OMIA 001561-9615 : Periodic Fever Syndrome in Canis lupus familiaris

Possibly relevant human trait(s) and/or gene(s) (MIM number): 249100

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".

Breed: Shar-Pei.

Associated genes:

Symbol Description Species Chr Location OMIA gene details page Other Links
HAS2 hyaluronan synthase 2 Canis lupus familiaris 13 NC_006595.3 (20342647..20310946) HAS2 Homologene, Ensembl, NCBI gene
MTBP MDM2 binding protein Canis lupus familiaris 13 NC_006595.3 (19313884..19385370) MTBP Homologene, Ensembl, NCBI gene

Variants

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Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
Shar-Pei Periodic Fever Syndrome HAS2 insertion, gross (>20) "several copies of a the "meatmouth" (CNV-E) duplication upstream of the HAS2 gene" 2011 21437276
Shar-Pei Periodic Fever Syndrome MTBP missense CanFam3.1 13 g.19383758G>A c.2623G>A p.E875K ss2136554981 2017 28472921 Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool

References


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.

Edit History


  • Created by Frank Nicholas on 21 Jul 2011
  • Changed by Frank Nicholas on 10 Aug 2011
  • Changed by Frank Nicholas on 12 Dec 2011
  • Changed by Frank Nicholas on 21 May 2013
  • Changed by Frank Nicholas on 06 Nov 2013
  • Changed by Frank Nicholas on 30 Apr 2015
  • Changed by Frank Nicholas on 26 Apr 2016
  • Changed by Frank Nicholas on 12 May 2017
  • Changed by Frank Nicholas on 19 May 2017