Categories: Immune system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 601636 (gene) , 605927 (gene)

Mendelian trait/disorder: no

Mode of inheritance: Multifactorial

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2011

Species-specific name: Hyaluronanosis; familial Shar-Pei fever; hereditary cutaneous hyaluronosis/mucinosis; canine autoinflammatory disease (AID); Shar-Pei autoinflammatory disease (SPAID); Shar-Pei recurrent fever syndrome; swollen hock syndrome

Species-specific symbol: FSF; AID; SPAID

Mapping: By genotyping 39 affected and 17 control Shar-Pei dogs with either the "27K (v1) and 50K (v2) canine Affymetrix SNP chips" (yielding 17,227 informative SNPs for analysis), Olssen et al. (2011) showed that a region of canine chomosome CFA13 is the likely site of a selective sweep in the Shar-Pei breed, reflecting selection for the breed-defining thickened, folded skin. By conducting a GWAS on the same data, they also showed that this same region of CFA13 has the strongest association with susceptibility to Familial Shar-Pei fever. Resquencing in this region of CFA13 revealed two duplications upstream of the HAS2 (hyaluronic acid synthase 2) gene: "The “meatmouth” duplication was the larger fragment, 16.1 Kb (CanFam 2.0 Chr13: 23,746,089–23,762,189) with breakpoints located in repeats (a SINE at the centromeric end and a LINE at the telomeric end) and individual copies separated by seven base pairs. . . . [and] The “traditional” duplication was 14.3 Kb (CanFam 2.0 Chr13: 23,743,906–23,758,214)" In a GWAS on 255 Shar-Pei, comprising five overlapping case subsets (fever, arthritis, vesicular hyaluronosis, otitis and amyloidosis) and three overlapping control subsets, each genotyped with the Illumina Canine 170 K SNP chip (yielding between 106,298 and 111,880 informative SNPs), Olsson et al. (2013) revealed a major QTL for all five subsets of the disorder on chromosome CFA13, between 21.5Mb and 28.3Mb (CanFam 2.0). For one of the subsets (amyloidosis), a modifer QTL was identified on CFA14 "at approximately 39 Mb and 55 Mb".

Molecular basis: Olsson et al. (2011), from the LUPA consortium, presented evidence suggestive that the "distinctive thick and heavily folded skin" of the Shar-Pei breed is associated with several copies of a the "meatmouth" (CNV-E) duplication upstream of the HAS2 gene that encodes hyaluronic acid synthase 2. The duplication results in over-expression of the HAS2 enzyme which in turn results in a build-up of hyaluronan (HA) in the skin, creating the breed-specific characteristic. Unfortunately, a build-up of HA also increases the risk of periodic fever syndrome, by triggering the innate immune response. Metzger and Distl (2014) reported no difference in the number of copies of either the "meatmouth" or "traditional" duplications between 16 "susceptible" and 79 "unaffected" Shar-Pei dogs. Using droplet digital PCR (ddPCR), Olsson et al. (2016) showed that alleles of CNV_14.3 and CNV_16.1 remain stable between generations (i.e. the number of copies remains stable). The authors also showed that "CNV_16.1 allele five (CNV_16.1|5) resulted in a four-fold increase in the odds for SPAID (p < 0.001). The inclusion of a genetic marker for CNV_16.1 in a genome-wide association test revealed that this variant explained 9.7 % of genetic variance and 25.8 % of the additive genetic heritability of this autoinflammatory disease." Metzger et al. (2017) reported "a missense variant in MTBP [g.19383758G >A; c.??G>A; p.E??K] acting via MDM2 [Mouse double minute 2 homolog] for a proinflammatory reaction" "to be highly associated with SPAID in Shar-Pei".

Clinical features: Shar-Pei autoinflammatory disease (SPAID) is characterized by five signs of inflammation: familial Shar-Pei fever (FSF), arthritis, vesicular hyaluronosis, otitis and amyloidosis.

Breed: Chinese Shar-Pei (Dog) (VBO_0200351).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated genes: