutations in these genes, indicating that further mutated genes remain to be identified. Here we report the identification of mutations in CTNNB1, the gene encoding b-catenin, as a cause of FEVR. We describe heterozygous mutations (c.2142_2157dup [p.His720*] and c.2128C>T [p.Arg710Cys]) in two dominant FEVR-affected families and a de novo mutation (c.1434_1435insC [p.Glu479Argfs*18]) in a simplex case subject. Previous studies have reported heterozygous de novo CTNNB1 mutations as a cause of syndromic intellectual disability (ID) and autism spectrum disorder, and somatic mutations are linked to many cancers. However, in this study we show that Mendelian inherited CTNNB1 mutations can cause non-syndromic FEVR and that FEVR can be a part of the syndromic ID phenotype, further establishing the role that b-catenin signaling plays in the development of the retinal vasculature.

Inflammasomes are assembled by innate immune sensors that cells employ to detect a range of danger signals and respond with pro‐inflammatory signalling. Inflammasomes activate inflammatory caspases, which trigger a cascade of molecular events with the potential to compromise cellular integrity and release the IL‐1β and IL‐18 pro‐inflammatory cytokines. Several molecular mechanisms, working in concert, ensure that inflammasome activation is tightly regulated; these include NLRP3 post‐translational modifications, ubiquitination and phosphorylation, as well as single‐domain proteins that competitively bind to key inflammasome components, such as the CARD‐only proteins (COPs) and PYD‐only proteins (POPs). These diverse regulatory systems ensure that a suitable level of inflammation is initiated to counteract any cellular insult, while simultaneously preserving tissue architecture. When inflammasomes are aberrantly activated can drive excessive production of pro‐inflammatory cytokines and cell death, leading to tissue damage. In several autoinflammatory conditions, inflammasomes are aberrantly activated with subsequent development of clinical features that reflect the degree of underlying tissue and organ damage. Several of the resulting disease complications may be successfully controlled by anti‐inflammatory drugs and/or specific cytokine inhibitors, in addition to more recently developed small‐molecule inhibitors. In this review, we will explore the molecular processes underlying the activation of several inflammasomes and highlight their role during health and disease. We also describe the detrimental effects of these inflammasome complexes, in some pathological conditions, and review current therapeutic approaches as well as future prospective treatments.

The NLRP3 inflammasome is a vital mediator of innate immune responses. There are numerous NLRP3 mutations that cause NLRP3-associated autoinflammatory diseases (NLRP3-AIDs), mostly in or around the NACHT domain. Here, we present a patient with a rare leucine-rich repeat (LRR) domain mutation, p.Arg920Gln (p.R920Q), associated with an atypical NLRP3-AID with recurrent episodes of sore throat and extensive oropharyngeal ulceration. Unlike previously reported patients, who responded well to anakinra, her oral ulcers did not significantly improve until the PDE4 inhibitor, apremilast, was added to her treatment regimen. Here, we show that this mutation enhances interactions between NLRP3 and its endogenous inhibitor, NIMA-related kinase 7 (NEK7), by affecting charge complementarity between the two proteins. We also demonstrate that additional inflammatory mediators, including the NF-кB and IL-17 signalling pathways and IL-8 chemokine, are upregulated in the patient’s macrophages and may be directly involved in disease pathogenesis. These results highlight the role of the NLRP3 LRR domain in NLRP3-AIDs and demonstrate that the p.R920Q mutation can cause diverse phenotypes between families.