Analysis of the liver soluble proteome from bull terriers affected with inherited lethal acrodermatitis

Abstract

Lethal acrodermatitis (LAD) is a genetic disease affecting bull terrier dogs. The phenotype is similar to that for acrodermatitis enteropathica in humans, but is currently without treatment. The purpose of the research presented here is to determine the biochemical defects associated with LAD using proteomic methodologies. Two affected (male and female) and one unaffected (male) bull terrier pups were euthanized at 14 weeks of age, their livers dissected and prepared for twodimensional gel electrophoresis (2DE) and densitometry. Approximately 200 protein spots were observed. The density of the spots within each gel was normalized to the total spot volume of the gel; only those soluble liver protein spots that were consistently different in both of the livers of the affected pups compared to the unaffected pup were excised manually and submitted for MALDI mass spectrometry. Thirteen proteins were identified as differentially expressed in the affected, compared to the unaffected, pups. The proteins were involved in numerous cellular physiological functions, including chaperones, calcium binding, and energy metabolism, as well as being associated with the inflammatory response. Of note were haptoglobin, glutamine synthetase, prohibitin and keratin 10 which exhibited at least a 4-fold level of differential expression. These data represent the first proteomic analysis of this mutation. The differentially expressed proteins that were identified may be key in understanding the etiology of LAD, and may lead to diagnostic tools for its identification within the bull terrier population.

MKLN1 splicing defect in dogs with lethal acrodermatitis

“…The lacking skin lesions in Mkln1 -/- knockout mice raise the questions whether muskelin 1 depletion does not result in disease in mice; whether their clinical signs would only manifest at a (much) older age; or whether the sterile environment of the laboratory animals prevented infections and thus the development of skin lesions. In the latter case, LAD would be a primary immunodeficiency disorder, in agreement with the observation of lower IgA levels and higher susceptibility to microbial infection in LAD affected dogs [ 8 – 10 , 12 ]. Given the diverse known protein-protein interactions of muskelin 1, it is however likely that absence of muskelin 1 leads to dysfunctions beyond the immune system.…”

“…In contrast to acrodermatitis enteropathica in humans, oral or intravenous supplementation of zinc does not lead to an improvement of the clinical signs in LAD affected dogs [ 6 ]. A proteomic analysis reported changes related to inflammatory response in the liver of LAD affected puppies [ 12 ].…”

The ubiquitous role of zinc in health and disease

“…A genetic defect in the Zip4 transporter was also identified in the lethal bovine hereditary zinc deficiency, also known as lethal trait A46 251 . A recent study suggests that the defect of zinc metabolism in LAD affects the inflammatory response and may increase oxidative stress 252 . Affected Bull Terrier puppies demonstrate early growth retardation and lethargy with cutaneous lesions, generalized bacterial and Malassezia dermatitis, generalized lymphadenopathy, a small or absent thymus, diarrhea, and chronic respiratory infections 149,253 .…”

Proteomics in Veterinary Medicine

“…33 Canine liver has also been examined in bull terriers with a genetic disorder leading to inherited lethal acrodermatitis. 49 Worth mentioning is an interesting study on rabies. Three areas of the central nervous system of dogs infected with rabies virus resulting in paralytic or furious manifestation of the disease have been compared by 2DE, followed by quadrupole TOF MS. 108 A total of 32 proteins were found to differ in the hippocampus, 49 in the brainstem, and 67 in the spinal cord.…”