Another Gene Mutation in Leber’s Congenital Amaurosis: NPHP5


Researchers described the discovery of yet another gene associated with Leber’s congenital amaurosis (LCA). The gene (NPHP5) was originally detected in one LCA patient and subsequently found in 11 of 225 patients examined. The gene appears to be involved in maintaining cilia at the junction of the inner and outer segments of photoreceptors. Healthy cilia facilitate the transport of compounds that maintain normal photoreceptor cell physiology. Otherwise, photoreceptor function is disrupted and retinal degeneration occurs.


The same NPHP5 mutation has been detected in patients with a rare heterogenetic autosomal recessive disorder called Senior-Loken syndrome (SLSN), which is characterized by defective cilia in kidney tubules, causing kidney failure, and retinal degeneration. When the researchers looked closely at the overall health of the 11 LCA patients, they found four with SLSN and suggest that the absence or presence of kidney disease in these patients is related to yet unidentified modifier alleles.


(R.K. Koenekoop)

Oral Therapy for LCA Shows Early Positive Results

Genes that cause Leber’s congenital amaurosis do so by affecting ciliary proteins (see above), retinoid cycle proteins, or other photoreceptor and retinal proteins. Without normal protein production and function, retinal cells undergo a process of cell death called apoptosis. Researchers are evaluating different test compounds hoping to prevent apoptosis. One that was recently reported uses an oral medication to replace a missing protein called lecithin:retinol acyltransferase in LCA patients with a genetic mutation in the LRAT gene. The protein is an enzyme that allows for the production of 11-cis retinal in retinal pigment epithelial cells. This vitamin A derivative is a key to normal function of rod cells.


In the study—a Phase 1b clinical proof-of-concept study—three patients (ages 10, 12, and 38) received a synthetic retinoid replacement for 11-cis-retinal. After just a week of treatment all three had improved visual acuity, visual field measurements, and/or retinal sensitivity. Interestingly, they experienced gains in vision beyond the treatment period. The sponsor of this research and developer of the compound, QLT Inc, plans additional clinical trials to evaluate the safety and efficacy of the compound.

(R.K. Koenekoop)

Molecular Basis of Leber’s Congenital Amaurosis Associated with RD3 and Guanylate Cyclases


Mutations in the RD3 gene are involved in a form of Leber’s congenital amaurosis (LCA12). The RD3 protein normally interacts with other proteins and is essential for retinal structure and function. Continuing to seek molecular explanations for LCA, scientists reported on their work localizing RD3 protein in normal mice and in mice with early onset retinal degeneration (rd3 mice). They found the protein in normal animals only, in rod and cone outer segments. In rd3 mice they also found a deficiency of two enzymes (guanylate cyclases, GC1 and GC2) that normally interact with RD3. Guanylate cyclases are responsible for the production of cyclic guanosine monophosphate (cGMP), which plays a critical role in converting light into electrical signals in photoreceptor and retinal ganglion cells.


(S. Azadi, L.L. Molday, R.S. Molday)