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Oncostatin M Receptor-β Mutations Underlie Familial Primary Localized Cutaneous Amyloidosis  Ken Arita, Andrew P. South, Günter Hans-Filho, Thais Harumi.

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Presentation on theme: "Oncostatin M Receptor-β Mutations Underlie Familial Primary Localized Cutaneous Amyloidosis  Ken Arita, Andrew P. South, Günter Hans-Filho, Thais Harumi."— Presentation transcript:

1 Oncostatin M Receptor-β Mutations Underlie Familial Primary Localized Cutaneous Amyloidosis 
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, John A. McGrath  The American Journal of Human Genetics  Volume 82, Issue 1, Pages (January 2008) DOI: /j.ajhg Copyright © 2008 The American Society of Human Genetics Terms and Conditions

2 Figure 1 Clinical, Histological, and Genetic Aspects of FPLCA
(A) The pedigree of Family 1 showing autosomal-dominant inheritance; filled symbols represent affected individuals. (B) Clinical features of FPLCA. Skin on the lower leg (individual III-16) appears dry, scaly, and thickened with some hyperpigmentation. (C) At higher magnification, there is accentuation of the normal skin creases and focal skin papules (lichenification). (D) Histopathological features of FPLCA. Skin biopsy of lesional skin shows pigmentary incontinence (arrow) and amorphous eosinophilic material (asterisk) in the superficial papillary dermis (hematoxylin and eosin) (scale bar represents 25 μm). (E) These collections of material show bright fluorescent labeling with thioflavin-T (white arrows) (scale bar represents 25 μm). The American Journal of Human Genetics  , 73-80DOI: ( /j.ajhg ) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

3 Figure 2 The Molecular Basis of FPLCA Involves Heterozygous Missense Mutations in the OSMR Gene (A) DNA sequencing of OSMR. Sequencing of genomic DNA in individuals with FPLCA reveals heterozygous single-nucleotide substitutions in OSMR c.2072T→C in Family 1 and c.1853G→C in Families 2/3 (NM_003999). These convert an isoleucine to threonine and a glycine to alanine, designated p.I691T and p.G618A, respectively. (B) Structural model of OSMRβ depicting the functional domains and the sites of the missense mutations. FNIII, fibronectin type III-like domain; CBD, cytokine binding domain; Ig-like domain, immunoglobulin-like domain. Amino acid (AA) numbers of the 979 amino acid OSMRβ protein are shown on the left of the figure. The missense mutations p.I691T and p.G618A are located within the extracellular FNIII domains. (C) Protein homology and amino acid identity indicate that amino acids p.I691 and p.G618 are well conserved across several species. The numbers at the start of the depicted sequences indicate the amino acid numbers. Underlined amino acids are conserved in all species shown here; p.I691 and p.G618 are highlighted in red. The American Journal of Human Genetics  , 73-80DOI: ( /j.ajhg ) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

4 Figure 3 Schematic Model of IL-6 Family Cytokine Receptors
The IL-6 receptor comprises two gp130 and one IL-6R molecules. There are two types of OSM receptors: type I is composed of gp130 and LIFR, whereas type II comprises gp130 and OSMRβ. The IL-31 receptor is composed of OSMRβ and IL31RA. Each domain of the receptors is colored similarly to the schematic shown in Figure 2B. The American Journal of Human Genetics  , 73-80DOI: ( /j.ajhg ) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

5 Figure 4 Western Blotting of Phosphorylated (p)-STATs, pErk1/2, and pAkt of Cultured Keratinocytes Stimulated with OSM or IL-31 Phosphorylation of STATs, Erk1/2, and Akt was observed after stimulation by OSM and IL-31 in normal human keratinocytes, but in FPLCA keratinocytes (here illustrated for Family 2), there was reduced phosphorylation of STATs, Erk1/2, and Akt by OSM and no activation by IL-31 (top and middle). The reduction of pSTAT3 was more clearly demonstrated at lower OSM concentrations (top). Stimulation by IL-6 did not result in altered phosphorylation in FPLCA keratinocytes (bottom). The American Journal of Human Genetics  , 73-80DOI: ( /j.ajhg ) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

6 Figure 5 Structural Representation of OSMR Type II and IL-31 Receptor Signaling in Normal and FPLCA Keratinocytes Each domain of the receptors is colored similarly to the schematic shown in Figure 2B. After binding of OSM or IL-31 to these receptors, the FNIII domains of both receptor subunits interact and signal transduction occurs. The missense mutations seen in our cases occur within the FNIII domains (black crosses), regions critical for receptor dimerization and subsequent signaling. Failure to form conformationally functional receptor complexes in FPLCA leads to reduced receptor signaling after stimulation with either OSM or IL-31. The American Journal of Human Genetics  , 73-80DOI: ( /j.ajhg ) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

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