Testing of dogs: PRA1

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Usual turnaround time: 10 business days
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PRA in Miniature Schnauzer

Progressive Retinal Atrophy (PRA) is a collection of inherited degenerative diseases that affects the retina and leads to blindness in the affected dogs of various dog breeds. The PRA-affected dogs exhibit a similar sequence of clinical abnormalities during the disease.  The symptoms start with night blindness which is followed with a slow deterioration of vision and complete blindness under any light conditions. Routine eye examinations reveal ongoing loss of photosensitive cells in the retina due to their degeneration or retina “atrophy” after which this disease is named.

The collective name „PRA“ includes a number of diseases caused by known, but also still unknown and non-characterized genetic  abnormalities – mutations that cause PRA. In Miniature Schnauzers, there have been recognized two forms PRA so far, as stated below:

Type A has been known since 2000, but it is rare in the Schnauzer population - none of the cases that occurred in the last years has been caused by PRA type A mutation.

In 2018, a genetic test was developed based on the discovery of PRA type B. This test has been performed only in one laboratory worldwide and that in OptiGen laboratory (now Mars Veterinary). Considering the recent findings, this test does not seem very convincing. With the highest probability, the mutation in PPT1-gene that was suggested responsible for the type B PRA is not directly associated with the eye defect. It has been reported only 79% penetration rate of this gene variant.  Moreover, the test is not supported sufficiently by clinical studies. Recently, a genetic association between mutation of PPT1-gene and the well-known candidate gene for neuronal ceroid lipofuscinoses (NCL) has been identified. However, the real causality of this type of the disease remains unknown.

In 2020, two genetically distinct types of PRA1 with faster and relatively homogeneous onset of clinical symptoms at the age of 4 years and a  “milder” PRA2 with slower progression and average onset age of around 7 years have been found.  While the defect for PRA2 has been found on chromosome X and further examinations of a larger amount of cases are needed for exact determination of the causal mutation, for PRA1 has been identified only one penetrating gene variant and a new genetic test has been developed.

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PRA1

PRA1 is caused by a mutation of the gene for transcription factor HIVEP3 that is located on chromosome 15.  The effect of the mutation g.1,432,293G>A in HIVEP3 is the gain of the function resulting in overexpression of two retinal target genes, EDN2 and COL9A2, and leading to degeneration of retina photoreceptors.

The inheritance pattern of this mutation is autosomal recessive. It is expressed only in individuals who inherited the mutated allele from both parents (recessive homozygotes). A heterozygote is an individual who inherited the mutated allele only from one parent and does not develop any symptoms and is clinically healthy. However, it can pass the mutated allele to its offspring. If mating two heterozygotes, theoretically 25% of the offspring will be healthy, 50 % will be carriers of the mutated allele and 25 % will inherit the mutated allele from both parents and will be affected by PRA1.

The genetic test for PRA1 has been designed very well. The gene variant of HIVEP3 has full penetration and corresponds with the clinical symptoms and expression studies. The result of this test is intended to help the breeders select a suitable breeding pair to avoid mating that would result in birth of puppies affected by PRA1.

The data show that the Miniature Schnauzer breed is affected by genetically more distinct forms of PRA, the genetic test for PRA1 is not able to explain all cases of this disease. In addition to PRA A, B and 1, it is supposed that there is at least one more form of PRA – X-linked PRA2 and maybe even more.

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References:

Kaukonen, M., Quintero, I.B., Mukarram, A.K., Hytönen, M.K., Holopainen, S., Wickström, K., Kyöstilä, K., Arumilli, M., Jalomäki, S., Daub, C.O., Kere, J., Lohi, H.: A putative silencer variant in a spontaneous canine model of retinitis pigmentosa. PLoS Genet 16:e1008659, 2020.

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Usual turnaround time: 10 business days
1 test price: 56.00 $ without VAT