Leber congenital amaurosis linked to AIPL1: A mouse model reveals destabilization of cGMP phosphodiesterase

doi:10.1073/pnas.0404197101

Leber congenital amaurosis linked to AIPL1: A mouse model reveals destabilization of cGMP phosphodiesterase

^*Department of Biochemistry, Box 357350, University of Washington, Seattle, WA 98195; and ^‡Department of Biological Structure, Box 357420, University of Washington, Seattle, WA 98195

Edited by Jeremy Nathans, The Johns Hopkins University School of Medicine, Baltimore, MD, and approved August 4, 2004 (received for review June 11, 2004)

Abstract

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.

Footnotes

↵ † To whom correspondence may be addressed. E-mail: visu{at}u.washington.edu or jbhhh{at}u.washington.edu.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: LCA, Leber congenital amaurosis; PDE, phosphodiesterase; Rho, rhodopsin; RK, Rho kinase; Pn, postnatal day n;Tγ, transducin γ; GC-E, guanylyl cyclase; ERG, electroretinogram.