Hereditary equine regional dermal asthenia (HERDA) is an autosomal recessive dermatological condition predominantly affecting Quarter horses. Cases have similarly been reported in Appaloosas and Paint Horses with Quarter horse bloodlines, due to the presence of a common ancestor. It has been previously coined “Hyperelastosis Cutis” due to a prior assumption that the disorder was linked to collagen misalignment however this term is discouraged. Clinical signs of the disorder include the development of sematomas,hematomas or ulceration on the dorsal aspect with chronic secondary infection, abscesses and scarring which worsen in frequency and severity with age. It develops at an average age of 1.5 years in accordance with saddling, initially apparent by loose, sloughing skin. Histopathologically, lesions are typified by thin collagen fibres in deep dermal tissue that are arranged in clusters in place of dense fibres in a longitudinal pattern. Skin of affected horses has been shown to be reduced in tensile strength by threefold compared to normal horses. Once lesions develop, the condition of affected individuals deteriorates rapidly with the majority euthanized due to a lack of treatment options.
Comparative genomic data has previously identified candidate genes for HERDA associated with Ehlers-Danlos syndrome in humans. Based on available pedigree information in which affected subjects had a common ancestor on both the paternal and maternal lineages, Tyrion et al., (2007) successfully mapped the HERDA locus to ECA1 by applying a homozygosity mapping approach. In this manner HERDA became the first novel disease gene to be identified using a whole genome scan. A scan of the genome identified regions identical by descent in affected HERDA animals on the q arm of ECA1. Fine mapping with SNP’s developed from the 10Mb interval was further honed to a 2.5Mb corresponding region. Comparative genomics denoted ~20 genes in this candidate region. Subsequent sequence analysis revealed a nonsynonymous mutation in exon 1 of equine PPIB for which all 64 samples were homozygous for the missense mutation. The SNP is postulated to induce a glycine-to-arginine switch in the putative N-terminal domain of the protein, mapped to a syntenic block which has been strictly maintained during vertebrae evolution.
PPIB as a causative candidate for HERDA is further supported by the biological toleration of PPIB deficiencies which instigate an adult inflammatory response. PPIB is a member of the PPI gene family which functions in protein folding of collagen, immune responses via binding of cyclosporine A and T cell activation. However the causative link between HERDA and the PPIB mutation is inconclusive due to the numerous roles of PPIB and the poorly characterised pathways lying downstream of the protein as well as the vast region of linkage disequilibrium within samples. Hence additional functional analysis is necessitated to certify the causative link between HERDA and the PPIB mutation.
Genotyping of the mutation has suggested an approximate carrier frequency of 3.5%. This may be attributed to the disproportionate breeding of popular carrier stallions as past pedigree analysis of families used to ascertain a LOD score for the HERDA locus exhibit an inbreeding loop which is probable cause for the circulation of the mutation within the Quarter horse population. The mutation is particularly common in certain lines of cutting horses, implying that a heterozygous genotype may bestow a competitive advantage in cutting. Ultimately, use of prolific stallions has increased the frequency of the allele and in particular, line breeding has resulted in a greater occurrence of HERDA. DNA testing individuals for the mutation confers two main advantages to breeders. It permits testing to genetically determine whether HERDA is the cause of skin irregularities in youngsters and preventing unnecessary euthanasia. In addition it allows carriers within the breeding population to be identified with the view of exclusion from breeding, and reducing the frequency of the allele in question.