The gene discovery links severe canine juvenile epilepsy to mitochondrial dysfunction

Credit: University of Helsinki

In a study conducted at the University of Helsinki, researchers found the cause of severe epilepsy that resulted in the death of Parson Russell Terrier puppies at the age of several months. Alteration of the PITRM1 gene can lead to mitochondrial dysfunction, the cellular energy pump. At the same time, amyloid-β accumulation and widespread neurodegeneration associated with Alzheimer’s disease have been identified in puppies ’brains. Changes in the PITRM1 gene in humans also cause serious but slowly progressing brain disease.

It has been observed that some Parson Russell Terrier puppies suddenly have epileptic seizures at the age of 6 to 12 weeks. The disease progressed very rapidly, within hours in the worst cases, to a situation where the seizures were continuous and did not respond to medication.

“All sick dogs either died spontaneously or had to be euthanized. At the tissue level, neuronal necrosis or dead neurons were identified in the brains of dead dogs. that such a buildup will only be found in older dogs, ”says Assistant Professor Marjo Hytönen of the University of Helsinki and the Folkhälsan Research Center.

With the help of several research groups from the University of Helsinki and international partners, samples were collected from all over Europe, which allowed the PITRM1 gene to be precisely identified at the base of the gene defect. This gene encodes an enzyme important for mitochondrial function. Because of their responsibility for cellular energy metabolism, mitochondria are crucial for cell function.

“In the study, we found the presence of the variant in nearly 30,000 dogs from 374 breeds, identifying a genetic defect only in the Parson Russell Terrier. Fortunately, the carrier frequency was low, only 5%. The findings will benefit dogs immediately because a genetic test available based on results helps in identifying carriers and avoiding breeding to create sick puppies. We have previously reported the results of a genetic test for approximately 700 dogs tested in the study, “says Professor Hannes Lohi of the University of Helsinki.

The disease associated with Parson Russell Terriers is a recessive trait, meaning that in order for the disease to develop, the damaged gene must be copied from both parents to offspring. The defect is found only in this specific breed.

“The PITRM1 protein serves as a type of mitochondrial cleanser that breaks down unnecessary pieces of protein and harmful amyloid-β. Accumulation of these substances in mitochondria impairs their function, while neurons are particularly intolerant of insufficient cellular respiration, which explains early neurodegeneration in dogs. amino acids in the enzyme PITRM1 and inhibits its normal functioning, ”says Hytönen.

In humans, changes to the same PITRM1 gene also cause neurodegeneration resulting in cerebellar ataxia with psychiatric and cognitive abnormalities.

“Human disease progresses more slowly, but the clinical picture and mechanisms are similar. Our canine study confirms the importance of PITRM1 for mitochondrial and neuronal function, also strengthening the link between mitochondrial dysfunction and neurodegeneration. So far, few human patients have been diagnosed with the disease. the model is revolutionary in terms of its understanding, ”says Professor Lohi.

A gene associated with serious canine lung disease associated with human lung problems

More information:
Marjo K. Hytönen et al., Deletion within the frame in canine PITRM1 is associated with severe early-onset epilepsy, mitochondrial dysfunction and neurodegeneration, Human genetics (2021). DOI: 10.1007 / s00439-021-02279-y

Provided by the University of Helsinki

Citation: The gene finding links severe canine juvenile epilepsy to mitochondrial dysfunction (2021, April 20) retrieved April 20, 2021 from html

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