Oncostatin M receptor-beta mutations underlie familial primary localized cutaneous amyloidosis.
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.
Arita
Ken
K
Genetic Skin Disease Group, St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine, The Guy's, King's College and St Thomas' School of Medicine, London SE1 9RT, UK.
South
Andrew P
AP
Hans-Filho
Günter
G
Sakuma
Thais Harumi
TH
Lai-Cheong
Joey
J
Clements
Suzanne
S
Odashiro
Maçanori
M
Odashiro
Danilo Nakao
DN
Hans-Neto
Günter
G
Hans
Nelise Ritter
NR
Holder
Maxine V
MV
Bhogal
Balbir S
BS
Hartshorne
Sian T
ST
Akiyama
Masashi
M
Shimizu
Hiroshi
H
McGrath
John A
JA
D000595:Amino Acid Sequence; D028226:Amyloidosis, Familial / Q000235:genetics* / Q000473:pathology; D001938:Brazil; D018929:Cell Culture Techniques; D002895:Chromosomes, Human, Pair 5; D004252:DNA Mutational Analysis; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D015603:Keratinocytes; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D053681:Oncostatin M Receptor beta Subunit / Q000737:chemistry / Q000235:genetics*; D010375:Pedigree; D017385:Sequence Homology; D013019:South Africa; D006113:United Kingdom
C508348:OSMR protein, human; D053681:Oncostatin M Receptor beta Subunit