Fuchs’ endothelial dystrophy - COL8A2 gen

Fuchs’ endothelial dystrophy, also known as Fuchs’ corneal dystrophy or Fuchs’ atrophy, is a process that mainly affects the cornea and causes vision problems. The first symptom of this condition is usually blurred vision in the morning, which usually disappears during the day. Over time, affected individuals lose visual acuity and become sensitive to bright lights.

Fuchs’ corneal dystrophy usually begins with the development of a series of bulges that simulate drops (corneal guttata). These increase in number progressively and extend from the center of the cornea to the periphery. These lesions contribute to cell death inside the cornea, which makes vision difficultiess worse. Subsequently, an accumulation of fluid occurs in the central layer of the cornea (corneal stroma). This becomes thicker and the vision is increasingly blurred. Small blisters can develop on the cornea, which can explode and cause eye pain.

The genetic origin of Fuchs’ endothelial dystrophy is unclear. Several genes and regions have been identified within a few chromosomes that can play a role in the development of the disease. However, many of these genetic associations have been found only in a few affected people or families, and the role that these genes play in the development of the pathology is unknown. It is believed that mutations in genes that are expressed primarily in corneal endothelial cells or in surrounding tissue contribute to the death of corneal endothelial cells. Some described cases of an early onset variant, which develops around age 20, are due to mutations in the COL8A2 gene (collagen type VIII alpha 2 chain). It is also believed that mutations in additional unidentified genes are involved in the development of both the early onset variant and a later onset form of the disease, which develops around 40 or 50 years.

The COL8A2 gene, located on the short arm of chromosome 1 (1p34.3), encodes a component of type VIII collagen known as alpha 2 (VIII) collagen. Type VIII collagen is largely found inside the cornea, where it is an important component of the Descemet membrane. This membrane is a structure that separates and supports corneal endothelial cells, which regulate the amount of fluid inside the cornea. To synthesize type VIII collagen, a subunit of the alpha 2 (VIII) collagen protein interacts with two subunits of alpha 1 (VIII) collagen. These three proteins bind to form procollagen. Procollagen molecules are secreted by the cell and processed by enzymes to remove extra segments from the ends of the protein. Once these molecules are processed, they are organized giving rise to mature type VIII collagen.

At least two mutations in the COL8A2 gene have been described in individuals with Fuchs’ endothelial dystrophy. The COL8A2 gene mutations that cause the early-onset variant replace individual amino acids in collagen alpha 2 (VIII). A mutation replaces the amino acid leucine with the amino acid tryptophan at position 450 (Leu450Trp or L450W). Another mutation replaces the amino acid glutamine with the amino acid lysine at position 455 (Gln455Lys or Q455K). These mutations affect the structure of alpha 2 (VIII) collagen, difficulting the incorporation of this protein into type VIII collagen fibers. As a consequence, there is a reduced amount of type VIII collagen in the cornea, specifically in the Descemet membrane.

In many cases, the inheritance pattern of Fuchs’ endothelial dystrophy is unknown. In some families this pathology seems to be inherited in an autosomal dominant pattern, which means that one copy of the altered gene in each cell is sufficient to express the disease. Some cases are due to new mutations in the gene and occur in people with no history of the disease in their family.

Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with the Fuchs’ endothelial dystrophy, by means of the complete PCR amplification of the exons of the COL8A2 gene, and their subsequent sequencing.

Recommended samples: non-coagulated blood obtained with EDTA for separation of blood leucocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).