AUTHOR=Oziębło Dominika , Leja Marcin L. , Jeznach Aldona , Orzechowska Magdalena , Skirecki Tomasz , Więsik-Szewczyk Ewa , Furmanek Mariusz , Bałdyga Natalia , Skarżyński Henryk , Ołdak Monika TITLE=Hearing Loss as the Main Clinical Presentation in NLRP3-Associated Autoinflammatory Disease JOURNAL=Frontiers in Immunology VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.904632 DOI=10.3389/fimmu.2022.904632 ISSN=1664-3224 ABSTRACT=

The NLRP3 gene mutations are the cause of autosomal dominant autoinflammatory disorders (NLRP3-AID). Recently, hearing loss (HL) has been found to be the sole or major manifestation of NLRP3-AID. Here, we tested 110 autosomal dominant HL families with a custom panel of 237 HL genes and found one family carrying the NLRP3 c.1872C>G, p.Ser624Arg mutation. Functional studies revealed that this novel variant is a gain of function mutation, leading to increased activity of caspase-1 and subsequent oversecretion of proinflammatory interleukin-1β. Clinical reanalysis of the affected individuals, together with serological evidence of inflammation and pathological cochlear enhancement on FLAIR-MRI images, guided our diagnosis to atypical NLRP3-AID. The study highlights the role of genetic analysis in patients with progressive postlingual HL. This can help to identify individuals with hereditary HL as a consequence of NLRP3-AID and allow timely and effective treatment with interleukin-1-receptor antagonist.