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Oncostatin M receptor-beta mutations underlie familial primary localized cutaneous amyloidosis

机译:抑癌素M受体-β突变是家族性原发性局部皮肤淀粉样变性的基础

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摘要

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 (OSMRbeta), in three families. OSMRbeta 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.
机译:家族性原发性局部皮肤淀粉样变性病(FPLCA)是一种常染色体显性疾病,与慢性皮肤瘙痒和表皮角蛋白丝相关的淀粉样物质沉积在真皮中有关。 FPLCA已被映射到5p13.1-q11.2,通过候选基因分析,我们在OSMR基因中识别了三个家族的编码抑癌素M特异性受体beta(OSMRbeta)的错义突变。 OSMRbeta是制瘤素M(OSM)II型受体和白介素(IL)-31受体的组成部分,并且经过培养的FPLCA角质形成细胞在OSM或IL-31细胞因子后显示出Jak / STAT,MAPK和PI3K / Akt通路的激活减少刺激。病原性氨基酸取代位于细胞外纤连蛋白III型(FNIII)域内,这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,但是我们在FPLCA患者中的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,并为皮肤瘙痒的机理提供了新见识。

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