Retinitis Pigmentosa & Investigations

Retinitis Pigmentosa & Investigations

December 21, 2020

Retinitis pigmentosa (RP) is a group of rare, genetic disorders that involve a breakdown and loss of cells in the retina — which is the light sensitive tissue that lines the back of the eye. Common symptoms include difficulty seeing at night and a loss of side (peripheral) vision.

What Causes RP

RP is an inherited disorder that results from harmful changes in any one of more than 50 genes. These genes carry the instructions for making proteins that are needed in cells within the retina, called photoreceptors.

Some of the changes, or mutations, within genes are so severe that the gene cannot make the required protein, limiting the cell’s function.

Other mutations produce a protein that is toxic to the cell. Still other mutations lead to an abnormal protein that doesn’t function properly. In all three cases, the result is damage to the photoreceptors.

What Are Photoreceptors

Photoreceptors are cells in the retina that begin the process of seeing. They absorb and convert light into electrical signals. These signals are sent to other cells in the retina and ultimately through the optic nerve to the brain where they are processed into the images we see.

There are two general types of photoreceptors, called rods and cones. Rods are in the outer regions of the retina, and allow us to see in dim and dark light. Cones reside mostly in the central portion of the retina, and allow us to perceive fine visual detail and color.

How Is RP Inherited

To understand how RP is inherited, it’s important to know a little more about genes and how they are passed from parent to child. Genes are bundled together on structures called chromosomes.

Each cell in your body contains 23 pairs of chromosomes. One copy of each chromosome is passed by a parent at conception through egg and sperm cells. The X and Y chromosomes, known as sex chromosomes, determine whether a person is born female (XX) or male (XY).

The 22 other paired chromosomes, called autosomes, contain the vast majority of genes that determine non-sex traits. RP can be inherited in one of three ways:

Autosomal Recessive Inheritance

In autosomal recessive inheritance, it takes two copies of the mutant gene to give rise to the disorder. An individual with a recessive gene mutation is known as a carrier. When two carriers have a child, there is a:

  • 1 in 4 chance the child will have the disorder
  • 1 in 2 chance the child will be a carrier
  • 1 in 4 chance the child will neither have the disorder nor be a carrier

Autosomal Dominant Inheritance

In this inheritance pattern, it takes just one copy of the gene with a disorder-causing mutation to bring about the disorder. When a parent has a dominant gene mutation, there is a 1 in 2 chance that any children will inherit this mutation and the disorder.

X-Linked Inheritance

In this form of inheritance, mothers carry the mutated gene on one of their X chromosomes and pass it to their sons. Because females have two X chromosomes, the effect of a mutation on one X chromosome is offset by the normal gene on the other X chromosome. If a mother is a carrier of an X-linked disorder there is a:

  • 1 in 2 chance of having a son with the disorder
  • 1 in 2 chance of having a daughter who is a carrier

The Symptoms

In the early stages of RP, rods are more severely affected than cones. As the rods die, people experience night blindness and a progressive loss of the visual field, the area of space that is visible at a given instant without moving the eyes.

The loss of rods eventually leads to a breakdown and loss of cones. In the late stages of RP, as cones die, people tend to lose more of the visual field, developing tunnel vision.

They may have difficulty performing essential tasks of daily living such as reading, driving, walking without assistance, or recognizing faces and objects.

How Does RP Progress

The symptoms of RP typically appear in childhood. Children often have difficulty getting around in the dark. It can also take abnormally long periods of time to adjust to changes in lighting.

As their visual field becomes restricted, patients often trip over things and appear clumsy. People with RP often find bright lights uncomfortable, a condition known as photophobia. Because there are many gene mutations that cause the disorder, its progression can differ greatly from person to person.

Some people retain central vision and a restricted visual field into their 50s, while others experience significant vision loss in early adulthood. Eventually, most individuals with RP will lose most of their sight.

New Investigations

Investigations into how retinitis pigmentosa (RP) occurs are being conducted at the molecular level.

A promising technology used in research is Förster resonance energy transfer (FRET), a biophysical method to study protein-protein interactions.

The disruptions of these cells cause various dysfunctions ranging from mild problems with night blindness to severe ones that result in retinal degenerations and complete blindness.

Rhodopsin, a protein that detects photons of light that start biochemical reactions, is involved in the initial events of vision and the focus of their work, specifically in relation to factors that maintain the health of the photoreceptor cells.

Rhodopsin’s light-sensing activity is mediated by a vitamin A derivative conjugated to the protein. Dysfunctions in rhodopsin cause RP, congenital night blindness, and Leber’s congenital amaurosis, and rhodopsin activity can have secondary effects in the pathogenesis of diabetic retinopathy and agerelated macular degeneration.

Proper production of rhodopsin with proper 3-dimensional conformation to form higher order structures is paramount for functioning in the eye; protein misfolding results in RP. Using atomic force microscopy, the clusters of rhodopsin in the disc membranes of the photoreceptor cells can be visualized.

When the proper structure of rhodopsin cannot be attained, the consequent misfolding results in toxic complexes-aggregates, with RP as the product.


RP is a group of diseases that begin with rod photoreceptor degeneration, leading to eventual cone photoreceptor degeneration and blindness.

Mutations in more than 40 genes can cause this process. Among them are mutations in rhodopsin. Mutations in the rhodopsin gene are among the leading cause of autosomal-dominant RP, and more than 100 mutations have been identified, a majority of which cause protein misfolding and aggregation.

The mechanism by which the misfolding and aggregation occur and lead to deterioration of the healthy retina is unclear. The misfolding and aggregation of different proteins also are common to Alzheimer disease, Parkinson disease, and prions disease.

The goal now is to gain an understanding of the malignant processes in the eye and to devise strategies to disrupt the aggregation. The challenge that we have is how to study the aggregates of rhodopsin.

FRET is used to detect protein-protein interactions. This is an artificial system devised in his laboratory that facilitates manipulation of rhodopsin DNA to genetically engineer a fluorescent protein that can be fused to the receptor.

This can then be expressed in cultured cells for study using FRET. FRET allows to determine if 2 protein molecules are far apart from each other or forming complexes.

The investigators look at aggregates by treating the cells with detergents that can disrupt complexes formed by normal rhodopsin but cannot disrupt aggregated rhodopsin.

FRET is being used on a range of different rhodopsin mutations that cause RP, including the P23H mutation, and characterizing the aggregation properties.

The investigators also are testing various pharmacologic agents. Investigators have learned that there is variability in the severity of misfolding and aggregation depending on specific mutations.

The autosomal-dominant phenotype does not result from physical interactions between mutations and wild-type receptors, useful information to aid in development of medications.

Proposed pharmacologic therapies are predicted to be ineffective for some mutations and detrimental for others. Finally, the species background of rhodopsin mutations can affect aggregation properties and the effects of pharmacologic therapies.

The plan is for investigators to correlate the biophysical studies with those in animal models and to formulate strategies to disrupt the mutant aggregates that can then be tested by biophysics and in animal models.