Haploinsufficiency is not the key mechanism of pathogenesis in a heterozygous Elovl4 knockout mouse model of STGD3 disease

Invest Ophthalmol Vis Sci. 2006 Aug;47(8):3603-11. doi: 10.1167/iovs.05-1527.


Purpose: Autosomal dominant Stargardt-like (STGD3) disease results from mutations in the ELOVL4 gene (elongation of very-long-chain fatty acids). This study was undertaken to characterize a mouse model with a targeted deletion of Elovl4 and to explore the role of this gene in retinal/macular degeneration.

Methods: A construct targeted to exon 2 of the Elovl4 gene was used to suppress expression of the gene. Elovl4 homozygous pups were nonviable and were not available for study. Hence, the analysis was performed on heterozygous Elovl4(+/-) mice 16 to 22 month of age and littermate wild-type (WT) control mice of the same age. Characterization included examining gene message and protein levels, electroretinogram (ERG), retinal morphology and ultrastructure, and plasma and retinal fatty acid composition.

Results: Although the level of Elovl4 mRNA was reduced in Elovl4(+/-) retinas, only minimal morphologic abnormalities were found, and the retinal (ERG) function was essentially normal in Elovl4(+/-) retinas compared with the WT control retinas. Systemic fatty acid profiles of Elovl4(+/-) mice were unremarkable, although the concentration of several fatty acids was significantly lower in Elovl4(+/-) retinas, particularly the monounsaturated fatty acids.

Conclusions: The detailed characterization of this animal model provides the first in vivo evidence that Elovl4 haploinsufficiency is not the underlying key disease mechanism in STGD3. The results are consistent with a dominant negative mechanism for the deletion mutation. The Elovl4 knockout mouse is one of three complementary animal models that will help elucidate the disease mechanism.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Blotting, Western
  • Disease Models, Animal*
  • Electroretinography
  • Eye Proteins / genetics*
  • Fatty Acids / metabolism
  • Female
  • Gene Deletion
  • Gene Expression Regulation / physiology*
  • Genotype
  • Haplotypes
  • Macular Degeneration / genetics*
  • Macular Degeneration / metabolism
  • Macular Degeneration / pathology
  • Male
  • Membrane Proteins / deficiency
  • Membrane Proteins / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • RNA, Messenger / metabolism
  • Retina / ultrastructure
  • Reverse Transcriptase Polymerase Chain Reaction
  • Rhodopsin / genetics


  • Elovl4 protein, mouse
  • Eye Proteins
  • Fatty Acids
  • Membrane Proteins
  • RNA, Messenger
  • Rhodopsin