Oncostatin M Receptor-β Mutations Underlie Familial Primary Localized Cutaneous Amyloidosis

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 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.

Novel IL31RA gene mutation and ancestral OSMR mutant allele in familial primary cutaneous amyloidosis

“…Within this critical region, Arita et al 22 have replicated the linkage data for chromosome 5p13.1-q11.2 in a large Brazilian family. Moreover, they identified a missense mutation (c.2072T4C; p.I691T) in all affected individuals in the OSMR gene, encoding oncostatin M-specific receptor b (OSMRb).…”

“…None of the 142 control subjects from Taiwan (or over 250 control chromosomes from other populations) showed presence of p.P694L or the other missense mutations. All these amino-acid substitutions occur within the fibronectin III-like domains of OSMRb, in a similar location to the mutations reported by Arita et al 22 No mutations in OSMR were identified in the other 19/29 pedigrees, including eight pedigrees that showed linkage to the chromosome 5 interval.…”

“…Two recurrent mutations (p.P694L and p.K697T) are located in exon 15, whereas the other mutation, p.D647V, occurs in exon 14 of the OSMR gene. Including the published p.G618A and p.I691T mutations reported by Arita et al, 22 substitutions of five different highly conserved amino-acid residues in the fibronectin III-like domains of OSMRb have now been determined as the molecular basis of FPCA. As shown in Figure 4a and 4b, the mutations reported in this paper are all located in the fibronectin III-like domains of OSMRb and IL-31RA.…”

“…Additional studies in two other white families from the United Kingdom and South Africa discovered another heterozygous missense mutation (c.1853G4C; p.G618A) common to the affected individuals in both pedigrees, thus establishing OSMR as a disease gene for some cases of FPCA. 22 The OSMR gene belongs to the interleukin-6 (IL-6) cytokine receptor gene family. Cytokines of the IL-6 family include IL-6, IL-11, IL-27, and IL-31, ciliary neurotrophic factor, cardiotrophin-1, cardiotrophin-like cytokine, leukemia inhibitory factor, neuropoietin, and OSM.…”

Lichen Amyloidosis; Evaluation of the Efficacy of Topical Dimethyl Sulfoxide (D.M.S.O) 70% in Abbasi Shaheed Hospital, Karachi

“…Although Oncostatin M Receptor (OSMR) gene and IL3IRA mutations has been reported. 1,6,8 P.L.C.A consists of macular and lichen amyloidosis, and sometimes both forms may co-exist. Rare forms are bullous, vitiliginous or ichthyosiform amyloidosis.…”