Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype
Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype
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DOI：
10.1086/342259
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发表时间：
2002-09-01
影响因子：
9.8
通讯作者：
Peltonen, L
中科院分区：
文献类型：
--
作者：
Paloneva, J;Manninen, T;Peltonen, L
多囊脂膜性骨发育不良伴硬化性白质脑病（PLOSL），也被称为“Nasu-Hakola病”，是一种全球分布的复发性遗传性疾病，导致50岁以下的死亡，其特征是早发性进行性痴呆和骨囊肿。在其他地方，我们已经确定了TYROBP（DAP 12）中的PLOSL突变，该突变编码自然杀伤细胞和骨髓细胞中的膜受体成分，并且还确定了PLOSL的遗传异质性，一些患者没有携带TYROBP突变。在这里，我们完成了PLOSL的分子病理学鉴定TREM 2作为第二个PLOSL基因。TREM 2与TYROBP形成受体信号传导复合物，并触发巨噬细胞和树突细胞中免疫应答的激活。PLOSL患者在细胞介导的免疫中没有缺陷，这表明人类免疫系统具有显著的能力来补偿失活的TYROBP介导的活化途径。我们的数据意味着TYROBP介导的信号通路在人脑和骨组织中起着重要作用，并提供了一个有趣的例子，说明多亚基受体复合物的两个不同亚基中的突变如何导致相同的人类疾病表型。
Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), also known as "Nasu-Hakola disease," is a globally distributed recessively inherited disease leading to death during the 5th decade of life and is characterized by early-onset progressive dementia and bone cysts. Elsewhere, we have identified PLOSL mutations in TYROBP (DAP12), which codes for a membrane receptor component in natural-killer and myeloid cells, and also have identified genetic heterogeneity in PLOSL, with some patients carrying no mutations in TYROBP. Here we complete the molecular pathology of PLOSL by identifying TREM2 as the second PLOSL gene. TREM2 forms a receptor signaling complex with TYROBP and triggers activation of the immune responses in macrophages and dendritic cells. Patients with PLOSL have no defects in cell-mediated immunity, suggesting a remarkable capacity of the human immune system to compensate for the inactive TYROBP-mediated activation pathway. Our data imply that the TYROBP-mediated signaling pathway plays a significant role in human brain and bone tissue and provide an interesting example of how mutations in two different subunits of a multisubunit receptor complex result in an identical human disease phenotype.