Spontaneous mutations in the mouse Sharpin gene result in multiorgan inflammation, immune system dysregulation and dermatitis
Spontaneous mutations in the mouse Sharpin gene result in multiorgan inflammation, immune system dysregulation and dermatitis
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DOI：
10.1038/sj.gene.6364403
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发表时间：
2007-07-01
影响因子：
5
通讯作者：
Sundberg, J. P.
中科院分区：
文献类型：
--
作者：
Seymour, R. E.;Hasham, M. G.;Sundberg, J. P.
SHARPIN（SHANK相关RH结构域相互作用蛋白）基因的同源物已在人类、大鼠和小鼠基因组中鉴定。SHARPIN及其同源物在许多组织中表达。SHARPIN蛋白形成同源二聚体，并与SHANK在大脑中兴奋性神经递质的突触后密度中结合。假设SHARPIN在SHANK蛋白的交联和肠神经系统功能中具有作用。我们证明，两个独立产生的自发突变的小鼠Sharpin基因，cpdm和cpdm（Dem），导致慢性增生性皮炎表型，其特征是严重的炎症，嗜酸性皮炎和缺陷，在次级淋巴器官发育的组织学。这些是Sharpin基因致病突变的第一个例子，证明了Sharpin蛋白在正常免疫发育和炎症控制中的重要性。
Homologues of the SHARPIN (SHANK-associated RH domain-interacting protein) gene have been identified in the human, rat and mouse genomes. SHARPIN and its homologues are expressed in many tissues. SHARPIN protein forms homodimers and associates with SHANK in the post-synaptic density of excitatory neurotransmitters in the brain. SHARPIN is hypothesized to have roles in the crosslinking of SHANK proteins and in enteric nervous system function. We demonstrate that two independently arising spontaneous mutations in the mouse Sharpin gene, cpdm and cpdm(Dem), cause a chronic proliferative dermatitis phenotype, which is characterized histologically by severe inflammation, eosinophilic dermatitis and defects in secondary lymphoid organ development. These are the first examples of disease-causing mutations in the Sharpin gene and demonstrate the importance of SHARPIN protein in normal immune development and control of inflammation.