Hereditary cutaneous mucinosis in shar pei dogs is associated with increased hyaluronan synthase‐2 mRNA transcription by cultured dermal fibroblasts

Abstract

Shar pei dogs are known for the distinctive feature of thick, wrinkled skin as a consequence of high dermal mucin content. Excessive dermal deposition of mucinous substance leading to severe skin folding, and/or to the more severe vesicular form characterized by dermal vesicles or bullae, is highly prevalent in this breed and is known as idiopathic mucinosis. Hyaluronic acid (HA) is the main component that accumulates in the dermis, and high levels of HA have also been detected in the serum of shar pei dogs. In this study, the cellular and molecular mechanisms underlying cutaneous mucinosis of shar pei dogs were investigated. Thirteen shar pei dogs and four control dogs of other breeds were included. In primary dermal fibroblast cultures, transcription of the family of hyaluronan synthases (HAS) involved in HA synthesis, and of hyaluronidases (HYAL) involved in HA degradation, were studied by reverse transcriptase polymerase chain reaction. The location of HA in cell cultures was studied by immunofluorescence and confocal laser microscopy. Dermal fibroblasts transcribed HAS2, HAS3, HYAL1 and HYAL2, but no amplification for HAS1 was found. A higher transcription of HAS2 was demonstrated in shar pei dogs compared with control dogs. By confocal microscopy, HA was detected as a more diffuse and intense network-like pattern of green fluorescence in the fibroblast cells of shar pei dogs in comparison with control dogs. Together, these results provide additional evidence that hereditary cutaneous mucinosis in shar pei dogs may be a consequence of over-transcription or increased activity of HAS2.

Insights into Morphology and Disease from the Dog Genome Project

“…HAS2 is integral for making hyaluronan, a major component of skin (Laurent & Fraser 1992). Interestingly, previous work suggested that Shar-Pei dogs have an excess of hyaluronan in their skin (Zanna et al 2009) and that excess hyaluronan is associated with abnormal skin phenotypes in both dogs and man (Ramsden et al 2000). In the Shar-Pei, the excess hyaluronan linked to skin wrinkling may occur by cis -acting misregulation of HAS or its negative regulator, HAS2 antisense RNA1, in a manner that is dose dependent in terms of copy number (Olsson et al 2011).…”

Deciphering the genetic basis of animal domestication

“…Regarding the other outlier SNPs identified in their study, one of the highest F ST values was only found in the Shar-Pei breed, which is characterized by its distinctive skin-folding phenotype. The region where the high F ST signal was found contains several genes, including HAS2, the expression of which had previously been associated with skin wrinkling in this breed [23]. A recently discovered duplication upstream of this gene appears to be responsible for the wrinkling phenotype [24].…”

Whole genome sequencing identifies missense mutation in MTBP in Shar-Pei affected with Autoinflammatory Disease (SPAID)

“…The distribution of genotypes actually confirmed the high incidence of SPAID in meatmouth Shar-Pei types but also detected SPAID-affected bonemouth types. In addition, HAS2 mRNA was further shown to be highly expressed in cells of severely folded skin and skin vesicles derived from vesicular hyaluronosis due to an accumulation of hyaluronic acid [33, 34]. Our pathohistologic examinations showed that both SPAID-affected and SPAID-unaffected dogs harboured signs of cutaneous mucinosis as a result of hyaluronic acid accumulation.…”