RP59 Retinal Degeneration: New Mouse Models Reveal Mechanisms
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novel Mouse Models Advance Understanding of Rare Retinal Degeneration,RP59
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What is Retinitis Pigmentosa and RP59?
Retinitis pigmentosa (RP) is a group of rare,inherited diseases that cause slow,progressive degeneration of the retina,ultimately leading to blindness. This degeneration is caused by mutations in nearly 100 different genes. One of these genes is DHDDS, and mutations in this gene specifically cause a form of RP known as RP59.
RP59 is a recessive genetic disease, meaning an individual must inherit a mutated copy of the DHDDS gene from both parents to develop the condition. The DHDDS gene encodes an enzyme involved in glycosylation, a crucial process for protein function in higher organisms.
Developing Mouse models to Study RP59
To better understand the mechanisms behind RP59 and explore potential treatments, researchers at the University of Alabama at Birmingham (UAB), led by Steven Pittler, Ph.D., have created novel mouse models carrying mutations in the mouse DHDDS gene.
The team initially developed a mouse model with a K42E/K42E mutation, reported in 2020 and 2023. This genetic notation indicates that both copies of the mouse DHDDS gene have a mutation at amino acid position 42,replacing the lysine (K) with glutamic acid (E). This specific mutation is also found in human RP59 patients.
building on this work, the UAB researchers have now created and studied two additional mouse models: a T206A/K42E mutant and a T206A/T206A mutant. The T206A designation signifies that the threonine (T) amino acid at position 206 of the DHDDS protein has been replaced by alanine (A).
Key findings: Retinal Changes in Mouse Models
At 12 months of age, both the T206A/K42E and T206A/T206A mice exhibited changes in retinal structure and function that closely mirrored those observed in the K42E/K42E mouse model. These findings were published in the journal Disease Models & Mechanisms.
Understanding the Disease Mechanism
“Because T206A/K42E is one of the prevalent variants reported in RP59 patients, these findings will bring us closer to understanding the mechanism underlying this disease. These results indicate that the DHDDS T206A allele, like the K42E allele, causes retinal disease, problably through a common pathobiological mechanism, and we propose that the physiological basis of retinal dysfunction in RP59 involves defective photoreceptor to bipolar cell synaptic transmission with concomitant bipolar/amacrine cell degeneration.”
Steven Pittler, Ph.D., professor in the UAB Department of Optometry and Vision Science