E. Defects in phototransduction pathway lead to human retinal diseases

The most common diseases of the retina include retinitis pigmentosa, macular degeneration, Leber's congenital amaurosis, various photoreceptor dystrophies, and congenital stationary night blindness. These diseases primarily affect the rod and cone photoreceptor cells of the retina. Retinal disease can result from both genetic and non-genetic/environmental factors.

Genetic defects in genes involved with the visual transduction pathway account for many retinal diseases. Defining the molecular basis of inherited retinal diseases is a daunting challenge. This is partly due to the fact that different mutations in single gene can cause different retinal diseases. Furthermore, in some cases mutations in different genes result in the same disease. For example, retinitis pigmentosa can result from defects in any of the following core components of the visual transduction pathway: rhodopsin, transducin, PDE6 α and β catalytic subunits, and the cGMP-gated ion channel protein.

For a current list of mutations in photoreceptor genes leading to retinal disease, consult the Retina Information Network (Retnet), listed in the Links section.

A homozygous loss-of-function mutation in the β catalytic subunit of PDE6 is the underlying cause of retinal degeneration in the rd mouse (Bowes et al., 1990). Nonsense and missense mutations in the α and β subunits of PDE6 have also been associated with autosomal recessive retinitis pigmentosa in humans (McLaughlin et al., 1993; McLaughlin et al., 1995). The reduced activity of PDE6 allows accumulation of high levels in cGMP in rod photoreceptor cells, whichis apparently toxic to photoreceptor cells.

In another instance, a missense mutation in the GAF domain of the PDE6 β subunit leads to autosomal dominant congenital stationary night blindness (Gal et al., 1994b; Gal et al., 1994a). It is possible that impaired regulation of PDE6 activation and inactivation may result from this mutation.

Reference List

Bowes,C., Li,T., Danciger,M., Baxter,L.C., Applebury,M.L., and Farber,D.B. (1990). Retinal degeneration in the rd mouse is caused by a defect in the beta subunit of rod cGMP-phosphodiesterase. Nature 347, 677-680.

Gal,A., Orth,U., Baehr,W., Schwinger,E., and Rosenberg,T. (1994a). Heterozygous missense mutation in the rod cGMP phosphodiesterase β-subunit gene in autosomal dominant stationary night blindness. Nature Genet. 7, 64-68.

Gal,A., Xu,S., Piczenik,Y., Eiberg,H., Duvigneau,C., Schwinger,E., and Rosenberg,T. (1994b). Gene for autosomal dominant congenital stationary night blindness maps to the same region as the gene for the β-subunit of the rod photoreceptor cGMP phosphodiesterase (PDEB) in chromosome 4p16.3. Hum. Mol. Genet. 3, 323-325.

McLaughlin,M.E., Ehrhart,T.L., Berson,E.L., and Dryja,T.P. (1995). Mutation spectrum of the gene encoding the β subunit of rod phosphodiesterase among patients with autosomal recessive retinitis pigmentosa. Proc. Natl. Acad. Sci. U. S. A. 92, 3249-3253.

McLaughlin,M.E., Sandberg,M.A., Berson,E.L., and Dryja,T.P. (1993). Recessive mutations in the gene encoding the β-subunit of rod phosphodiesterase in patients with retinitis pigmentosa. Nature Genet. 4, 130-134.