Mutations of RHO

Figure 16: diagram depicting the visual differences between an eye with a normal retina, and one with retinitis pigmentosa.

Retinitis Pigmentosa

Retinitis pigmentosa (RP) is a genetic condition that causes damage to the retina of the eye, caused by degeneration of the retina and associated epithelium, including the loss of rod and cone photoreceptor cells (1). Mutations to the RHO gene can cause RP.

What type of mutations cause retinitis pigmentosa?

While RP can follow a X-linked, autosomal recessive, and autosomal dominant inheritance pattern, the majority of patients present with an autosomal dominant inheritance pattern for rhodopsin mediated RP (2).

Those affected with autosomal dominant RP can have one or two copies of the affected allele - both homozygotes and heterozygotes can be affected.

Autosomal dominant retinitis pigmentosa - P23H mutation

The P23H mutation characterises a substitution missense mutation.

At the DNA level, the RHO DNA sequence GGG would undergo a substitution missense mutation to form GTG (3).
In transcription, mRNA codon 23 would be altered from CCC to CAC.
In translation, the amino acid histadine will be added to the polypeptide chain instead of proline. This causes the missense mutation effect to be displayed.

As the P23H mutation effects the 23rd codon of the RHO gene, the mutation takes place in the N-terminal intradiscal domain (4).

At the protein level, the change in amino acid sequence disrupts the disulfide bond that takes place between Cys110 and Cys187 (5), inducing a conformational change (causing misfolding) in rhodopsin. Hydrophobic interactions are disrupted at the N-terminal.

At the level of cellular processes:

Reduction of retinal interactions and sensitivity, contributing to rod cell death (6), and reduced functional rhodopsin levels.
Misfolded proteins aggregate in the endoplasmic recticulum of the cell instead of being transported to the cell membrane, leading to enhanced rhodospin aggregation and degradation by the cellular proteasome.

Figure 17: P23H mutation location within a rhodopsin monomer, as highlighted by the red arrow in both diagram A and B.

Pathogenic mutations of RHO

Figure 18: ClinVar database analysis demonstrating the location of the known pathogenic variants of the RHO (red lines) in relation to the gene (exons highlighted in green boxes).

Pathogenic mutations for RHO include:

Substitution mutations - missense mutations were over-represented in the ClinVar.
Deletion mutations - also over-represented.
Substitution mutations - nonsense mutations were also visible in the data.

Mutations that were under-represented in the data include:

Frameshift mutations.
Mutations in untranslated regions of the gene.

The majority of known mutations take place within the exons. This reveals that RHO mutations will likely cause a change to the physical rhodpsin protein itself, therefore potentially inducing negative conformational changes such as those seen in RP.

References:

1. Hartong D. Retinitis pigmentosa. The Lancet. doi:10.1007/springerreference_33812

2. Boughman JA, Fishman GA. A genetic analysis of retinitis pigmentosa. British Journal of Ophthalmology. 1983;67(7):449–54. doi:10.1136/bjo.67.7.449

3. Price BA, Sandoval IM, Chan F, Simons DL, Wu SM, Wensel TG, et al. Mislocalization and degradation of Human P23H-Rhodopsin-GFP in a knockin mouse model of retinitis pigmentosa. Investigative Opthalmology & Visual Science. 2011;52(13):9728. doi:10.1167/iovs.11-8654

4. Mitchell J, Balem F, Tirupula K, Man D, Dhiman HK, Yanamala N, et al. Correction: Comparison of the molecular properties of retinitis pigmentosa P23H and N15s amino acid replacements in rhodopsin. PLOS ONE. 2019;14(11). doi:10.1371/journal.pone.0225153

5. Woods KN, Pfeffer J. Conformational perturbation, allosteric modulation of cellular signaling pathways, and disease in P23h rhodopsin. Scientific Reports. 2020;10(1). doi:10.1038/s41598-020-59583-2

6. Wells-Gray EM, Choi SS, Bries A, Doble N. Variation in rod and cone density from the fovea to the mid-periphery in healthy human retinas using adaptive optics scanning laser ophthalmoscopy. Eye. 2016;30(8):1135–43. doi:10.1038/eye.2016.107

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