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Progressive retinal atrophy in the Miniature Poodle: an electrophysiologic study

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... Previous studies in canines demonstrate that PRCD-associated disease is heterogeneous, with spatial and temporal differences in disease onset and progression between dog breeds 14,15,41 In these models, it is reported that changes in ERG response correspond to the presence of morphological defects in affected animals 16 . In our Prcd-KO mouse model, retina appear to develop normally, exhibiting proper lamination. ...
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Progressive rod-cone degeneration (PRCD) is a small protein localized to photoreceptor outer segment (OS) disc membranes. Several mutations in PRCD are linked to retinitis pigmentosa (RP) in canines and humans, and while recent studies have established that PRCD is required for high fidelity disc morphogenesis, its precise role in this process remains a mystery. To better understand the part which PRCD plays in disease progression as well as its contribution to photoreceptor OS disc morphogenesis, we generated a Prcd-KO animal model using CRISPR/Cas9. Loss of PRCD from the retina results in reduced visual function accompanied by slow rod photoreceptor degeneration. We observed a significant decrease in rhodopsin levels in Prcd-KO retina prior to photoreceptor degeneration. Furthermore, ultrastructural analysis demonstrates that rod photoreceptors lacking PRCD display disoriented and dysmorphic OS disc membranes. Strikingly, atomic force microscopy reveals that many disc membranes in Prcd-KO rod photoreceptor neurons are irregular, containing fewer rhodopsin molecules and decreased rhodopsin packing density compared to wild-type discs. This study strongly suggests an important role for PRCD in regulation of rhodopsin incorporation and packaging density into disc membranes, a process which, when dysregulated, likely gives rise to the visual defects observed in patients with PRCD-associated RP.
... Progressive rod-cone degeneration disease dates to 1972 in a study of miniature poodles suffering from a set of symptoms classified as progressive retinal atrophy (Aquirre and Rubin 1972). Later, it was termed progressive rodcone degeneration (PRCD) after an in-depth study of the pathogenesis . ...
Chapter
Leber congenital amaurosis (LCA) caused by AIPL1 mutations is one of the most severe forms of inherited retinal degeneration (IRD). The rapid and extensive photoreceptor degeneration challenges the development of potential treatments. Nevertheless, preclinical studies show that both gene augmentation and photoreceptor transplantation can regenerate and restore retinal function in animal models of AIPL1-associated LCA. However, questions regarding long-term benefit and safety still remain as these therapies advance towards clinical application. Ground-breaking advances in stem cell technology and genome editing are examples of alternative therapeutic approaches and address some of the limitations associated with previous methods. The continuous development of these cutting-edge biotechnologies paves the way towards a bright future not only for AIPL1-associated LCA patients but also other forms of IRD.
... Attempts to understand the functional role of PRCD began over four decades ago in a study of mutant dogs, 33 and continued long before their retinal degeneration phenotype was explained by the C2Y mutation in PRCD. 3 Mutant photoreceptors initially develop normally and then die, one after another, as the animal ages. 1,34,35 Photoreceptors of young C2Y dogs have normal ultrastructure 35 and unaffected visual function, as evident from electroretinographic analysis of their light responses. ...
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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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Résumé Les atrophies progressives de la rétine chez le chien sont initialement explorées par un examen clinique approfondi et des examens complémentaires selon nécessité. La description d’un phénotype typique est une condition nécessaire pour exploiter les données fournies par l’étude des généalogies de sujets d’intérêt. Malgré des signes physiques comparables, des évolutions différentes doivent interroger le clinicien, car homogénéité ophtalmoscopique ne signifie pas homogénéité génétique. Jointe à une description fiable, interprétable des signes cliniques, c’est la connaissance aussi détaillée que possible de la physiopathologie de l’affection qui permet d’entreprendre son étude génétique moléculaire dans de bonnes conditions, afin de choisir les meilleures stratégies d’étude (gènes candidats, analyses de liaison, séquençage du génome entier) pour identifier les mutations impliquées. Ces différentes étapes ont pour but de valider et proposer des tests génétiques diagnostiques, dont les résultats doivent toujours être confrontés à ceux de la clinique. Les modalités de ces stratégies sont illustrées à l’aide d’exemples de dégénérescences rétiniennes dans différentes races.
Chapter
PRCD (progressive rod-cone degeneration) is a small ~6 kDa protein with unknown function that specifically resides in photoreceptor discs and interacts with rhodopsin. PRCD's discovery resulted from decades-long study of a canine retinal disease called progressive rod-cone degeneration which is one of the most frequent causes of blindness in dogs characterized by the slow, progressive death of rod photoreceptors followed by cones. A series of genetic studies eventually mapped the disease to a single point mutation in a novel gene which was then named Prcd. Highlighting the importance of this gene, this and several other mutations have been identified in human patients suffering from retinitis pigmentosa. In this review, we highlight what is currently known about PRCD protein, including the etiology and pathology of the retinal disease caused by its mutation, the protein's trafficking, localization, and biochemical characterization.
Article
The influence of AM-715 on the retina was studied by electroretinogram (ERG) and histopathological observation in cats and compared with that of nalidixic acid. 1. AM-715 and nalidixic acid were infused intravenously (0.8 ml/ min) at a dose of 40mg/kg. AM-715 caused no remarkable change in ERG. In contrast, nalidixic acid caused a prolongation of latency followed by an abolition of op and b waves in ERG components. 2. AM-715 was administered orally at doses of 50, 100 and 200mg/kg/ day for 2 weeks. There was no remarkable changes in ERG and histopathological observation of the retina. Nalidixic acid was administered orally at doses of 100-200mg/kg/ day for 2 weeks. In ERG components and histopathological observation of the retina, abnormalities were observed in a majority of cats used. From these results, it was concluded that AM-715 had no retinal toxicity in cat.
Chapter
Since the first German edition of the Pathology of Laboratory Animals, interest in animal pathology has increased (House, 1972) not only to many morbid conditions but also to include formerly neglected species. It is perhaps characteristic that primates were originally entirely omitted. With the establishment of the Regional Primate Research Centers across the United States the study of physiology and pathology of subhuman primates has greatly advanced.
Book
Veterinary Ocular Pathology: A Comparative Review links the clinical features of ocular disease with gross and microscopic pathology to demonstrate the essential features observable during diagnosis. It is designed to be kept next to the microscope as an invaluable guide to accurate diagnosis in ocular pathology. The book presents a wide range of images of the highest quality. A unique and distinctive feature is the juxtaposition of clinical and pathological images while offering detailed enumeration of the diagnostic features. Expert comparative comments by Dr Daniel Albert and contextual information on relative incidence are provided throughout. The authors address spontaneous disease of the eye in all animal species, with a particular emphasis on companion species. In addition, specific, common or interesting conditions of exotic species are included. A convenient, comprehensive and easy-to-use reference for veterinary pathologists, veterinary ophthalmologists, students and comparative vision scientists. The first text devoted to the pathology of spontaneous diseases of the eyes and periocular tissues of domestic animal species Exceptionally high quality illustrations are presented throughout, demonstrating clinical features, gross pathology and histopathology Written by pathologists and clinicians Includes a chapter devoted to the pathology of conditions associated with glaucoma in domestic animals.
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