Oncostatin M receptor-beta mutations underlie familial primary localized cutaneous amyloidosis |
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| Authors: | Arita Ken South Andrew P Hans-Filho Günter Sakuma Thais Harumi Lai-Cheong Joey Clements Suzanne Odashiro Maçanori Odashiro Danilo Nakao Hans-Neto Günter Hans Nelise Ritter Holder Maxine V Bhogal Balbir S Hartshorne Sian T Akiyama Masashi Shimizu Hiroshi McGrath John A |
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| Affiliation: | Ken Arita, Andrew P. South, Günter Hans-Filho, Thais Harumi Sakuma, Joey Lai-Cheong, Suzanne Clements, Maçanori Odashiro, Danilo Nakao Odashiro, Günter Hans-Neto, Nelise Ritter Hans, Maxine V. Holder, Balbir S. Bhogal, Sian T. Hartshorne, Masashi Akiyama, Hiroshi Shimizu, and John A. McGrath |
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| Abstract: | 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 β (OSMRβ), in three families. OSMRβ 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. |
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