AIPL1, the protein that is defective in Leber congenital amaurosis, is essential for the biosynthesis of retinal rod cGMP phosphodiesterase

doi:10.1073/pnas.0405160101

AIPL1, the protein that is defective in Leber congenital amaurosis, is essential for the biosynthesis of retinal rod cGMP phosphodiesterase

^*Berman–Gund Laboratory for the Study of Retinal Degenerations and ^†Howe Laboratory, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114; and ^‡Department of Physiological Science and ^§Jules Stein Eye Institute, University of California, Los Angeles, CA 90095

Edited by Jeremy Nathans, Johns Hopkins University School of Medicine, Baltimore, MD, and approved August 16, 2004 (received for review July 16, 2004)

Abstract

Aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1) is a member of the FK-506-binding protein family expressed specifically in retinal photoreceptors. Mutations in AIPL1 cause Leber congenital amaurosis, a severe early-onset retinopathy that leads to visual impairment in infants. Here we show that knockdown of AIPL1 expression in mice also produces a retinopathy but over a more extended time course. Before any noticeable pathology, there was a reduction in the level of rod cGMP phosphodiesterase (PDE) proportional to the decrease in AIPL1 expression, whereas other photoreceptor proteins were unaffected. Consistent with less PDE in rods, flash responses had a delayed onset, a reduced gain, and a slower recovery of flash responses. We suggest that AIPL1 is a specialized chaperone required for rod PDE biosynthesis. Thus loss of AIPL1 would result in a condition that phenocopies retinal degenerations in the rd mouse and in a subgroup of human patients.

Footnotes

↵ ¶ To whom correspondence should be addressed. E-mail: tli{at}meei.harvard.edu.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: AIP, aryl hydrocarbon receptor-interacting protein; AIPL1, AIP-like 1; FKBP, FK-506-binding protein; LCA, Leber congenital amaurosis; PDE, cGMP phosphodiesterase; ERG, electroretinogram.