Alteration of the ABCA4 gene

Stargardt disease is a rare genetic disease.

In most cases, it is caused by the alteration of a gene: the ABCA4 gene (= ATP-Binding Cassette, Subfamily A, Member 4).

It is found on only one chromosome: chromosome 1. It is a large gene (50 exons) and is subject to many mutations.

In the vast majority of cases, Stargardt disease is only caused by alterations made to this gene, which is a significant advantage for gene therapy and cell therapy treatment strategies. However, its large size forces gene therapy researchers to find complex strategies in order to either reduce the mass of the healthy ABCA4 gene before its vectorisation (being transported by a vector) in the eye cells or cut it before its transportation and reassemble it after having penetrated the cell.

The ABCA4 protein, coded by the ABCA4 gene and produced in photoreceptor cells, plays an important role in the retina’s functioning. This protein helps to transport vitamin A by-products through the retina’s cell layers.

Protein ABCA4’s properties are modified when this gene is mutated.

When this protein does not work normally, there is an accumulation of a toxic by-product called lipofuscin in the retinal pigment epithelium. Lipofuscin causes malfunction and damage to the epithelium. Subsequently, photoreceptor cells are damaged and then destroyed, leading to macular atrophy.

The greater the light exposure, the greater the lipofuscin accumulation.

ABCA4 gene mutations cause the variable residual protein activity found in different forms of Stargardt disease:

• Mutations causing an important decrease in activity à early onset disease
• Mutations preserving some residual activity à moderate late onset disease

1. A rarer, autosomal dominant form of Stargardt disease exists and is caused by the mutation of a different gene, ELOV4 (located on chromosomes 6 and 13).