Because dog ownership in China was heavily taxed in the late 1960s and early 1970s, the shar-pei breed was endangered and a handful of shar-peis were exported to the U.S. From this gene pool came the breed as we recognize it today. Strong selective breeding has produced the shar-pei’s distinctive wrinkled skin and heavily padded muzzle. The skin wrinkling is caused by excessive deposition of hyaluronan (HA) in the dermis. Shar-peis have a 2- to 5-fold increase in serum HA concentrations compared with the concentration in other dogs. The role of HA is complex and, when fragmented, it may act as a proinflammatory. Shar-peis are predisposed to familial shar-pei fever (FSF), which presents as recurrent episodes of high fever with localized inflammation of the major joints and is associated with renal amyloidosis. FSF resembles several hereditary fever syndromes in humans, including familial Mediterranean fever. In this study, the investigators performed a genome analysis of shar-peis. They identified 16.1 Kb duplication on chromosome 13, a regulatory mutation that up-regulates the hyaluronic acid synthase 2 (HAS2) gene in affected dogs. Enhanced HA synthesis allows HA to accumulate in the dermis. HA fragments may cause autoinflammation by mimicking the surface markers of pathogens. Higher copy numbers of the 16.1 Kb duplication were associated both with increased expression of HAS2 and the periodic fever syndrome. This study is significant in being the first to associate HA with autoinflammatory disease and FSF, making the disease a potential model for periodic fever syndromes in humans.

Commentary:
It is estimated that approximately 23% of shar-peis are affected with FSF in the U.S. alone.1 There is great interest in the findings of this study because of the similarities between FSF and hereditary periodic fever syndromes in humans, approximately 60% of which have yet to be worked out from a genetic standpoint. The finding that HA is a major trigger in this disease will help direct research on both the human and veterinary sides. The recognition that the wrinkling and disease are related is important to breeding programs. A crucial next step would be a genetic screening test suitable for general use.—Karen A. Moriello, DVM, Diplomate ACVD

A novel unstable duplication upstream of HAS2 predisposes to a breed-defining skin phenotype and a periodic fever syndrome in Chinese shar-pei dogs. Olsson M, Meadows JRS, Truvé K, et al. PLOS GENET doi:10.1371/journal.pgen.1001332.

1 Familial autoinflammatory diseases: Genetics, pathogenesis, and treatment. Stojanov S, Kastner DL. Curr Opin Rheumatol 17:586-599, 2005.