Genetic Basis of Choroideremia

Genetic Basis of Choroideremia

IRDs are characterised by the fact that they are genetic conditions that can be inherited. Some IRDs, such as Leber’s congenital amaurosis (LCA), can be due to mutations in many different genes. However, choroirderemia is unlike most other forms of IRDs as it is mainly due to mutations in just one gene, called CHM. The CHM gene (OMIM 303390) encodes a protein call Rab escort protein 1 (REP1). REP1 is involved in transporting small sacs (vesicles) containing proteins, molecules and cell components to different locations within cells.

The exact mechanism and origin of the degradation of the different parts of the retina is still not fully clear and may differ between people affected. So far, there have been 280 mutations in the CHM gene that can result in the choroideremia condition. Most of these mutations result in a non-functional copy of the gene, known as a null allele. This means that the mutation can result in the production of a protein that doesn’t work properly or lack of production of any protein.  There has been a second gene connected with some cases of choroideremia. The CHM-like (CHML) gene encodes the REP2 protein, which is very similar to REP1. As they are so similar, the two proteins may be able to compensate for the loss of the each other.

The CHM gene is located on the X chromosome. As males have one X chromosome and one Y chromosome, they are vulnerable to diseases that are caused by mutations in their single x chromosome. Therefore, only males suffer the full effects of complete blindness of choroideremia. Females have two X chromosomes, one inherited from each parent.

If one of their X chromosomes carries a mutation, the other unmutated X chromosome may be able to compensate for the loss. In females, only one of the two X chromosomes is used, while the other is inactivated. This occurs randomly in individual cells and so in the whole retina, approximately 50% of the cells will use one of the X chromosomes and 50% will use the other X chromosome. Thus, females can be carriers of the disease and show no symptoms or they can have below normal sensitivity of vision, pigment changes in the back of the eye and problems with seeing in dim light.

Choroideremia has a 50% chance of being passed onto the children of an affected parent. However, men with choroideremia cannot pass the gene onto their sons, as the mutation is on the X chromosome and sons get their single X chromosome from their mother. Daughters, however, will inherit their father’s X chromosome as well and their mother’s X chromosome. Daughters can therefore inherit the mutated chromosome and will be carriers but may not be affected.

For a woman with a CHM mutation who is pregnant a female child, there is a 50% chance of passing the gene onto a daughter and 50% chance of passing on the normal gene to a daughter. For a male child, there is a 50% chance the son will inherit the mutated gene from his mother and a 50% chance the son will inherit the normal copy. You can read more about inheritance patterns the Knoe Your Code toolkit here: Inheritance Patterns.