title: The molecular skin pathology of familial primary localized cutaneous amyloidosis.
abstract: Familial primary localized cutaneous amyloidosis (FPLCA) is an autosomal dominant disorder associated with chronic itching and skin lichenification. In lesional skin, there are apoptotic basal keratinocytes and deposits of amyloid material on degenerate keratin filaments in the upper dermis. The genetic basis of FPLCA involves mutations in the OSMR and IL31RA genes but the disease pathophysiology is not fully understood. In this study, we identified new pathogenic heterozygous missense mutations in the OSMR gene (p.Val631Leu and p.Asp647Tyr) in two Dutch FPLCA families. We then compared gene expression profiles between FPLCA lesional skin (n = 4) and site-matched control skin (n = 6). There was twofold or greater upregulation of 34 genes and downregulation of 43 genes. Most changes in gene expression (verified by quantitative RT-PCR) reflected alterations in epidermal differentiation and proliferation consistent with lichenification, but we also noted a reduction in several interfollicular keratinocyte stem cell markers in FPLCA skin. Differences in gene expression were also noted for proteins involved in apoptosis and nerve conduction. Collectively, this study expands the molecular basis of FPLCA and provides new insight into the skin pathology of this condition.
authors.affiliation: St John's Institute of Dermatology, King's College London, London, UK.
authors.forename: Akio
authors.initials: A
authors.lastname: Tanaka
authors.forename: Joey E
authors.initials: JE
authors.lastname: Lai-Cheong
authors.forename: Peter C
authors.initials: PC
authors.lastname: van den Akker
authors.forename: Nikoletta
authors.initials: N
authors.lastname: Nagy
authors.forename: George
authors.initials: G
authors.lastname: Millington
authors.forename: Gilles F H
authors.initials: GF
authors.lastname: Diercks
authors.forename: Pieter C
authors.initials: PC
authors.lastname: van Voorst Vader
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Clements
authors.forename: Noor
authors.initials: N
authors.lastname: Almaani
authors.forename: Tanasit
authors.initials: T
authors.lastname: Techanukul
authors.forename: Michihiro
authors.initials: M
authors.lastname: Hide
authors.forename: Andrew P
authors.initials: AP
authors.lastname: South
authors.forename: John A
authors.initials: JA
authors.lastname: McGrath
mesh_terms: D028226:Amyloidosis, Familial / Q000235:genetics* / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D006579:Heterozygote; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics; D009426:Netherlands; D053681:Oncostatin M Receptor beta Subunit / Q000235:genetics*; D012867:Skin / Q000378:metabolism; D012875:Skin Diseases, Metabolic / Q000235:genetics* / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; D009419:Nerve Tissue Proteins; C508348:OSMR protein, human; D053681:Oncostatin M Receptor beta Subunit