WP5 Monogenic diseases

WP5.1 Exocrine Pancreatic Insufficiency (EPI) – Leader : University of Copenhagen

Exocrine pancreatic insufficiency is a degenerative disease of the exocrine pancreas present in several dog breeds. Affected dogs show polyphagia, weight loss and voluminous faeces of light colour due to the lack of pancreatic enzymes. EPI has been found in Eurasians, German Shepherds and Collies with a high prevalence, and in these it has been suggested that a single gene segregating in an autosomal recessive fashion is causative of the disease.

This insufficiency resulting from pancreatic acinar atrophy is unique to the dog. However, exocrine pancreatic insufficiency does occur in the human arising as a secondary condition to underlying diseases such as cystic fibrosis and Shwachmann-Diamond Syndrome. The autoimmune nature of the disease together with the clinical characteristics lends some resemblance to diabetes mellitus (DM). Our goal is to get more insight into the cellular mechanisms causing the cellular destruction of the acinar cells that might provide information of importance for the development of diabetes.

WP5.2 Multiple Epiphyseal Dysplasia (MED) – Leader : Norwegian School of Veterinary Medicine

MED is a disorder of cartilage and bone development primarily affecting the ends of the long bones in the arms and legs (epiphyses). It has been extensively described in humans. The symptoms of this inherited include joint pain that most commonly affects the hips and knees, early-onset arthritis, and a waddling walk. Causal mutations have been described in a number of genes, including COMP, collagen genes and matrilin-3, but the molecular defect remains unknown in at least 50% of familial cases.

We will study a dog pedigree with several cases of MED segregating in an apparent autosomal dominant fashion. The lack of mineralisation and bone formation in all the epiphyses is striking in the young affected puppies compared to their littermates. Our goal is to discover mutations responsible for MED and get insight into the cellular mechanisms involved.

WP5.3 Primary Ciliary Diskinesis – Leader : University of Liège

Inherited ciliopathies are an important group of genetic defects in human and include Bardet-Biedl, Alstrom, Meckel-Gruber and Kartagener syndrome. A number of genes have been found mutated in human ciliopathies but the genetic defects remain unknown for many afflicted families. Analyzing a dog pedigree can lead to the identification of a novel gene that may help such families.

We have a dog pedigree of Old English sheep dog showing a clear autosomal dominant segregation of a form of Primary Ciliary Dyskenesis (PCD), a model for the Kartagener syndrome. The diagnosis has been confirmed by electron microscopic examination of ciliary structures in cell culture. The ciliary proteome is very well characterized which will greatly facilitate positional cloning despite the limited resolution that can be expected from linkage analysis. Moreover having a molecularly characterized dog model of Kartagener syndrome offers perspectives towards gene therapy.

WP5.4 Meningoencephalitis – Leader : University College of Dublin

Neuroinflammatory disorders are complex multifactorial diseases involving microbial agents, environmental factors, autoimmune processes and genetic predispositions. Thirty to fifty % of cases have no confirmed aetiologies and treatment is therefore problematic. Compelling evidence for genetic predisposition to neuro-inflammation is provided by Viliuisk encephalomyelitis, a progressive meningoencephalitis endemic among native Sahka populations of central Siberia (up to 1% of the population affected). Furthermore, up to 20% of patients with multiple sclerosis (MS), an inflammatory autoimmune disorder of the central nervous system, are related by family. The need to unravel the complexities of genetic predispositions and autoimmunity in these disorders is also highlighted by Rasmussen’s Syndrome, a chronic immunologically-triggered encephalitis of children that leads to severe epileptic states and marked debility.

We have identified a unique fatal neuroinflammatory disorder in the Greyhound breed. We characterised the clinical and pathological features and extensively evaluated tissues for suspected microbial agents, but have not identified any. This condition has familial tendencies and develops in greyhounds under 1 year of age, affecting roughly a quarter of pups within a single litter, suggesting a possible recessive inheritance. It is therefore classified as an idiopathic breed-restricted neuroinflammatory disorder. The aim of this study is the identification of gene(s) conferring susceptibility to greyhound meningoencephalitis and this should suggest candidates for involvement in human neuroinflammatory disorders, and novel strategies for detection and treatment of these debilitating diseases.

WP5.5 Copper-associated disease – Leader : University of Utrecht

Two human inherited disorders of copper metabolism have been characterized at the molecular level. Wilson disease and Menkes disease are autosomal recessive inherited copper storage disorders. Wilson Disease is the best characterized copper toxicity disease. Patients with this disorder accumulate copper in various tissues, particularly the liver and brain and small amounts in the cornea and kidney. Menke’s disease is a copper deficiency disorder. Indian childhood cirrhosis, Endemic Tyrolean infantile cirrhosis, and Idiopathic Copper Toxicosis (ICT) are unresolved human copper storage diseases. The proteins known to be involved in copper metabolism have been excluded in these diseases. Therefore, unknown elements in copper metabolism are responsible.

Labrador Retrievers display a world-wide breed predisposition for chronic hepatitis and liver cirrhosis, which is explained by an inherited form of copper storage in the liver. In the Netherlands 10-15% of the population is affected. All known candidate genes in cellular copper trafficking have been excluded. Thus finding the causative gene(s) will elucidate new parts of cellular copper trafficking, orthologs of these genes will be candidates for resolution of human disorders. More generally, new copper-associated elements will provide new routes for intervention to treat copper storage diseases.