title: Haploinsufficiency is not the key mechanism of pathogenesis in a heterozygous Elovl4 knockout mouse model of STGD3 disease.
abstract: OBJECTIVE
  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.
authors.affiliation: NIDCD/NEI, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Dorit
authors.initials: D
authors.lastname: Raz-Prag
authors.forename: Radha
authors.initials: R
authors.lastname: Ayyagari
authors.forename: Robert N
authors.initials: RN
authors.lastname: Fariss
authors.forename: Md Nawajes A
authors.initials: MN
authors.lastname: Mandal
authors.forename: Vidyullatha
authors.initials: V
authors.lastname: Vasireddy
authors.forename: Sharon
authors.initials: S
authors.lastname: Majchrzak
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Webber
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Bush
authors.forename: Norman
authors.initials: N
authors.lastname: Salem
authors.forename: Konstantin
authors.initials: K
authors.lastname: Petrukhin
authors.forename: Paul A
authors.initials: PA
authors.lastname: Sieving
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D004596:Electroretinography; D005136:Eye Proteins / Q000235:genetics*; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000502:physiology*; D005838:Genotype; D006239:Haplotypes; D008268:Macular Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D012160:Retina / Q000648:ultrastructure; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012243:Rhodopsin / Q000235:genetics
chemical_list: C498834:Elovl4 protein, mouse; D005136:Eye Proteins; D005227:Fatty Acids; D008565:Membrane Proteins; D012333:RNA, Messenger; D012243:Rhodopsin