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A Novel Unstable Duplication Upstream of HAS2 Predisposes to a Breed-Defining Skin Phenotype and a Periodic Fever Syndrome in Chinese Shar-Pei Dogs
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
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2011 (English)In: PLoS Genetics, ISSN 1553-7390, Vol. 7, no 3, e1001332- p.Article in journal (Refereed) Published
Abstract [en]

Hereditary periodic fever syndromes are characterized by recurrent episodes of fever and inflammation with no known pathogenic or autoimmune cause. In humans, several genes have been implicated in this group of diseases, but the majority of cases remain unexplained. A similar periodic fever syndrome is relatively frequent in the Chinese Shar-Pei breed of dogs. In the western world, Shar-Pei have been strongly selected for a distinctive thick and heavily folded skin. In this study, a mutation affecting both these traits was identified. Using genome-wide SNP analysis of Shar-Pei and other breeds, the strongest signal of a breed-specific selective sweep was located on chromosome 13. The same region also harbored the strongest genome-wide association (GWA) signal for susceptibility to the periodic fever syndrome (p(raw) = 2.3 x 10(-6), p(genome) = 0.01). Dense targeted resequencing revealed two partially overlapping duplications, 14.3 Kb and 16.1 Kb in size, unique to Shar-Pei and upstream of the Hyaluronic Acid Synthase 2 (HAS2) gene. HAS2 encodes the rate-limiting enzyme synthesizing hyaluronan (HA), a major component of the skin. HA is up-regulated and accumulates in the thickened skin of Shar-Pei. A high copy number of the 16.1 Kb duplication was associated with an increased expression of HAS2 as well as the periodic fever syndrome (p, < 0.0001). When fragmented, HA can act as a trigger of the innate immune system and stimulate sterile fever and inflammation. The strong selection for the skin phenotype therefore appears to enrich for a pleiotropic mutation predisposing these dogs to a periodic fever syndrome. The identification of HA as a major risk factor for this canine disease raises the potential of this glycosaminoglycan as a risk factor for human periodic fevers and as an important driver of chronic inflammation.

Place, publisher, year, edition, pages
2011. Vol. 7, no 3, e1001332- p.
National Category
Veterinary Science
Identifiers
URN: urn:nbn:se:uu:diva-153228DOI: 10.1371/journal.pgen.1001332ISI: 000288996600014PubMedID: 21437276OAI: oai:DiVA.org:uu-153228DiVA: diva2:415745
Available from: 2011-05-09 Created: 2011-05-09 Last updated: 2015-02-17Bibliographically approved
In thesis
1. Uncovering a Novel Pathway for Autoinflammation: With a Little Help from a Wrinkled Friend
Open this publication in new window or tab >>Uncovering a Novel Pathway for Autoinflammation: With a Little Help from a Wrinkled Friend
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

A major challenge in medical genetics is to identify the mutations underlying heritable diseases. Dogs are excellent genetic models in the search for causative mutations, as they constitute a large library of naturally occurring heritable diseases many of which are analogous to those suffered by man. In addition, these animals have a genome structure well suited to gene mapping. The Shar-Pei dog has two breed-specific features; a strongly selected for wrinkled skin and a high predisposition to an autoinflammatory disease (AID). Abnormalities in the innate immune system cause this type of disease, presenting as spontaneous attacks of inflammation. Persistent inflammation puts an affected Shar-Pei at risk of amyloidosis, organ failure and premature death. In humans, similar AIDs occur and for a majority of cases, no underlying genetic cause has yet been identified. The aim of this thesis was to use the Shar-Pei as a genetic model for autoinflammation in order to find new genes and signalling pathways involved in disease. In paper I, a pleiotropic mutation was identified that could explain both the wrinkled skin and autoinflammation in Shar-Pei. The mutation is associated with an up-regulation of Hyaluronic Acid Synthase 2 (HAS2). Increased expression of HAS2 leads to abnormal depositions of hyaluronic acid (HA) in the skin, resulting in the wrinkled appearance. When fragmented, HA also function as a damage signal sensed by the innate immune system which then responds with inflammation. By selecting for the wrinkled skin, the autoinflammatory disease has inadvertently been enriched in the breed. In paper II, five different inflammatory signs could be associated with the same genetic risk factor, allowing the introduction of a new terminology: Shar-Pei autoinflammatory disease (SPAID) to describe the whole disease complex. In addition, a modifying locus containing several biologically attractive genes was suggested to contribute to varying incidence of amyloidosis in Shar-Pei. In paper III, signs of pathological changes in HA metabolism were investigated in human AID. HA concentration was found to be both higher in subjects with no molecular diagnosis and also associated to disease activity and severity. Taken together, this suggests HA is also involved in human AID.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 54 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 837
Keyword
autoinflammation, hyaluronic acid, amyloidosis, canine model, genetic association
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Molecular Genetics
Identifiers
urn:nbn:se:uu:diva-183657 (URN)978-91-554-8528-3 (ISBN)
Public defence
2012-12-13, B42, BMC, Husargatan 3, Uppsala, 13:15 (English)
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Available from: 2012-11-22 Created: 2012-10-31 Last updated: 2013-02-11Bibliographically approved

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Meadows, Jennifer R. S.Pielberg, Gerli RosengrenWebster, Matthew T.Andersson, LeifLindblad-Toh, Kerstin

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