Abstract
Primary cutaneous amyloidosis (PCA) is an itchy skin disorder associated with amyloid deposits in the superficial dermis. The disease is relatively common in Southeast Asia and South America. Autosomal dominant PCA has been mapped earlier to 5p13.1–q11.2 and two 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 (one family), p.P694L (six families), and p.K697T (three families). The mutation p.P694L was associated with the same haplotype in five of six families and also detected in two 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 identified a point mutation in the IL31RA gene, c.1562C>T that results in a missense mutation, p.S521F, which is also sited within a fibronectin 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 two biologically associated cytokine receptor genes located on chromosome 5. The identification 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.
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Acknowledgements
We thank Dr Tsung-Sheng Su for critical reading of the manuscript, the patients, and members of the PCA families who participated in this study, Ms Li-Ru Chen, Ms Ying-Chen Chang, and Ms Ying-Yen Weng for excellent technical support, and the staff of the Department of Dermatology, Taipei Veterans General Hospital, for referral of PCA subjects. This work was supported in part by grants VGH 93-354, VGHUST94-P1-14, NSC94-3112-B-010-019, NSC95-3112-B-010-001, NSC96-3112-B-010-001, NSC97-2314-B-010-016-MY2, and a grant from The Ministry of Education, Taiwan, Aim for the Top University Plan. The linkage analysis server was supported by grants VGH 94-368-2, V95S2-003, and V96S2-005. The sequencing services and Affymetrix 10K SNP assays were provided by the Sequencing Core Facility and Gene Expression Core Facility of the National Research Program for Genomic Medicine supported by grants from the National Science Council, Taiwan, respectively. Studies on PCA in the UK were kindly supported by a grant from Action Medical Research.
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Lin, MW., Lee, DD., Liu, TT. et al. Novel IL31RA gene mutation and ancestral OSMR mutant allele in familial primary cutaneous amyloidosis. Eur J Hum Genet 18, 26–32 (2010). https://doi.org/10.1038/ejhg.2009.135
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DOI: https://doi.org/10.1038/ejhg.2009.135
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