A novel mutation in equine cyclophilin B (PPIB) associated with hereditary equine regional dermal asthenia (HERDA) in the American Quarter Horse

Hereditary equine regional dermal asthenia (HERDA) is a novel, degenerative skin disease that primarily affects the American Quarter Horse breed. Classic lesions primarily develop along the dorsum between six months and two years of age and the majority of affected horses are euthanized since there are no effective treatments for managing the disease. Pedigree analysis of fifty-two Quarter Horses support an autosomal recessive mode of inheritance and the mutation appears to be relatively new since all affected horses can be traced to a recent (1930s) common ancestor.;A homozygosity mapping approach was used to localize the HERDA locus to ECA1, in close association with microsatellite marker AHT58. Comparative genomics was used to develop equine gene-specific SNP markers that could be used to refine the area of identity-by-decent common to all affected horses. Recombinants within the dataset allowed the narrowing of the critical interval down to a ∼2.5 Mb region. Screening of the genes within the interval led to the discovery of a novel missense mutation in cyclophilin B (PPIB), an intriguing candidate gene given the HERDA phenotype. Expression, purification, and characterization of wild-type and HERDA PPIB demonstrated key differences in heparin binding affinity for the two variants, supporting the hypothesis that this mutation is causative for HERDA.;Screening of the general Quarter Horse population indicates a HERDA allele frequency of 0.021 +/- 0.007. Population stratification is evident in the modern Quarter Horse due to selection strategies for a variety of different competitive subgroups. In particular, the HERDA allele is highly concentrated in cutting lines as 28.3% of elite competitive cutting horses were found to be carriers. Other subgroups with an increased risk for carrying HERDA are reining, working cow, and western pleasure Quarter Horses.;The development of a genetic test for assaying the mutation in cyclophilin B is significant in permitting the reduction of affected HERDA horses. Breeding stocks can be screened for their carrier status and the mating of two horses should be avoided. In addition, young horses showing dermatological signs consistent with HERDA can be genotyped to confirm affected status and prevent the unnecessary euthanasia of misdiagnosed animals.