New Mouse Models Reveal Mechanisms Of Rp59 Retinal Degeneration

Retinitis pigmentosa retinal degeneration is caused by a family of hereditary mutations successful astir 100 genes that slow lead to blindness complete years aliases decades.

One of those genes encodes nan enzyme DHDDS, portion of nan pathway that glycosylates proteins successful higher cells. Retinitis pigmentosa from DHDDS mutations is called RP59. This is simply a recessive familial disease, meaning mutations must beryllium coming connected some copies of nan DHDDS cistron to origin disease.

To amended understand and perchance dainty RP59, Steven Pittler, Ph.D., and colleagues astatine nan University of Alabama astatine Birmingham person created caller rodent models pinch mutations successful nan rodent cistron for DHDDS.

Their first model, reported successful 2020 and 2023, was a K42E/K42E mutant. The terminology K42E/K42E is familial shorthand, meaning that some copies of nan rodent DHDDS cistron had a mutation astatine amino acerb number 42, and those mutations replaced nan lysine amino acerb (K) pinch glutamic acerb (E). The K42E/K42E allele is seen successful quality RP59 disease.

The UAB researchers now study 2 much rodent models - a T206A/K42E mutant and T206A/T206A mutant. T206A intends nan threonine (T) amino acerb 206 of DHDDS has been replaced by alanine (A). At property 12 months, some nan T206A/K42E mice and T206A/T206A mice showed changes successful retinal building and usability akin to nan K42E/K42E rodent model, according to nan study published successful nan diary Disease Models & Mechanisms.

"Because T206A/K42E is 1 of nan prevalent variants reported successful RP59 patients, these findings will bring america person to knowing nan system underlying this disease," said Pittler, a professor successful nan UAB Department of Optometry and Vision Science. "These results bespeak that nan DHDDS T206A allele, for illustration nan K42E allele, causes retinal disease, astir apt done a communal pathobiological mechanism, and we propose that nan physiological ground of retinal dysfunction successful RP59 involves defective photoreceptor to bipolar compartment synaptic transmission pinch concomitant bipolar/amacrine compartment degeneration."

Bipolar cells are intermediaries successful nan layers of nan retina from nan ray gathering cells astatine nan backmost of nan retina to nan optic nerve, which past sends that accusation to nan ocular cortex of nan brain.

A uncovering that T206A/T206A causes illness akin to nan T206A/K42E and K42E/K42E models shows that nan T206A allele itself is pathogenic, Pittler says, moreover though nan T206A/T206A allele has not been seen successful humans.

In humans, nan T206A/K42E allele causes nan aforesaid phenotype but is little robust than K42E/K42E.

The changes successful retinal building and usability successful nan T206A/T206A and T206A/K42E mice, for illustration those reported earlier for K42E/K42E mice, were simplification of soul atomic furniture thickness and reduced densities of bipolar and amacrine cells. Electroretinography revealed a simplification successful b-waves, but spared simplification successful a-wave amplitudes. Electroretinography uses an electrode connected nan aboveground of nan oculus to measurement nan electrical responses of retinal neurons to a flash of ray and find which layers of retinal neurons are defective. The first electrical response, nan a-wave, reflects nan wellness of nan photoreceptor cells successful nan outer retina that observe photons. The 2nd response, nan b-wave, reflects nan wellness of nan soul layers of nan retina, which dishonesty downstream from nan photoreceptor cells.

Co-authors pinch Pittler successful nan study, "Dhdds T206A and Dhdds K42E knock-in rodent models of retinitis pigmentosa 59 are phenotypically similar," are Mai N. Nguyen, Dibyendu Chakraborty, Jeffrey Messinger and Timothy W. Kraft, UAB Department of Optometry and Vision Science; David M. Sherry, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; and Steven J. Fliesler, Veterans Affairs Western New York Healthcare System, Buffalo, New York.

Optometry and Vision Science is nan section successful nan UAB School of Optometry, and Pittler is head of nan Vision Science Research Center, besides successful nan School of Optometry.