The Loss of Vacuolar Protein Sorting 11 (vps11) Causes Retinal Pathogenesis in a Vertebrate Model of Syndromic Albinism
| Autor: | Jennifer L. Thomas, Ryan Thummel, Xixia Luo, Ronald G. Gregg, Aaron D. denDekker, Thomas S. Vihtelic, David R. Hyde, Taylor R. Murphy, Gregory B. Willer |
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| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Hearing Loss
Sensorineural Melanophores Vesicular Transport Proteins Retinal Pigment Epithelium Biology medicine.disease_cause Polymorphism Single Nucleotide Pericardial Effusion Microscopy Electron Transmission Retinal Diseases medicine Animals Fluorescent Antibody Technique Indirect Zebrafish Griscelli syndrome Elejalde syndrome In Situ Hybridization Melanosome Vacuolar protein sorting Genetics Melanins Mutation Melanosomes Models Genetic Reverse Transcriptase Polymerase Chain Reaction Piebaldism Articles Syndrome Zebrafish Proteins medicine.disease biology.organism_classification Oculocutaneous albinism eye diseases Disease Models Animal Albinism Oculocutaneous Hermanski-Pudlak Syndrome Albinism Chediak-Higashi Syndrome Pigmentation Disorders Hepatomegaly |
| Popis: | Oculocutaneous albinism (OCA) is a group of genetically inherited conditions that result in pigmentation defects in the eyes, skin, and hair.1 The types of albinism have been divided into tryosinase-negative (no pigmentation) and those that produce various levels of melanin, termed tyrosinase-positive. In many cases, the data are contradictory in regard to how pigmentation affects photoreceptor viability in albinism. In certain model systems, albinism can exacerbate photoreceptor degeneration2 or cause fewer rod photoreceptors to develop.3 In contrast, other models of albinism exhibit no defects in either photoreceptor formation or viability.4–7 Clinically, the type of albinism is referenced based on the gene that causes the phenotype (if known) and classified as either “syndromic” or “nonsyndromic”.8 Cases of syndromic albinism are associated with other systemic diseases in addition to OCA. These include such syndromes as Chediak-Higashi syndrome (CHS), Griscelli syndrome (GS), Elejalde syndrome (ES), Cross-McKusick-Breen syndrome (CMBS), and Hermansky-Pudlak syndrome (HPS). In some cases, the genetic defects associated with these syndromes are known. For example, there are at least eight genes (HPS1–HPS8) that cause HPS.9 These syndromes all exhibit defects in protein sorting and trafficking in lysosomes and lysosome-related organelles, such as melanosomes.8 Recently, other genes known to play roles in protein trafficking have been linked to syndromic albinism. We describe the characterization of a zebrafish mutant, termed platinum, which contains a mutation in vps11, one of the HOPS/C-Vps class of genes that have been identified based on HPS-like phenotypes in mutant model organisms.10,11 Although the specific pathways that are defective in C-Vps-related HPS are not yet known in vertebrates, these genes have been highly studied in yeast. The C-Vps class encodes four proteins (Vps11, Vps16, Vps18, and Vps33) that physically interact to form a complex on the cytosolic side of the yeast vacuolar membrane.12 Originally, studies focused on the ability of this complex to bind to vacuolar t-SNARE proteins and facilitate tethering and membrane fusion of a transport vesicle from the late-Golgi to the yeast vacuole.12,13 For example, loss of Vps11 in yeast results in an absence of normal vacuoles and the accumulation of intermediate transport vesicles.12,14 However, more recent evidence indicates that Vps11 functions at multiple steps in vesicle-mediated transport, including Golgi-to-endosome anterograde and retrograde transport, and in the endocytic pathway.15 Because the yeast vacuole is analogous to the vertebrate lysosome and melanosome, Vps11 is hypothesized to function in endosome-to-lysosome and endosome-to-melanosome protein trafficking, resulting in both OCA and systemic defects related to lysosomal abnormalities. We showed that, consistent with other cases of syndromic albinism, loss of Vps11 results in both OCA and systemic defects, such as pericardial edema, hepatomegaly, and premature death. Specifically, platinum mutant zebrafish exhibited reduced pigmentation in body melanophore and retinal pigmented epithelium (RPE) due to a disruption in melanosome maturation. Vps11 was not required for photoreceptors or the RPE to form normally; however, platinum zebrafish exhibited subsequent degeneration of the RPE and eventual photoreceptor loss. |
| Databáze: | OpenAIRE |
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