Genome-wide expression analysis of hereditary hyperplastic gingivitis in silver foxes (Vulpes vulpes) using canine microarrays

Abstract

Hereditary hyperplastic gingivitis (HHG) is an autosomal recessive condition found predominantly in farmed silver foxes, first documented in Europe in the 1940s. Hereditary gingival fibromatosis (HGF) is an analogous condition occurring in humans. HGF has a heterogeneous aetiology with emphasis placed on the autosomal dominant forms of inheritance for which there are three known loci: HGF1, HGF2, and HGF3. Among these, only one causative mutation has been determined, in the Son of sevenless homolog 1 (SOS1) gene. The goal of this study was to explore potential molecular or cellular mechanisms underlying HHG by analysis of global gene expression patterns from Affymetrix Canine 2.0 microarrays cross-referenced against candidate genes within the human loci. We conclude that the SOS1 gene involved in HGF1 is not significantly up-regulated in HHG. However, the structurally and functionally similar SOS2 gene is up-regulated in affected foxes, and we propose this as a candidate gene for HHG. At HGF2 we identify RASA1 (rat sarcoma viral p21 protein activator 1) as a candidate gene for HHG, as it is up-regulated in affected foxes and is involved in MAPK signalling. From comparison to the genes within the HGF3 locus, we find evidence for a role of androgens in HHG phenotype severity by differential up-regulation of SRD5A2 in HHG-affected foxes. We hypothesize that the putative mutation occurs upstream of RAS in the extracellular signal-regulated kinase component of MAPK signalling.

Generalized hypertrichosis syndromes in Mexico

“…Regarding the possible participation of the MAPK pathway, it should be noted that in mammals, it consists of four sub-pathways (i.e., ERK1/2, ERK5, JNK, and p38) (Clark et al, 2014), of which two, JNK and p38, reported altered in silver foxes, are related to differential expression in processes related to cell differentiation, proliferation, and apoptosis. The differential gene expression pattern of MAPK pathway in silver foxes with gingival hyperplasia and hypertrichosis compared to unaffected animals, suggests the participation of this cascade also in humans with CGHT.…”

“…HGF has been described in humans as an autosomal dominant trait, and three loci are known for the condition: HGF1 at 2p21‐p22, HGF2 at 5q13‐q22, and HGF3 at 2p22.3‐p23.3. Among these, only HGF1 has been determined to be caused by a variant in codon 1083 of SOS1 , which is also involved in the MAPK signaling pathway (Clark, Booman, Hudson, & Marshall, 2014). However, Mangino et al (2003) excluded linkage to both HGF1 and HGF2 loci in the Italian family with HGF, suggesting broader genetic heterogeneity for this disease.…”