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

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 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".

Genetic engineering: Unknown
Have human generated variants been created, e.g. through genetic engineering and gene editing

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. For breeds in which a likely causal variant has been documented, see the variant table below

Associated genes:

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

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

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 Chinese Shar-Pei (Dog) 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", variant is associated with the disease but may not be causal 2011 21437276
112 Chinese Shar-Pei (Dog) 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

Cite this entry

Nicholas, F. W., Tammen, I., & Sydney Informatics Hub. (2023). OMIA:001561-9615: Online Mendelian Inheritance in Animals (OMIA) [dataset]. https://omia.org/. https://doi.org/10.25910/2AMR-PV70

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.

2023 O'Neill, D.G., Engdahl, K.S., Leach, A., Packer, R.M.A., Church, D.B., Brodbelt, D.C. :
Is it now time to iron out the wrinkles? Health of Shar Pei dogs under primary veterinary care in the UK. Canine Med Genet 10:11, 2023. Pubmed reference: 38093396. DOI: 10.1186/s40575-023-00134-z.
Work, M., Scudder, C., Bergum Hjellegjerde, K., Dunning, M., Gajanayake, I., Kent, A., Tintle, L., Sparks, T., Allerton, F. :
A survey on Shar Pei autoinflammatory disease in the United Kingdom. J Small Anim Pract 64:401-408, 2023. Pubmed reference: 36978210. DOI: 10.1111/jsap.13602.
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.
1993 Rivas, A.L., Tintle, L., Meyers-Wallen, V.N., Scarlett, J.M., Vantassell, C.P., Quimby, F.W. :
Inheritance of renal amyloidosis in Chinese Shar-Pei dogs, Journal of Heredity 84:438-442, 1993. Pubmed reference: 8270767.
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
  • Changed by Imke Tammen2 on 10 Jun 2023
  • Changed by Imke Tammen2 on 11 Jun 2023