Leber congenital amaurosis linked to AIPL1: a mouse model reveals destabilization of cGMP phosphodiesterase.
Leber congenital amaurosis (LCA4) has been linked to mutations in the photoreceptor-specific gene Aryl hydrocarbon interacting protein like 1 (Aipl1). To investigate the essential role of AIPL1 in retina, we generated a mouse model of LCA by inactivating the Aipl1 gene. In Aipl1(-/-) retinas, the outer nuclear layer develops normally, but rods and cones then quickly degenerate. Aipl1(-/-) mice have highly disorganized, short, fragmented photoreceptor outer segments and lack both rod and cone electroretinogram responses. Recent biochemical evidence indicates that AIPL1 can enhance protein farnesylation. Our study reveals that rod cGMP phosphodiesterase, a farnesylated protein, is absent and cGMP levels are elevated in AIPL1(-/-) retinas before the onset of degeneration. Our findings demonstrate that AIPL1 enhances the stability of phosphodiesterase and is essential for photoreceptor viability.
Ramamurthy
Visvanathan
V
Department of Biochemistry, Box 357350, University of Washington, Seattle, WA 98195, USA.
Niemi
Gregory A
GA
Reh
Thomas A
TA
Hurley
James B
JB
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000235:genetics*; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D029242:Optic Atrophy, Hereditary, Leber / Q000235:genetics*; D012160:Retina / Q000473:pathology / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; C498604:Aipl1 protein, mouse; D002352:Carrier Proteins; D015106:3',5'-Cyclic-GMP Phosphodiesterases