Autosomal dominant Retinitis Pigmentosa caused by the rhodopsin isoleucine 255 deletion features rapid neuroretinal degeneration, decreased synaptic connectivity, and neuroinflammation
Authors: Cao Bowen , Zhu Yu , Günter Alexander , Kilger Ellen , Bolz Sylvia , Henes Christine , Mühlfriedel Regine , Seeliger Mathias W. , Paquet-Durand François , Arango-Gonzalez Blanca , Ueffing Marius 
Published: September 2024

Retinitis Pigmentosa (RP) is a group of inherited retinal diseases that initially affects rod photoreceptors and causes progressive vision loss and blindness. Mutations in rhodopsin (RHO) can cause both autosomal recessive (ar) and dominant (ad) forms of RP, yet, the underlying degenerative mechanisms remain largely unknown, rendering the disease untreatable. Here, we focus on an in-frame, 3-base pair deletion, eliminating the isoleucine residue at codon 255 (i.e., RHOΔI255) and resulting in adRP.

We generated a novel knock-in mouse homologous to the humanRHOΔI255mutation. This new mouse model displays a severe disruption of photoreceptor structure and function, as is seen in human patients. Our results indicate that this form of RP is a systems disease of the neuroretina that also impacts neuronal connectivity of bipolar- and horizontal cells, initiates neuroinflammation, and reduces the structural and functional integrity of the retina.

Typical for adRP,RhoΔI255mice exhibit primary rod photoreceptor loss, followed by secondary cone degeneration, rhodopsin protein (RHO) mislocalization, progressive shortening of outer segments (OS), and disorganized OS structures. Subsequently, increasing gliosis, morphologic abnormalities of the inner retina, and impaired cone-driven visual function developed. In adRP, a single mutated allele is sufficient to cause the disease, as confirmed here inRhoΔI255/+heterozygous animals, where most photoreceptors were lost within two months after birth. Compared to this, homozygousRhoΔI255/ΔI255mutants exhibit an accelerated onset and even faster progression of retinal degeneration. The degeneration ofRhoΔI255-mutant photoreceptors was linked to the activation of both caspase- and calpain-type proteases, as well as poly(ADP-ribose) polymerase (PARP), indicating a parallel execution of both apoptotic and non-apoptotic processes.

In conclusion, our data indicate that this form of RP affects the neuroretina beyond photoreceptor cell loss sharing features typical for other degenerative central nervous systems diseases, an insight, which may bear critical impact to understand and eventually develop treatment for these currently untreatable forms of blindness.

Author summary

Dominant mutations in the human rhodopsin gene are among the most common causes for the blinding disease retinitis pigmentosa (RP). To date, the underlying pathophysiological mechanisms are still largely unknown and dominant RP remains untreatable. Here, we introduce a new knock-in mouse model carrying the dominant humanRhoΔI255mutation. As in humans, theRhoΔI255mouse suffers from a rapid degeneration of rod photoreceptors followed by subsequent cell death of cone photoreceptors and complete loss of visual function. The new mouse model displays sign of neuroinflammation and the concomitant activation of both apoptotic and non-apoptotic cell death mechanisms. These results will likely stimulate further studies into the degenerative processes governing dominant RP and may facilitate future therapy development for inherited retinal diseases that are still untreatable to this day.