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Progressive Retinal Atrophy 3              PRA3           Code 318

For breeds: Tibetan Terrier & Tibetan Spaniel 

Symptoms/Disease description
Late onset Progressive Retinal Atrophy (PRA) is one of the relatively few health concerns for Tibetan Spaniels and Tibetan Terriers, two breeds that share both their ancient origins as well as a reputation of being long lived dogs. Most PRA cases in these two breeds are diagnosed relatively late, typically at approximately 5 years of age or older, but the range of age-at-diagnosis is broad and the variation in disease severity is significant.

PRA3 mutation
Joint efforts of Dr. Mellersh's research team at the Animal Health Trust and devoted breeders led to the identification of a new mutation associated with late onset PRA--first in Tibetan Spaniels and subsequently in Tibetan Terriers (1). An insertion of a SINE element in the FAM161A gene was found to segregate with the disease in a manner that suggests a recessive mode of inheritance. The form of PRA associated with this mutation was named PRA3 to distinguish it from other genetically distinct forms of PRA that are caused by different mutations.

Correlation of PRA3 test result to clinical disease
Of the 24 Tibetan Spaniels included in the research project that tested as homozygous for (i.e. having two copies of) the PRA3 mutation, 22 (92%) showed clinical signs of PRA. The remaining 2 dogs lacked clinical eye disease descriptions. None of the 100 dogs that were known to be clear of PRA signs ("controls") were shown to be homozygous for the PRA3 mutation. This points to a strong correlation between the presence of two copies of the PRA3 mutation and the development of PRA signs.

The situation is complicated by the PRA-affected Tibetan Spaniels and Terriers that are not homozygous for the mutation. Although a majority--22 out of 35 (63%) of all PRA cases in Tibetan Spaniels, and a third (4 out of 12) of the PRA cases in Tibetan Terriers were homozygous for the PRA3 mutation, there remain PRA cases that are not homozygous for this mutation. This discordance suggests that the PRA3 mutation represents a major susceptibility locus for late onset PRA, but other genetic and/or environmental factors contribute to the development of PRA in these breeds. At least one other known mutation, rcd4-PRA, contributes to the development of late onset PRA in the Tibetan Terrier. Identifying other mutation(s) that cause PRA in these breeds is part of ongoing research efforts.

DNA test for PRA3
OptiGen's DNA based test for PRA3 is designed to detect the presence of 0, 1 or 2 copies of the mutation in the FAM161A gene and to clearly distinguish three genotypes:

NORMAL/CLEAR: these dogs have two normal copies of the FAM161A gene. Clear dogs will not develop PRA as a result of the PRA3 mutation, although there is a possibility that they might develop PRA due to other mutations not detected by this test.

CARRIER: these dogs have one copy of the mutation and one normal copy of the FAM161A gene. These dogs will not develop PRA themselves as a result of the FAM161A mutation but they will pass it on to approximately 50% of their offspring. Carriers might develop PRA due to other mutations not detected by this test.

HOMOZYGOUS AFFECTED: these dogs have two copies of the PRA3 mutation and will almost certainly develop PRA3.

Testing/Breeding Recommendations:
It is recommended to test dogs prior to breeding to avoid producing PRA3-affected progeny. Please, refer to the chart below for a detailed explanation of the expected results for various breeding strategies.

Expected results for breeding strategies using the
mutation test for PRA3

Parent 1

Status

Parent 2 Status

Normal/Clear

Carrier

Affected

Normal/Clear

All = Normal/Clear

1/2 = Normal/Clear

1/2 = Carrier

All = Carrier

Carrier

1/2 = Normal/Clear

1/2 = Carrier

1/4 = Normal/Clear

1/2 = Carrier

1/4 = Affected

1/2 = Carrier

1/2 = Affected

Affected

All = Carrier

1/2 = Carrier

1/2 = Affected

All = Affected

Note that dogs with a Normal/Clear or Carrier genotype do not show symptoms of PRA3. Matings should aim to produce litters with the gray highlighted outcome, i.e. no PRA3-attected genotypes.

For the Tibetan Terrier breed it is advisable to use the PRA3 test in combination with the rcd4-PRA test to get a more comprehensive evaluation of mutations causing late onset PRA. Both tests are available at OptiGen and receive "combo discount" pricing when ordered at the same time.

Reference:

  1. Downs LM and Mellersh CS. 2014. An intronic SINE insertion in FAM161A that causes exon-skipping is associated with progressive retinal atrophy in Tibetan Spaniels and Tibetan Terriers. PLoS ONE, V. 9, e93990.

 

 

 


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