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Uncovering a Novel Pathway for Autoinflammation: With a Little Help from a Wrinkled Friend
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. (Science for Life Laboratory)
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 [en]
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: urn:nbn:se:uu:diva-183657ISBN: 978-91-554-8528-3 (print)OAI: oai:DiVA.org:uu-183657DiVA: diva2:563671
Public defence
2012-12-13, B42, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2012-11-22 Created: 2012-10-31 Last updated: 2013-02-11Bibliographically approved
List of papers
1. A Novel Unstable Duplication Upstream of HAS2 Predisposes to a Breed-Defining Skin Phenotype and a Periodic Fever Syndrome in Chinese Shar-Pei Dogs
Open this publication in new window or tab >>A Novel Unstable Duplication Upstream of HAS2 Predisposes to a Breed-Defining Skin Phenotype and a Periodic Fever Syndrome in Chinese Shar-Pei Dogs
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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.

National Category
Veterinary Science
Identifiers
urn:nbn:se:uu:diva-153228 (URN)10.1371/journal.pgen.1001332 (DOI)000288996600014 ()21437276 (PubMedID)
Available from: 2011-05-09 Created: 2011-05-09 Last updated: 2015-02-17Bibliographically approved
2. Thorough investigation of a canine autoinflammatory disease (AID) syndrome confirms one main risk factor and suggests a modifier locus for amyloidosis
Open this publication in new window or tab >>Thorough investigation of a canine autoinflammatory disease (AID) syndrome confirms one main risk factor and suggests a modifier locus for amyloidosis
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2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 10, e75242- p.Article in journal (Refereed) Published
Abstract [en]

Autoinflammatory disease (AID) manifests from the dysregulation of the innate immune system and is characterised by systemic and persistent inflammation. Clinical heterogeneity leads to patients presenting with one or a spectrum of phenotypic signs, leading to difficult diagnoses in the absence of a clear genetic cause. We used separate genome-wide SNP analyses to investigate five signs of AID (recurrent fever, arthritis, breed specific secondary dermatitis, otitis and systemic reactive amyloidosis) in a canine comparative model, the pure bred Chinese Shar-Pei. Analysis of 255 DNA samples revealed a shared locus on chromosome 13 spanning two peaks of association. A three-marker haplotype based on the most significant SNP (p<2.6x10(-8)) from each analysis showed that one haplotypic pair (H13-11) was present in the majority of AID individuals, implicating this as a shared risk factor for all phenotypes. We also noted that a genetic signature (F-ST) distinguishing the phenotypic extremes of the breed specific Chinese Shar-Pei thick and wrinkled skin, flanked the chromosome 13 AID locus; suggesting that breed development and differentiation has played a parallel role in the genetics of breed fitness. Intriguingly, a potential modifier locus for amyloidosis was revealed on chromosome 14, and an investigation of candidate genes from both this and the chromosome 13 regions revealed significant (p<0.05) renal differential expression in four genes previously implicated in kidney or immune health (AOAH, ELMO1, HAS2 and IL6). These results illustrate that phenotypic heterogeneity need not be a reflection of genetic heterogeneity, and that genetic modifiers of disease could be masked if syndromes were not first considered as individual clinical signs and then as a sum of their component parts.

Keyword
autoinflammatory disease (AID), 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
Genetics
Identifiers
urn:nbn:se:uu:diva-183651 (URN)10.1371/journal.pone.0075242 (DOI)000325810900025 ()
Available from: 2012-10-31 Created: 2012-10-31 Last updated: 2017-12-07Bibliographically approved
3. Circulating hyaluronic acid is elevated in subjects with genetically undefined autoinflammatory disease
Open this publication in new window or tab >>Circulating hyaluronic acid is elevated in subjects with genetically undefined autoinflammatory disease
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(English)Manuscript (preprint) (Other academic)
Keyword
autoinflammation, hyaluronic acid, ELISA, adult onset Still’s disease, systemic juvenile idiopathic arthritis
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-183652 (URN)
Available from: 2012-10-31 Created: 2012-10-31 Last updated: 2013-02-11

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