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PDP1 Deficiency – Pyruvate Dehydrogenase Phosphatase
| Acronym: | PDP1 Deficiency |
| Gene: | PDP1 |
| Mutation: | c.829C>T |
| Inheritance: | Autosomal recessive |
| Sample type: | CHS (Cheek Swab), WBE (Whole Blood EDTA) |
Genetics and characteristics
Pyruvate Dehydrogenase Phosphatase 1 deficiency, or PDP1 Deficiency, is an inherited disorder affecting the Clumber and Sussex Spaniels, and it is a form of exercise intolerance syndrome. The exercise intolerance syndromes are well known to be associated with inborn errors of metabolism affecting glycolysis and fatty acid oxidation. The Clumber and Sussex Spaniels are an old breed, originating from the 18th and early 19th centuries. PDP 1 deficiency was first described in a population of Clumber spaniels during the late 1970s. The disorder is characterized by a lack of pyruvate dehydrogenase phosphatase 1, resulting in the dog’s extreme exhaustion.
Pyruvate dehydrogenase, as well as pyruvate kinase, is just some of the enzymes involved in carbohydrate metabolism. Understanding pathways and regulation of this metabolism are of crucial importance for understanding metabolism disorders such as diabetes and obesity. Pyruvate dehydrogenase (E1) is part of the large protein complex known as pyruvate dehydrogenase complex (PDHc). The complex consists of two other components, E2 and E3. Pyruvate dehydrogenase phosphatase reverses the action of pyruvate dehydrogenase kinase. Pyruvate dehydrogenase kinase catalyzes the phosphorylation of the E1 component, which inhibits the PDHc, while pyruvate dehydrogenase phosphatase catalyzes the dephosphorylation and activates the PDHc. Mutations within the gene encoding result in a metabolic disorder known as Pyruvate Dehydrogenase Phosphatase 1 deficiency. Due to inactive PDHc, resting plasma lactate and pyruvate concentrations are high among affected dogs. Glycolysis increases to compensate for lack of oxidative energy, and less ATP is being produced, resulting in exercise intolerance in dogs.
Affected dogs at first appear normal as their littermates, and first clinical signs appear around 1 year of age. The dog would, after a short exercise, need to slow down and eventually sit. After a few minutes of resting, a dog can continue with the exercise but only for short time. Physical and neurological examinations give results within the normal range. Cardiovascular examination shows mild mitral insufficiency, a disorder of the heart in which the mitral valve does not close properly when the heart pumps out the blood. Death onset varies in age among affected dogs. An affected dog that passed away at three years of age has been reported with hypertrophic cardiomyopathy found on necropsy.
PDP1 Deficiency is caused by a mutation in PDP 1 gene. The disorder is inherited in an autosomal recessive pattern. Dog carrying one copy of the mutated gene is heterozygous and will not show the PDP1 deficiency, or exercise intolerance syndrome symptoms. When mating two carriers (heterozygotes) at conception each cub has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Research conducted on 100 randomly selected Clumber and Sussex Spaniels, revealed a high carrier rate of 20%.
Results Reported As
Test Result |
Interpretation of test result |
CLEAR |
Tested mutation was not detected in animal with „clear“ result. Animal tested as clear has wild-type allele in homozygous state (i.e. two pairs of healthy alleles). It will not develop disease caused by tested mutation.* It will pass only wild-type allele to its offspring. |
CARRIER |
Tested mutation was detected in animal with „carrier“ result. Animal tested as carrier has one wild-type and one mutation allele, it is in heterozygous state. It will not develop disease caused by tested mutation.* It can pass wild-type or mutation allele to its offspring. |
AFFECTED |
Tested mutation was detected in animal with „affected“ result. Animal tested as affected has two copies of mutation alleles affecting the gene. It is likely the animal will experience a genetic disorder due to this mutation.** It will pass only mutation allele to its offspring. |
*Test excludes only tested mutation but not possible unknown mutations or factors that can lead to similar condition/symptoms.
** Potential unknown mutations or multiple other factors can possibly affect the likelihood of experiencing a genetic disorder.
References:
Cameron JM, Maj MC, Levandovskiy V, MacKay N, Shelton GD, Robinson BH. Identification of a canine model of pyruvate dehydrogenase phosphatase 1 deficiency. Mol Genet Metab. 2007 Jan; 90(1):15-23.