OTULIN-related conditions: Report of a new case and review of the literature using GenIA

IF 4.5 3区 医学 Q2 IMMUNOLOGY Clinical immunology Pub Date : 2024-06-22 DOI:10.1016/j.clim.2024.110292
Andrés Caballero-Oteyza , Laura Crisponi , Xiao P. Peng , Hongying Wang , Pavla Mrovecova , Stefania Olla , Chiara Siguri , Farida Marnissi , Zineb Jouhadi , Ivona Aksentijevich , Bodo Grimbacher , Michele Proietti
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Abstract

OTULIN encodes an eponymous linear deubiquitinase (DUB) essential for controlling inflammation as a negative regulator of the canonical NF-κB signaling pathway via the regulation of M1-Ub dynamics. Biallelic loss-of-function (LOF) mutations in OTULIN cause an autosomal recessive condition named Otulin-Related Autoinflammatory Syndrome (ORAS), also known as Otulipenia or AutoInflammation, Panniculitis, and Dermatosis Syndrome (AIPDS). Monoallelic OTULIN LOF, also known as OTULIN Haploinsufficiency (OHI) or Immunodeficiency 107 (IMD107), has been linked to an incompletely penetrant, dominantly inherited susceptibility to invasive Staphylococcal infections. At the same time, a recent novel ORAS-like inflammatory syndrome was described in association with a heterozygous missense mutation that appears to exert dominant negative (DN) effects. In this manuscript, we report the identification of a novel homozygous missense mutation, c.595 T > A; p.(Trp199Arg), in a Moroccan infant with an ORAS phenotype and provide experimental evidence for its pathogenicity. We go on to systematically review the literature for OTULIN-associated conditions by using the GenIA database (www.geniadb.net) to collect, extract and harmonize all clinical, laboratory and functional data for published patients and variants. Our comprehensive synthesis of genotypic, phenotypic, and mechanistic data enables a more in-depth view of the diverse mechanisms and pathways by which the OTULIN pathogenic variants may lead to human immune disease. This review may help variant classification activities and inform future variant evaluation, as well as the development of diagnostic and management guidelines. It also identifies current knowledge gaps and raises additional questions warranting future investigation.

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与 OTULIN 相关的病症:一个新病例的报告和使用 GenIA 的文献综述。
OTULIN编码一种同名的线性去泛素化酶(DUB),它是通过调节M1-Ub动态来控制炎症的重要负调控因子。OTULIN的双等位功能缺失(LOF)突变会导致一种常染色体隐性遗传病,名为 "Otulin相关自体炎症综合征(ORAS)",也称为 "Otulipenia "或 "自体炎症、泛发性皮肤炎和皮肤病综合征(AIPDS)"。单等位基因 OTULIN LOF(又称 OTULIN Haploinsufficiency (OHI) 或 Immunodeficiency 107 (IMD107))与不完全渗透、显性遗传的侵袭性葡萄球菌感染易感性有关。与此同时,最近描述了一种新的类似 ORAS 的炎症综合征,该综合征与一个杂合错义突变有关,该突变似乎具有显性负(DN)效应。在本手稿中,我们报告了在一名具有 ORAS 表型的摩洛哥婴儿身上发现了一个新的同源错义突变,c.595 T > A; p.(Trp199Arg) ,并为其致病性提供了实验证据。接着,我们利用 GenIA 数据库 (www.geniadb.net) 收集、提取并统一了已发表的患者和变异体的所有临床、实验室和功能数据,系统地回顾了与 OTULIN 相关的文献。我们对基因型、表型和机理数据进行了全面综合,从而能够更深入地了解 OTULIN 致病变体可能导致人类免疫疾病的各种机制和途径。本综述有助于变异体分类活动,为未来的变异体评估以及诊断和管理指南的制定提供信息。它还确定了当前的知识差距,并提出了更多值得未来研究的问题。
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来源期刊
Clinical immunology
Clinical immunology 医学-免疫学
CiteScore
12.30
自引率
1.20%
发文量
212
审稿时长
34 days
期刊介绍: Clinical Immunology publishes original research delving into the molecular and cellular foundations of immunological diseases. Additionally, the journal includes reviews covering timely subjects in basic immunology, along with case reports and letters to the editor.
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