The loss of vacuolar protein sorting 11 (vps11) causes retinal pathogenesis in a vertebrate model of syndromic albinism

Invest Ophthalmol Vis Sci. 2011 May 11;52(6):3119-28. doi: 10.1167/iovs.10-5957.

Abstract

Purpose: To establish the zebrafish platinum mutant as a model for studying vision defects caused by syndromic albinism diseases such as Chediak-Higashi syndrome, Griscelli syndrome, and Hermansky-Pudlak syndrome (HPS).

Methods: Bulked segregant analysis and candidate gene sequencing revealed that the zebrafish platinum mutation is a single-nucleotide insertion in the vps11 (vacuolar protein sorting 11) gene. Expression of vps11 was determined by RT-PCR and in situ hybridization. Mutants were analyzed for pigmentation defects and retinal disease by histology, immunohistochemistry, and transmission electron microscopy.

Results: Phenocopy and rescue experiments determined that a loss of Vps11 results in the platinum phenotype. Expression of vps11 appeared ubiquitous during zebrafish development, with stronger expression in the developing retina and retinal pigmented epithelium (RPE). Zebrafish platinum mutants exhibited reduced pigmentation in the body and RPE; however, melanophore development, migration, and dispersion occurred normally. RPE, photoreceptors, and inner retinal neurons formed normally in zebrafish platinum mutants. However, a gradual loss of RPE, an absence of mature melanosomes, and the subsequent degradation of RPE/photoreceptor interdigitation was observed.

Conclusions: These data show that Vps11 is not necessary for normal retinal development or initiation of melanin biosynthesis, but is essential for melanosome maturation and healthy maintenance of the RPE and photoreceptors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Albinism, Oculocutaneous / genetics*
  • Albinism, Oculocutaneous / metabolism
  • Albinism, Oculocutaneous / pathology
  • Animals
  • Chediak-Higashi Syndrome / genetics
  • Disease Models, Animal*
  • Fluorescent Antibody Technique, Indirect
  • Hearing Loss, Sensorineural / genetics
  • Hepatomegaly / genetics
  • Hermanski-Pudlak Syndrome / genetics
  • In Situ Hybridization
  • Melanins / biosynthesis
  • Melanophores / metabolism
  • Melanosomes / genetics
  • Melanosomes / metabolism
  • Microscopy, Electron, Transmission
  • Models, Genetic
  • Mutation
  • Pericardial Effusion / genetics
  • Piebaldism / genetics
  • Pigmentation Disorders / genetics
  • Polymorphism, Single Nucleotide*
  • Retinal Diseases / genetics*
  • Retinal Diseases / metabolism
  • Retinal Diseases / pathology
  • Retinal Pigment Epithelium / metabolism
  • Retinal Pigment Epithelium / pathology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Syndrome
  • Vesicular Transport Proteins / physiology*
  • Zebrafish / embryology
  • Zebrafish / genetics*
  • Zebrafish Proteins / physiology*

Substances

  • Melanins
  • Vesicular Transport Proteins
  • Zebrafish Proteins
  • vacuolar protein sorting 11, zebrafish

Supplementary concepts

  • Griscelli syndrome type 1