OMIA:001561-9615 : Periodic Fever Syndrome in Canis lupus familiaris
Categories: Immune system phene
Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 601636 (gene) , 605927 (gene)
Links to MONDO diseases: No links.
Mendelian trait/disorder: yes
Mode of inheritance: Autosomal
Considered a defect: yes
Key variant known: yes
Year key variant first reported: 2011
Species-specific name: Hyaluronanosis; Familial Shar-Pei fever; Hereditary cutaneous mucinosis; Canine Autoinflammatory Disease (AID); Shar-Pei Autoinflammatory Disease (SPAID)
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 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".
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|HAS2||hyaluronan synthase 2||Canis lupus familiaris||13||NC_051817.1 (20697736..20646614)||HAS2||Homologene, Ensembl , NCBI gene|
|MTBP||MDM2 binding protein||Canis lupus familiaris||13||NC_051817.1 (19644280..19710517)||MTBP||Homologene, Ensembl , NCBI gene|
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WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.
Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.
|OMIA Variant ID||Breed(s)||Variant Phenotype||Gene||Allele||Type of Variant||Source of Genetic Variant||Reference Sequence||Chr.||g. or m.||c. or n.||p.||Verbal Description||EVA ID||Inferred EVA rsID||Year Published||PubMed ID(s)||Acknowledgements|
|709||Shar-Pei||Periodic Fever Syndrome||HAS2||insertion, gross (>20)||Naturally occurring variant||13||"several copies of a the "meatmouth" (CNV-E) duplication upstream of the HAS2 gene"||2011||21437276|
|112||Shar-Pei||Periodic Fever Syndrome||MTBP||missense||Naturally occurring variant||CanFam3.1||13||g.19383758G>A||c.2623G>A||p.(E875K)||rs1152388482||rs1152388482||2017||28472921||Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool|
Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
|2017||Metzger, J., Nolte, A., Uhde, A.K., Hewicker-Trautwein, M., Distl, O. :|
|Whole genome sequencing identifies missense mutation in MTBP in Shar-Pei affected with Autoinflammatory Disease (SPAID). BMC Genomics 18:348, 2017. Pubmed reference: 28472921 . DOI: 10.1186/s12864-017-3737-z.|
|2016||Olsson, M., Kierczak, M., Karlsson, Å., Jabłońska, J., Leegwater, P., Koltookian, M., Abadie, J., De Citres, C.D., Thomas, A., Hedhammar, Å., Tintle, L., Lindblad-Toh, K., Meadows, J.R. :|
|Absolute quantification reveals the stable transmission of a high copy number variant linked to autoinflammatory disease. BMC Genomics 17:299, 2016. Pubmed reference: 27107962 . DOI: 10.1186/s12864-016-2619-0.|
|2014||Metzger, J., Distl, O. :|
|A study of Shar-Pei dogs refutes association of the 'meatmouth' duplication near HAS2 with Familial Shar-Pei Fever. Anim Genet 45:763-4, 2014. Pubmed reference: 25040095 . DOI: 10.1111/age.12193.|
|2013||Olsson, M., Tintle, L., Kierczak, M., Perloski, M., Tonomura, N., Lundquist, A., Murén, E., Fels, M., Tengvall, K., Pielberg, G., Dufaure de Citres, C., Dorso, L., Abadie, J., Hanson, J., Thomas, A., Leegwater, P., Hedhammar, A., Lindblad-Toh, K., Meadows, J.R. :|
|Thorough investigation of a canine autoinflammatory disease (AID) confirms one main risk locus and suggests a modifier locus for amyloidosis. PLoS One 8:e75242, 2013. Pubmed reference: 24130694 . DOI: 10.1371/journal.pone.0075242.|
|2011||Docampo, M.J., Zanna, G., Fondevila, D., Cabrera, J., López-Iglesias, C., Carvalho, A., Cerrato, S., Ferrer, L., Bassols, A. :|
|Increased HAS2-driven hyaluronic acid synthesis in shar-pei dogs with hereditary cutaneous hyaluronosis (mucinosis). Vet Dermatol 22:535-45, 2011. Pubmed reference: 21718367 . DOI: 10.1111/j.1365-3164.2011.00986.x.|
|Olsson, M., Meadows, J.R., Truvé, K., Rosengren Pielberg, G., Puppo, F., Mauceli, E., Quilez, J., Tonomura, N., Zanna, G., Docampo, M.J., Bassols, A., Avery, A.C., Karlsson, E.K., Thomas, A., Kastner, D.L., Bongcam-Rudloff, E., Webster, M.T., Sanchez, A., Hedhammar, A., Remmers, E.F., Andersson, L., Ferrer, L., Tintle, L., Lindblad-Toh, K. :|
|A novel unstable duplication upstream of HAS2 predisposes to a breed-defining skin phenotype and a periodic fever syndrome in Chinese Shar-Pei dogs. PLoS Genet 7:e1001332, 2011. Pubmed reference: 21437276 . DOI: 10.1371/journal.pgen.1001332.|
|2010||Akey, JM., Ruhe, AL., Akey, DT., Wong, AK., Connelly, CF., Madeoy, J., Nicholas, TJ., Neff, MW. :|
|Tracking footprints of artificial selection in the dog genome. Proc Natl Acad Sci U S A 107:1160-5, 2010. Pubmed reference: 20080661 . DOI: 10.1073/pnas.0909918107.|
|2009||Zanna, G., Docampo, M.J., Fondevila, D., Bardagí, M., Bassols, A., Ferrer, L. :|
|Hereditary cutaneous mucinosis in shar pei dogs is associated with increased hyaluronan synthase-2 mRNA transcription by cultured dermal fibroblasts. Vet Dermatol 20:377-82, 2009. Pubmed reference: 20178474 . DOI: 10.1111/j.1365-3164.2009.00799.x.|
|1992||Rivas, AL., Tintle, L., Kimball, ES., Scarlett, J., Quimby, FW. :|
|A canine febrile disorder associated with elevated interleukin-6. Clin Immunol Immunopathol 64:36-45, 1992. Pubmed reference: 1606750 .|
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