FBLN5

Researchers have been studying FBLN5 gene variants (also called mutations) as a possible risk factor for age-related macular degeneration, an eye disease that is a leading cause of vision loss among older people worldwide. Variants in the FBLN5 gene have been found in a small number of people with age-related macular degeneration, but changes in this gene are probably not a major risk factor for this common eye disorder. A combination of genetic and environmental factors likely determine the risk of developing this disease.

Variants in the FBLN5 gene have been identified in people with cutis laxa. Variants in this gene can cause two different types of cutis laxa: autosomal dominant cutis laxa type 2 (ADCL2) and autosomal recessive cutis laxa type 1A (ARCL1A). In autosomal dominant cutis laxa, one copy of the altered FBLN5 gene in each cell is sufficient to cause the characteristic features of the disorder. In autosomal recessive cutis laxa, both copies of the gene in each cell must be altered to result in the disease.

The FBLN5 gene variant known to cause autosomal dominant cutis laxa leads to the production of an abnormally long, nonfunctional version of fibulin-5. This abnormal protein interferes with the normal fibulin-5 produced from the other, unaltered copy of the FBLN5 gene. As a result, the amount of functional fibulin-5 in the extracellular matrix is severely reduced. A shortage of this protein prevents the assembly of elastic fibers, which weakens connective tissue in the skin, arteries, lungs, and other organs. These defects in connective tissue underlie the major features of cutis laxa.

Autosomal recessive cutis laxa results from FBLN5 gene variants that change single protein building blocks (amino acids) in fibulin-5. These variants alter the structure of the protein, trapping it within the cell. Because the defective fibulin-5 never makes it to the extracellular matrix, it is not available for the assembly of elastic fibers. A shortage of normal elastic fibers weakens connective tissue throughout the body, leading to the signs and symptoms of cutis laxa.