Oncostatin M receptor-β mutations underlie familial primary localized cutaneous amyloidosis
Oncostatin M receptor-β mutations underlie familial primary localized cutaneous amyloidosis
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DOI：
10.1016/j.ajhg.2007.09.002
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发表时间：
2008-01-01
影响因子：
9.8
通讯作者：
McGrath, John A.
中科院分区：
文献类型：
--
作者：
Arita, Ken;South, Andrew P.;McGrath, John A.
家族性原发性局限性皮肤淀粉样变性（FPLCA）是一种常染色体显性遗传疾病，与慢性皮肤瘙痒和表皮角蛋白丝相关淀粉样物质在真皮中的沉积有关。 FPLCA 已被定位到 5p13.1-q11.2，通过候选基因分析，我们在三个家族中鉴定了 OSMR 基因的错义突变，该基因编码制瘤素 M 特异性受体 β (OSMR β)。 OSMR beta 是制瘤素 M (OSM) II 型受体和白细胞介素 (IL)-31 受体的组成部分，培养的 FPLCA 角质形成细胞在 OSM 或 IL-31 细胞因子刺激后显示出 jak/STAT、MAPK 和 PI3K/Akt 通路的激活减少。致病性氨基酸取代位于细胞外纤连蛋白 III 型样 (FNIII) 结构域内，该区域对受体二聚化和功能至关重要。 OSM 和 IL-31 信号传导与角质形成细胞的增殖、分化、凋亡和炎症有关，但我们对 FPLCA 患者的 OSMR 数据代表了该细胞因子受体复合物中的第一个人类种系突变，并为皮肤瘙痒机制提供了新的见解。
Familial primary localized cutaneous amyloidosis (FPLCA) is an autosomal-dominant disorder associated with chronic skin itching and deposition of epidermal keratin filament-associated amyloid material in the dermis. FPLCA has been mapped to 5p13.1-q11.2, and by candidate gene analysis, we identified missense mutations in the OSMR gene, encoding oncostatin M-specific receptor beta (OSMR beta), in three families. OSMR beta is a component of the oncostatin M (OSM) type II receptor and the interleukin (IL)-31 receptor, and cultured FPLCA keratinocytes showed reduced activation of jak/STAT, MAPK, and PI3K/Akt pathways after OSM or IL-31 cytokine stimulation. The pathogenic amino acid substitutions are located within the extracellular fibronectin type III-like (FNIII) domains, regions critical for receptor dimerization and function. OSM and IL-31 signaling have been implicated in keratinocyte cell proliferation, differentiation, apoptosis, and inflammation, but our OSMR data in individuals with FPLCA represent the first human germline mutations in this cytokine receptor complex and provide new insight into mechanisms of skin itching.