Elovl4 5-bp-deletion knock-in mice develop progressive photoreceptor degeneration

Vidyullatha Vasireddy, Monica M. Jablonski, Md Nawajes A. Mandal, Dorit Raz-Prag, Xiaofei F. Wang, Lesli Nizol, Alessandro Iannaccone, David C. Musch, Ronald A. Bush, Norman Salem, Paul A. Sieving, Radha Ayyagari

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

Abstract

PURPOSE. To develop and characterize a heterozygous knock-in mouse model carrying the 5-bp deletion in Elovl4 (E_mut+/-) and to study the pathology underlying Stargardt-like macular degeneration (STGD3). METHODS. E_mut+/- mice were generated by targeting a 5-bp deletion (AACTT) in the Elovl4 gene by homologous recombination. E_mut+/- mice of age 2 to 18 months and age-matched wild-type (Wt) littermate control animals were analyzed for the expression of Elovl4 transcript, ELOVL4 protein, photoreceptor-specific genes, and retinal fatty acid composition. Functional retinal changes were evaluated by electroretinography (ERG) and by morphologic and ultrastructural criteria. RESULTS. E_mut+/- mice retinas showed the presence of both Wt and mutant Elovl4 transcripts and proteins. Morphologic evaluation revealed cone photoreceptor ultrastructural abnormalities as early as 2 months of age, accumulation of lipofuscin in retinal pigment epithelium (RPE), and subretinal deposits at later ages. Shortening of rod outer segments (OS) was observed at ∼10 months of age. Both cone and rod changes progressed with age. Unlike rod-specific genes, expression of selected cone specific genes was significantly reduced by 7 months of age. Mixed rod-cone and light-adapted b-waves were higher than normal at both 8 and 15 months. Levels of the fatty acids 20:5 (P = 0.027), 22:5 (P = 0.040) and 24:6 (P = 0.005) were found to be significantly lower in the retinas of E_mut+/- mice than in retinas of control subjects. CONCLUSIONS. E_mut+/- animals display characteristic features associated with Stargardt-like macular degeneration and serve as a model for the study of the mechanism underlying STGD3.

Original languageEnglish (US)
Pages (from-to)4558-4568
Number of pages11
JournalInvestigative Ophthalmology and Visual Science
Volume47
Issue number10
DOIs
StatePublished - Oct 2006
Externally publishedYes

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

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