A mutation in Nischarin causes otitis media via LIMK1 and NF-κB pathways.
A mutation in Nischarin causes otitis media via LIMK1 and NF-κB pathways.
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Nischarin的突变通过LIMK1和NF-κB途径引起中耳炎。
DOI：
10.1371/journal.pgen.1006969
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发表时间：
2017-08
期刊：
影响因子：
4.5
通讯作者：
Brown SDM
中科院分区：
文献类型：
--
作者：
Crompton M;Purnell T;Tyrer HE;Parker A;Ball G;Hardisty-Hughes RE;Gale R;Williams D;Dean CH;Simon MM;Mallon AM;Wells S;Bhutta MF;Burton MJ;Tateossian H;Brown SDM
中耳炎（OM），中耳炎症（ME），是传导性听力障碍的常见原因。尽管疾病的重要性，慢性和复发形式的中耳炎症性疾病的病因仍然知之甚少。对人类群体的研究表明，有一个显著的遗传成分易导致慢性OM的发展，尽管潜在的基因在很大程度上是未知的。利用n -乙基-n -亚硝基脲诱变技术，我们发现了一种隐性小鼠突变体edison，它会自发地发展为慢性OM引起的传导性听力损失。病因突变被确定为Nischarin （NISCH）基因的L972P错义改变。爱迪生小鼠出现浆液性或粒细胞积液，随着年龄的增长，巨噬细胞和中性粒细胞越来越丰富，同时黏液骨膜增厚、发炎。我们还发现了第二个亚形态等位基因V33A，它只会适度增加听觉阈值，降低OM的发病率。NISCH与几种蛋白质相互作用，包括ITGA5，被认为在调节vegf诱导的血管生成和血管形成中起作用。我们发现Nisch和Itga5之间存在显著的遗传相互作用；Itga5-null杂合和edison突变纯合的小鼠显示出显着增加的外显率和慢性OM的严重程度。为了了解OM表型背后的病理机制，我们研究了edison小鼠中耳上皮中NISCH的相互作用伙伴以及下游信号分子。我们的分析表明，PAK1和RAC1以及LIMK1和NF-κB通路中的下游信号通路参与了慢性OM的发展。中耳炎（OM）是儿童耳聋最常见的原因，主要表现为中耳炎症。在发达国家，这是儿童手术的最常见原因，许多患有复发性和慢性形式的OM的儿童接受鼓膜造口管插入。有证据表明，一个重要的遗传成分有助于发展的复发和慢性形式的OM。小鼠已经成为识别慢性OM相关基因的有力工具。在这项研究中，我们鉴定并鉴定了一种新的慢性OM小鼠模型edison，它与人类的慢性疾病具有相同的重要特征。Nisch基因的突变导致爱迪生小鼠在出生后自发发展为OM，随后发展为慢性OM，并伴有听力损失。我们对该突变的分子分析揭示了edison小鼠OM的潜在病理机制和通路，包括PAK1、RAC1和下游信号通路LIMK1和NF-κB。爱迪生突变体的发现为慢性骨髓瘤提供了一个重要的遗传疾病模型，揭示了一种新的基因和遗传途径与骨髓瘤易感性有关。
Otitis media (OM), inflammation of the middle ear (ME), is a common cause of conductive hearing impairment. Despite the importance of the disease, the aetiology of chronic and recurrent forms of middle ear inflammatory disease remains poorly understood. Studies of the human population suggest that there is a significant genetic component predisposing to the development of chronic OM, although the underlying genes are largely unknown. Using N-ethyl-N-nitrosourea mutagenesis we identified a recessive mouse mutant, edison, that spontaneously develops a conductive hearing loss due to chronic OM. The causal mutation was identified as a missense change, L972P, in the Nischarin (NISCH) gene. edison mice develop a serous or granulocytic effusion, increasingly macrophage and neutrophil rich with age, along with a thickened, inflamed mucoperiosteum. We also identified a second hypomorphic allele, V33A, with only modest increases in auditory thresholds and reduced incidence of OM. NISCH interacts with several proteins, including ITGA5 that is thought to have a role in modulating VEGF-induced angiogenesis and vascularization. We identified a significant genetic interaction between Nisch and Itga5; mice heterozygous for Itga5-null and homozygous for edison mutations display a significantly increased penetrance and severity of chronic OM. In order to understand the pathological mechanisms underlying the OM phenotype, we studied interacting partners to NISCH along with downstream signalling molecules in the middle ear epithelia of edison mouse. Our analysis implicates PAK1 and RAC1, and downstream signalling in LIMK1 and NF-κB pathways in the development of chronic OM. Otitis media (OM) is the most common cause of deafness in children and is primarily characterised by inflammation of the middle ear. It is the most common cause of surgery in children in the developed world, with many children developing recurrent and chronic forms of OM undergoing tympanostomy tube insertion. There is evidence that a significant genetic component contributes towards the development of recurrent and chronic forms of OM. The mouse has been a powerful tool for identifying the genes involved in chronic OM. In this study we identified and characterised edison, a novel mouse model of chronic OM that shares important features with the chronic disease in humans. A mutation in the Nisch gene causes edison mice to spontaneously develop OM following birth and subsequently develop chronic OM, with an associated hearing loss. Our molecular analysis of the mutation reveals the underlying pathological mechanisms and pathways involved in OM in the edison mouse, involving PAK1, RAC1 and downstream signalling in LIMK1 and NF-κB pathways. Identification of the edison mutant provides an important genetic disease model of chronic OM and implicates a new gene and genetic pathways involved in predisposition to OM.
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影响因子：
3.7
作者：
Mburu P;Romero MR;Hilton H;Parker A;Townsend S;Kikkawa Y;Brown SD
通讯作者：
Brown SD
DOI：
10.1093/jnci/djr350
发表时间：
2011-10-01
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
Baranwal, Somesh;Wang, Yanfang;Alahari, Suresh K.
通讯作者：
Alahari, Suresh K.
影响因子：
4.8
作者：
Jain, Prachi;Baranwal, Somesh;Alahari, Suresh K.
通讯作者：
Alahari, Suresh K.
影响因子：
4.5
作者：
Cheeseman MT;Tyrer HE;Williams D;Hough TA;Pathak P;Romero MR;Hilton H;Bali S;Parker A;Vizor L;Purnell T;Vowell K;Wells S;Bhutta MF;Potter PK;Brown SD
通讯作者：
Brown SD
影响因子：
120.7
作者：
Casselbrant, ML;Mandel, EM;Ferrell, RE
通讯作者：
Ferrell, RE