Primary cutaneous amyloidosis (PCA) is an itchy skin disorder associated with amyloid deposits in the superfi cial dermis. The disease is relatively common in Southeast Asia and South America. Autosomal dominant PCA has been mapped previously to 5p13.1-q11.2 and 2 pathogenic missense mutations in the OSMR gene, which encodes the interleukin-6 family cytokine receptor oncostatin M receptor beta (OSMRβ), were reported. Here, we investigated 29 Taiwanese pedigrees with PCA and found that 10 had heterozygous missense mutations in OSMR: p.D647V (1 family), p.P694L (6 families), and p.K697T (3 families). The mutation p.P694L was associated with the same haplotype in 5 of 6 families and also detected in 2 sporadic cases of PCA. Of the other 19 pedigrees that lacked OSMR pathology, 8 mapped to the same locus on chromosome 5, which also contains the genes for 3 other interleukin-6 family cytokine receptors, including interleukin-31 receptor A (IL31RA), which can form a heterodimeric receptor with OSMRβ through interleukin-31 signaling. In one family, we identifi ed a point mutation in the IL31RA gene, c.1562C>T, that results in a missense mutation, p.S521F, which is also sited within a fi bronectin type III-like repeat domain as observed in the OSMR mutations. PCA is a genetically heterogeneous disorder but our study shows that it can be caused by mutations in 2 biologically associated cytokine receptor genes located on chromosome 5. The identifi cation of OSMR and IL31RA gene pathology provides an explanation of the high prevalence of PCA in Taiwan as well as new insight into disease pathophysiology and management. The pathogenesis mechanisms of FPCA involving the two genes are under investigation by expressing mutant receptor components in the cell culture system.
Date:
2009-09
Relation:
Journal of Investigative Dermatology. 2009 Sep;129(S2):S46.
