Advisor

Swiderski, Cyprianna E.

Committee Member

Elder, Steven H.

Committee Member

Pasquali, Marzia

Committee Member

Brashier, Michael K.

Date of Degree

1-1-2012

Document Type

Dissertation - Open Access

Abstract

Hereditary Equine Regional Derma Asthenia (HERDA) is a painful disfiguring autosomal recessive skin disorder of Quarter Horse lineages. Affected horses cannot be ridden and most are humanely destroyed. Five years following homozygosity mapping of a putative causal mutation responsible for HERDA, it remains unclear how this mutation causes the HERDA syndrome. HERDA horses have a missense mutation in peptidyl-prolyl cis-trans isomerase B (PPIB) which encodes cyclophilin B (CYPB) and alters folding and post-translational modifications of fibrillar collagen. Loss of function mutations in CYPB recognized in other species classically present as the debilitating bone disease, severe to lethal osteogenesis imperfect (OI). Objectives of this study were to develop a novel method for cryogenic clamping of tendons and ligaments of high tensile strength and validate its performance by ultimate tensile strength testing of normal equine deep digital flexor tendon. This validated method was then used to compare tendon and ligament of HERDA vs. control horses along with great vessels and skin. We hypothesized that all tissues of high fibrillar collagen content would have altered tensile properties due to the CYPB mutation affecting fibrous connective tissue globally within HERDA horses. Based on previous studies in our laboratory identifying reduced hydroxylysine content and altered collagen crosslink ratios in the skin of HERDA affected animals that implicate lysyl hydroxylase-1 (LH1) dysfunction, we hypothesized that the HERDA PPIB mutation modified an interaction between CYPB and LH1, interfering with hydroxylysine synthesis and its availability for collagen crosslink formation. In addition, we hypothesized that mutant CYPB may also lead to modifications of other known CYPB protein complexes, such as the CYPB, prolyl-3 hydroxylase-1 (P3H1) and cartilage associated protein (CRTAP) triplex. Goals of this study were to investigate the tensile properties of tissues with high fibrillar collagen content from HERDA homozygotes, to elucidate the mechanistic relationship of the HERDA CYPB mutation to the clinical disease, and to provide evidence to substantiate a heterozygote phenotype in HERDA which could be useful to explaining the correlation between lineages that carry the HERDA allele and performance outcomes in the discipline of western cutting competition.

URI

https://hdl.handle.net/11668/18911

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