Elovl4 5-bp-deletion knock-in mice develop progressive photoreceptor degeneration.
OBJECTIVE
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 approximately 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.
Vasireddy
Vidyullatha
V
Ophthalmology and Visual Sciences, W. K. Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan 48105, USA.
Jablonski
Monica M
MM
Mandal
Md Nawajes A
MN
Raz-Prag
Dorit
D
Wang
Xiaofei F
XF
Nizol
Lesli
L
Iannaccone
Alessandro
A
Musch
David C
DC
Bush
Ronald A
RA
Salem
Norman
N
Sieving
Paul A
PA
Ayyagari
Radha
R
D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002849:Chromatography, Gas; D004195:Disease Models, Animal; D018450:Disease Progression; D004596:Electroretinography; D005136:Eye Proteins / Q000235:genetics*; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism / Q000473:pathology*; D016133:Polymerase Chain Reaction; D012162:Retinal Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017384:Sequence Deletion
C498834:Elovl4 protein, mouse; D005136:Eye Proteins; D005227:Fatty Acids; D008565:Membrane Proteins