Mouse Models of Retinitis Pigmentosa Mirror the Human Disease RP59 Pathobiology

Retinitis pigmentosa (RP) is a hereditary eye condition characterized by progressive retinal degeneration that ultimately leads to vision loss. This condition involves mutations in nearly 100 different genes, making it a complex and genetically diverse disease. Among these genes, one encodes the enzyme DHDDS, which plays a crucial role in protein glycosylation. Mutations in DHDDS cause a specific form of RP called RP59, which is inherited in a recessive pattern—meaning both copies of the gene must contain mutations for the disease to manifest.

To deepen the understanding of RP59 and to explore potential treatments, researchers at the University of Alabama at Birmingham, led by Dr. Steven Pittler, have developed novel mouse models carrying mutations in the mouse equivalent of the DHDDS gene. The initial model, identified as the K42E/K42E mutant, features mutations at amino acid position 42, where lysine (K) is replaced by glutamic acid (E). This particular mutation mirrors a common variant found in human RP59 patients.

Building on this, the team has now established two additional mouse models featuring mutations at a different site: T206A/K42E and T206A/T206A. The T206A mutation involves replacing threonine (T) at amino acid position 206 with alanine (A). At 12 months of age, both the T206A/K42E and T206A/T206A mice demonstrated retinal structural and functional changes similar to the earlier K42E/K42E model. These alterations include a reduction in inner nuclear layer thickness, decreased densities of bipolar and amacrine cells, and altered electrical responses of the retina, assessed through electroretinography. Notably, while the light-sensitive photoreceptor cells (a-wave) remained relatively intact, inner retinal layers (b-wave) showed significant decline, indicating inner retinal dysfunction.

These findings suggest that the T206A mutation causes retinal degeneration through mechanisms similar to the K42E mutation. Importantly, the T206A allele, although not yet observed in humans, appears to be pathogenic. This supports the idea that defective synaptic transmission between photoreceptors and bipolar cells—a critical component of visual signal processing—plays a central role in RP59 pathogenesis. Since bipolar cells transmit visual information from the retina to the optic nerve, their degeneration contributes to vision loss.

Dr. Pittler emphasizes that understanding these mutations enhances our knowledge of how genetic variants lead to retinal degeneration, potentially guiding the development of targeted therapies. The mouse models serve as vital tools for future research aimed at halting or reversing retinal damage associated with RP59.

Source: https://medicalxpress.com/news/2025-08-retinitis-pigmentosa-mouse-pathobiology-human.html