Dr. Jeff Vidt

With a special interest in the medical problems of the Chinese Shar-Pei

The Answer!

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An important paper published March 17, 2011 in the journal PLoS Genetics has given important new information concerning the relationship between hyaluronan (as present in the folds and wrinkles of the Chinese Shar-Pei), FSF and amyloidosis. The link to the article “A Novel Unstable Duplication Upstream of the HAS2 Predisposes to a Breed-Defining Skin Phenotype and a Periodic Fever Syndrome in Chinese Shar-Pei Dogs” is at http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1001332 .

An international research group at Uppsala University, Sweden and the Broad Institute of MIT and Harvard including Linda Tintle, DVM of Wurtsboro, New York has uncovered a copy number variant mutation upstream from the hyaluronan synthase2 gene (HAS2) responsible for the thickened skin and wrinkles characteristic of the breed. This duplication event is not found in other breeds. Increased copy number variant (CNV) is associated with increased HAS2 expression and also increased incidence of FSF and amyloidosis. Copies of the duplication increase the risk for FSF and the overproduction of hyaluronan is the predisposing factor.

A genetic test for FSF is currently undergoing validation studies with a large number of samples collected in October 2010 from dogs at the Chinese Shar-Pei Club of America’s 2010 National Specialty as well as samples from Shar-Pei in Sweden and Spain. Genetic test results are currently being correlated to individual health records to develop a commercial test which is accurate, meaningful and useful in the fight to decrease the incidence of FSF and amyloidosis in the breed.

I am very thankful to Shar-Pei owners and breeders who have contributed to this research through the Chinese Shar-Pei Club Charitable Trust and in providing blood samples of your dogs. Your commitment over the years has finally produced fruit. More information is available on Dr. Linda Tintle’s web site at http://www.wvc.vetsuite.com/Templates/Clean.aspx .

Way back in 1983 we first started recognizing episodic fevers in Shar-Pei often associated with a swollen, painful hock joint. Later on it was observed that an early-onset kidney failure occurred in many of these dogs as well. I remember many individuals, including myself, remarking that this has to be associated with the wrinkles in some way and now we know it does.

An important article was recently published in March, 2011, entitled “A Novel Unstable Duplication Upstream of HAS2 Predisposes to a Breed-Defining Skin Phenotype and a Periodic Fever Syndrome in Chinese Shar-Pei Dogs”, Mia Olsson et al. It is the product of a consortium of researchers from several countries, working in several laboratories and our own Dr. Linda Tintle.http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1001332

The major points of the article are as follows:

  1. Chromosome 13
    • Using a genome-wide analysis of Shar-Pei and other breeds a breed-specific signal occurred on chromosome 13.
    • That same region had the strongest association for susceptibility to FSF.
    • Two partially overlapping duplications 14.3 kb and 16.1 kb in size were located which are unique to Shar-Pei and upstream from the HAS2 gene.
  2. HAS2
    • This gene encodes the rate-limiting enzyme synthesizing hyaluronan (HA).
    • HA is up-regulated in the folded skin of the Shar-Pei. This is reflected in the higher levels of serum hyaluronan seen in the majority of the breed.
  3. 16.1 kb duplication
    • A high copy number of this duplication results in expression of HAS2 and  incidence of FSF and/or amyloidosis. It appears this region has a regulatory function and the mutation results in over expression of HAS2.
  4. Hyper HA syndrome
    •  copy number variation (CNV) in this mutation predisposes these dogs to FSF.
    • Identification of HA as a major risk factor for FSF (and human periodic fevers?).
    • Cutaneous mucinosis (Hyper HA syndrome) and FSF are connected and have the same genetic origin – a regulatory gene mutation located close to HAS2.
    •  HA responsible for the skin condition (excessive folds) predisposes to sterile fever and inflammation.
  5. Copy number
    • A high copy number is not just a genetic marker for FSF but is causally related to the development of disease.
    • A higher copy number enhanced the appearance of the phenotype.
    • Lowest copy number in Shar-Pei is 5 and the highest is 15 (so far).
    • < 4 copies – OK
    • 5-10 copies – increased risk of FSF
    • > 10 copies – increased risk of FSF and amyloidosis
    • 2 alleles involved – total copy number of both alleles
    • The mutation occurs as a single copy in other dog breeds (it is a derived mutation in Shar-Pei).
    • It is being called “the meatmouth Shar-Pei duplication” because the 16.1 kb duplication appears only in meatmouth Shar-Pei – a type which has elevated levels of HA compared to both traditional Shar-Pei and other breeds.
  6. Alterations in balance between native high molecular weight HA vs. fragmented low molecular weight HA (including oligomers) may result in activation of the innate immune system.
    1. Two pathways lead to increased formation of IL-1β, a pro-inflammatory cytokine.
    2. One pathway involves Toll-like receptors TLR2 and TLR4.
    3. The other pathway involves the NLRP3 inflammasome – a NLRP3 scaffold, ASC adaptor protein and caspase-1 enzyme. This inflammasome is present in the cytoplasm of monocytes, macrophages and mast cells.
  7. It is likely a blood test may be available in the near future to screen Shar-Pei for their CNV number and the meatmouth mutation. Breeders can avoid using those individuals with high CNV numbers in their breeding programs. This test may also be useful in the general Shar-Pei population to pick out those individuals who may be at risk for FSF +/- amyloidosis. A possible blood test is being validated at this time.
  8. A more general conclusion from this paper is the association of degree of wrinkling in American Shar-Pei with the incidence of FSF and amyloidosis. A general guideline would be to only use those individuals with mild to moderate wrinkling in breeding programs and breed away from Hyper HA dogs. It would appear these guidelines are not necessary in the traditional Chinese Shar-Pei.
  9. Lastly, the association of over-expression of HAS2 and autoinflammation most certainly has implications in the periodic fever syndromes in humans many of which are unexplained at this time.

 

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