Real-time PCR genotyping assay for canine progressive rod-cone degeneration and mutant allele frequency in Toy Poodles, Chihuahuas and Miniature Dachshunds in Japan

Kohyama, Moeko; Tada, Naomi; Mitsui, Hiromi; Tomioka, Hitomi; Tsutsui, Toshihiko; Yabuki, Akira; Rahman, Mohammad Mahbubur; Kushida, Kazuya; Mizukami, Keijiro; Yamato, Osamu

doi:10.1292/jvms.15-0279

Cited by 13 publications

(14 citation statements)

References 9 publications

(12 reference statements)

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“…photoreceptor | PRCD | retinal degeneration | microglia P rogressive rod-cone degeneration (PRCD) is a canine retinal disease and the most common known cause of blindness in dogs, affecting over 35 breeds with allelic frequency as high as 45% (1)(2)(3)(4)(5). The disease is caused by a single C2Y mutation in the Prcd gene, which is expressed specifically in the retina (6,7).…”

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PRCD is essential for high-fidelity photoreceptor disc formation

Spencer

Ding

Lewis

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Progressive rod-cone degeneration (PRCD) is a small protein residing in the light-sensitive disc membranes of the photoreceptor outer segment. Until now, the function of PRCD has remained enigmatic despite multiple demonstrations that its mutations cause blindness in humans and dogs. Here, we generated a PRCD knockout mouse and observed a striking defect in disc morphogenesis, whereby newly forming discs do not properly flatten. This leads to the budding of disc-derived vesicles, specifically at the site of disc morphogenesis, which accumulate in the interphotoreceptor matrix. The defect in nascent disc flattening only minimally alters the photoreceptor outer segment architecture beyond the site of new disc formation and does not affect the abundance of outer segment proteins and the photoreceptor’s ability to generate responses to light. Interestingly, the retinal pigment epithelium, responsible for normal phagocytosis of shed outer segment material, lacks the capacity to clear the disc-derived vesicles. This deficiency is partially compensated by a unique pattern of microglial migration to the site of disc formation where they actively phagocytize vesicles. However, the microglial response is insufficient to prevent vesicular accumulation and photoreceptors of PRCD knockout mice undergo slow, progressive degeneration. Taken together, these data show that the function of PRCD is to keep evaginating membranes of new discs tightly apposed to each other, which is essential for the high fidelity of photoreceptor disc morphogenesis and photoreceptor survival.

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mentioning

confidence: 99%

PRCD is essential for high-fidelity photoreceptor disc formation

Spencer

Ding

Lewis

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…However, the frequency of this mutant allele in each dog breed is almost unknown. In Japan, the allelic frequency in Toy poodle and Chihuahua was found to be 0.088 and 0.019, respectively [ 4 ].…”

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confidence: 99%

“…The allelic frequency of c.5G>A in domestic population is 0.114 and incidence of PRCD is predicted to be 1.3%. The allelic frequency in Toy poodle and Chihuahua in Japan has been reported to be 0.088 and 0.019, respectively [ 4 ], indicating that PRCD incidence is 0.77 and 0.036%, respectively. Incidence of PRCD in domestic Labrador Retrievers is higher than that in Toy poodle or Chihuahua, suggesting that c.5G>A mutation is spreading widely in this population before people realize this disease.…”

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Different allelic frequency of progressive rod-cone degeneration in two populations of Labrador Retrievers in Japan

Takanosu

2017

The Journal of Veterinary Medical Science

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Progressive rod-cone degeneration (PRCD) is an autosomal recessive disease caused by c.5G>A mutation of the PRCD exon 2. This mutation has been identified in various breeds, including Labrador Retriever. The present study aimed to examine the allelic frequency of PRCD in Labrador Retrievers in Japan. A domestic and a guide dog population were genotyped for PRCD using polymerase chain reaction-restriction fragment length polymorphism. The allelic frequency of c.5G>A in domestic and guide dog populations (0.114 and 0.026, respectively) differed significantly. The allele with c.5G>A mutation appeared to spread widely in the domestic population as compared to that in the guide dog population. This might be the result of mating control for PRCD in the guide dog population.

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“…1–3 The same mutation was identified in 35 different dog breeds and is among the most frequent causes of inherited dog blindness. 4–6 More recently, PRCD mutations, including C2Y, have been identified in human patients suffering from retinitis pigmentosa. 3, 7–11 As evident from its name, the disease affects both rod and cone photoreceptors.…”

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confidence: 99%

Progressive Rod–Cone Degeneration (PRCD) Protein Requires N-Terminal S-Acylation and Rhodopsin Binding for Photoreceptor Outer Segment Localization and Maintaining Intracellular Stability

et al. 2016

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The light-sensing outer segments of photoreceptor cells harbor hundreds of flattened membranous discs containing the visual pigment, rhodopsin, and all the proteins necessary for visual signal transduction. PRCD (Progressive Rod-Cone Degeneration) is one of a few proteins residing specifically in photoreceptor discs, and the only one with completely unknown function. The importance of PRCD is highlighted by its mutations causing photoreceptor degeneration and blindness in canine and human patients. Here we report that PRCD is S-acylated at its N-terminal cysteine and anchored to the cytosolic surface of disc membranes. We also showed that mutating the S-acylated cysteine to tyrosine, a common cause of blindness in dogs and found in affected human families, causes PRCD to be completely mislocalized from the photoreceptor outer segment. We next undertook a proteomic search for PRCD interacting partners in disc membranes and found that it binds rhodopsin. This interaction was confirmed by reciprocal precipitation and co-chromatography experiments. We further demonstrated this interaction to be critically important for supporting the intracellular stability of PRCD, as the knockout of rhodopsin caused a drastic reduction in the photoreceptor content of PRCD. These data reveal the cause of photoreceptor disease in PRCD mutant dogs, and implicate rhodopsin to be involved in PRCD’s unknown, yet essential function in photoreceptors.

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Real-time PCR genotyping assay for canine progressive rod-cone degeneration and mutant allele frequency in Toy Poodles, Chihuahuas and Miniature Dachshunds in Japan

Cited by 13 publications

References 9 publications

PRCD is essential for high-fidelity photoreceptor disc formation

PRCD is essential for high-fidelity photoreceptor disc formation

Different allelic frequency of progressive rod-cone degeneration in two populations of Labrador Retrievers in Japan

Progressive Rod–Cone Degeneration (PRCD) Protein Requires N-Terminal S-Acylation and Rhodopsin Binding for Photoreceptor Outer Segment Localization and Maintaining Intracellular Stability

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