rcd4-PRA (Progressive Retina Atrophy / rcd4 type)

Die rcd4-PRA gehört zu den spät einsetzenden PRA-Erkrankungen. 

Erste Symptome zeigen sich typischerweise zwischen 5–12 Jahren, das Mittel liegt bei ~9–10 Jahre. 
Zunächst entsteht eine Nachtblindheit durch Ausfall der Stäbchen-Sehzellen ('rods'); dann fallen fortschreitend auch die für das Tages- und Farbsehen erforderlichen Zapfen-Sehzellen ('cones') aus. Das Einsetzen variiert innerhalb/zwischen Rassen und führt zur vollständigen Erblindung. 

Eine Nachtblindheit zeigt sich oft nur in einer fremden Umgebung. Die Hunde wirken bei wenig Licht ängstlich und sind zögerlich unbekannte, dunkle Räume zu betreten. In diesen stoßen sie an Gegenstände, die sie nicht erkennen können. In der gewohnten Umgebung kompensiert der Hund die fehlenden Augensinneseindrücke durch Geruch und Gehör, so dass die Nachtblindheit lange unerkannt bleiben kann.

Mit Fortschreiten der rcd4-PRA fällt zunehmend auch das Tagessehen aus. Hunde mit Tagblindheit sind dann generell zurückhaltend und ängstlich bei Verlassen der gewohnten Umgebung. 

Die klinische Augenuntersuchung durch den Tierarzt schafft Klarheit über das Ausmaß der PRA. Der DNA-Test kann in der Differentialdiagnostik helfen zu beurteilen, ob die klinisch manifeste PRA durch die PCARE (c.3149_3150insC) Mutation hervorgerufen wird.

rcd4-PRA is one of the late-onset forms of PRA.

The first symptoms typically appear between the ages of 5 and 12, with the average age being around 9 to 10. 
Initially, night blindness develops due to the loss of rod photoreceptor cells; then, the cone photoreceptor cells required for daytime and colour vision also progressively fail. The onset varies within/between breeds and leads to complete blindness.

Night blindness often only becomes apparent in unfamiliar surroundings. Dogs appear fearful in low light and are hesitant to enter unknown, dark rooms. In these rooms, they bump into objects that they cannot see. In familiar surroundings, dogs compensate for their lack of visual input with their sense of smell and hearing, so that night blindness can remain undetected for a long time.

As rcd4-PRA progresses, daytime vision loss is manifesting in addition. Dogs with daytime blindness are then generally cautious and fearful when leaving their familiar surroundings.

A clinical eye examination by a veterinarian provides clarity about the extent of PRA. DNA testing can help in the differential diagnosis to assess whether the clinically manifest PRA is caused by the PCARE (c.3149_3150insC) mutation.

The frameshift mutation leads to a shortened/dysfunctional PCARE protein. PCARE stands for “photoreceptor cilium actin regulator”.  The protein acts as a regulator of F-actin assembly in photoreceptors at the cilium/outer segment junction and is essential for the correct formation of the retina. A loss of function causes impaired renewal of the outer segments of the cilia, leading to progressive degeneration of the rods and cones (rod-cone degeneration).

The mutation resulted in an additional guanidine base (G) in the DNA of the affected gene. When the gene is transcribed, this results in a frameshift of the mRNA (position c.3149-3150insC). As a result, only a defective PCARE protein can be synthesized. If only one of the two genes is defect (heterozygous occurrence), the remaining single functional copy is sufficient to provide sufficient intact PCARE protein and the rcd4-PRA symptoms will not occur.

The DNA test reliably detects whether the gene variant with the c.3149-3150insC mutation is present in the dog being tested.

Indications for the DNA test are:

• Identification of healthy, heterozygous carriers for breeding selection

• Differential diagnosis in late-onset forms of PRA

   

Order DNA test

rcd4-PRA occurs predominantly in dogs of the Gordon Setter and Irish Red Setter breeds. It has also been described as relevant for: Australian Cattle Dog, Irish Red & White Setter, Polish Lowland Sheepdog, Small Munsterlander, Standard Poodle, Miniature Poodle, Tibetan Terrier, Boykin Spaniel, Dachshund, French Bulldog, Golden Retriever, Bolonka Zwetna, Japanese Spitz, Old Danish Pointing Dog, Tatra Shepherd Dog and mixed breeds with representatives of the aforementioned breeds. 

Inheritance: autosomal-rezessiv

The disease only occurs when both copies of the gene are affected by the mutation (rcd4/rcd4). Dogs that have only one copy with the causative mutation (N/rcd4) are clinically healthy carriers.

Genotypes and statements

N/N = homozygous normal - healthy

The dog examined does not have the c.3149_3150insC mutation in either copy of the PCARE gene. The hereditary disease rcd4-PRA will not occur in this dog and will not be inherited. In breeding, the dog can be mated with any other dogs (N/N or N/rcd4) without offspring being affected by rcd4-PRA. If mated to a carrier animal (N/rcd4), on average 50 % of the offspring would be heterozygous carriers, but they would all be healthy due to recessive inheritance.

N/rcd4 = heterozygous for the mutation - healthy

The examined dog has the c.3149_3150insC mutation in one of the two PCARE genes. The other copy is normal at this site. The dog itself will not develop rcd4-PRA, but can pass the mutation on to its offspring with a probability of 50 %. Heterozygous rcd4-PRA carriers may only be bred to animals that are homozygous free (N/N) of the variant.

rcd4/rcd4 = rhomozygous for the mutation - affected

Both copies of the PCARE gene have the c.3149_3150insC mutation. With advancing age affected dogs develop rcd4-PRA related symptoms. Currently, there is no therapy available for genetic disease.

1. Downs, L. M., et al. 2012: "Late-onset progressive retinal atrophy in the Gordon and Irish Setter breeds is associated with a frameshift mutation in C2orf71." Animal Genetics, vol. 44, no. 2, 2012, pp. 169–177. Wiley Online Library.
   https://doi.org/10.1111/j.1365-2052.2012.02379.x 
    
2. Online Mendelian Inheritance in Animals:  Retinal atrophy - Rod-cone dysplasia 4 in Canis lupus familiaris (dog) - OMIA - Online Mendelian Inheritance in Animals ):  OMIA