142 research outputs found
A large deletion in the GP9 gene in Cocker Spaniel dogs with Bernard-Soulier syndrome
No full textInherited bleeding disorders including abnormalities of platelet number and function rarely occur in a variety of dog breeds, but are probably underdiagnosed. Genetically characterized canine forms of platelet disorders provide valuable large animal models for understanding similar platelet disorders in people. Breed-specific disease associated genetic variants in only eight different genes are known to cause intrinsic platelet disorders in dogs. However, the causative genetic variant in many dog breeds has until now remained unknown. Four cases of a mild to severe bleeding disorder in Cocker Spaniel dogs are herein presented. The affected dogs showed a platelet adhesion defect characterized by macrothrombocytopenia with variable platelet counts resembling human Bernard-Soulier syndrome (BSS). Furthermore, the lack of functional GPIb-IX-V was demonstrated by immunocytochemistry. Whole genome sequencing of one affected dog and visual inspection of the candidate genes identified a deletion in the glycoprotein IX platelet (GP9) gene. The GP9 gene encodes a subunit of a platelet surface membrane glycoprotein complex; this functions as a receptor for von Willebrand factor, which initiates the maintenance of hemostasis after injury. Variants in human GP9 are associated with Bernard-Soulier syndrome, type C. The deletion spanned 2460 bp, and included a significant part of the single coding exon of the canine GP9 gene on dog chromosome 20. The variant results in a frameshift and premature stop codon which is predicted to truncate almost two-thirds of the encoded protein. PCR-based genotyping confirmed recessive inheritance. The homozygous variant genotype seen in affected dogs did not occur in 98 control Cocker Spaniels. Thus, it was concluded that the structural variant identified in the GP9 gene was most likely causative for the BSS-phenotype in the dogs examined. These findings provide the first large animal GP9 model for this group of inherited platelet disorders and greatly facilitate the diagnosis and identification of affected and/or normal carriers in Cocker Spaniels
Characterising pancreatic organoids from hereditary pancreatitis patients and their viability as a disease model
No full textAbstract #265.8James Zuiani, Griffith Perkins, Denghao Wu, Christopher Drogemuller, Toby Coate
Identification of missense mutation in the bovine ATP2A1 gene in the congenital pseudomyotonia od Chianina cattle: an human model of human Brody disease
No full textCongenital pseudomyotonia in Chianina cattle is a muscle function disorder very similar to that of Brody disease in humans. Mutations in the human ATP2A1 gene, encoding SERCA1, cause Brody myopathy. The analysis of the collected Chianina pedigree data suggested monogenic autosomal recessive inheritance and revealed that all 17 affected individuals traced back to a single founder. A deficiency of SERCA1 function in skeletal muscle of pseudomyotonia affected Chianina cattle was observed as SERCA1 activity in affected animals was decreased by about 70%. Linkage analysis showed that the mutation was located in the ATP2A1 gene region on BTA25 and subsequent mutation analysis of the ATP2A1 exons revealed a perfectly associated missense mutation in exon 6 (c.491G>A) leading to a p.Arg164His substitution. Arg164 represents a functionally important and strongly conserved residue of SERCA1. This study provides a suitable large animal model for human Brody disease
A de novo mutation in KRT5 in a crossbred calf with epidermolysis bullosa simplex
No full textA 6-day-old Belgian Blue-Holstein calf was referred because of a syndrome resembling epidermolysis bullosa simplex (EBS). The clinical phenotype included irregular and differently sized erosions and ulcerations spread over the body, in particular on the limbs and over bone prominences, as well as in the nasal planum and oral mucosa. Blisters were easily induced by rubbing the skin. The skin lesions displayed a clear dermal-epidermal separation at the level of the basal cell layer. Post mortem examination revealed erosions in the pharynx, proximal esophagus, and rumen. Whole-genome sequencing revealed a heterozygous disruptive in-frame deletion variant in KRT5 (c.534_536delCAA). Genotyping of both parents confirmed the variant as de novo mutation. Clinicopathological and genetic findings were consistent with the diagnosis of KRT5-related EBS providing the second example of a spontaneous mutation causing epidermolysis bullosa in cattle
118.9: Growing pancreatic organoids for hereditary pancreatitis
No full textAbstract - 118.9James Zuiani, Denghao Wu, Griffith Perkins, Shane Grey, Christopher Drogemuller, Patrick Toby Coate
Loss of zinc and alteration of zinc transporters in db/db mice pancreatic islets in early type 2 diabetes
No full textBosco Mariea, Mohanasundaram Daisy, Zalewski Peter, Drogemuller Chris, Coyle Peter, Rofe Allan, Coates PT
P.01: Remote Isolation in Total Pancreatectomy and Auto-Islet Transplantation
No full textAbstract - P.01Colleen Etherton, Alice Rickard, Chris Drogemuller, Sanjeev Khurana, Richard Couper, John Chen, Tom Loudovaris, Tom Kay, Toby Coate
337.2: The Epidemiology of Hereditary Pancreatitis in Australia and its effect on patient of Total Pancreatectomy with Islet Auto-Transplantation (TPIAT).
No full textAbstract - 337.2Denghao Wu, James Zuiani, Christopher Drogemuller, Sunita De Sousa, David Adelson, David J Torpy, Patrick Toby H Coate
Australia and New Zealand Islet and Pancreas Transplant Registry Annual Report 2019: Islet Donations, Islet Isolations, and Islet Transplants.
No full textRegistry ReportAngela C. Webster, James A. Hedley, Patricia F. Anderson, Wayne J. Hawthorne, Toni Radford, Chris Drogemuller, Natasha Rogers, David Goodman, Melissa H. Lee, Thomas Loudovaris, and Patrick J. Kelly, on behalf of the Australian Islet-cell Transplant consortiu
In vitro covalent binding of Nafenopin-CoA to human liver proteins
No full textEndogenous fatty acyl-CoAs play an important role in the acylation of proteins. A number of xenobiotic carboxylic acids are able to mimic fatty acids, forming CoA conjugates and acting as substrates in pathways of lipid metabolism. In this study nafenopin, a substrate for human hepatic fatty acid-CoA ligases, was chosen as a model compound to study xenobiotic acylation of human liver proteins. (3)H-nafenopin (+/- unlabeled palmitate) or (14)C-palmitate (+/- unlabeled nafenopin) were incubated for up to 120 min at 37 degrees C with ATP, CoA, and homogenate protein (1 mg/ml) from four individual human livers. Nafenopin covalently bound to proteins was detectable in all human livers and increased with time. Nafenopin adduct formation was directly proportional to nafenopin-CoA formation (r = 0.985, p 100 and 50-100 kDa, respectively. Protein acylation by palmitate was also demonstrated. Palmitate significantly inhibited nafenopin-CoA formation by 29% but had no effect on nafenopin-CoA-mediated protein acylation. In contrast, nafenopin significantly inhibited protein palmitoylation by palmitoyl-CoA. This is the first study to demonstrate a direct relationship between xenobiotic-CoA formation, acylation of human liver proteins, and inhibition of endogenous palmitoylation. The ability of xenobiotics to acylate tissue proteins may have important biological consequences including perturbation of endogenous regulation of protein localization and function.Sallustio, Benedetta C. ; Nunthasomboon, Sirimas ; Drogemuller, Christopher J. ; Knights, Kathleen M
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