Pseudoxanthoma Elasticum - Genetics

Genetics

80% of clinical cases of pseudoxanthoma elasticum have detectable mutations in the ABCC6 gene. Mutations in almost all parts of the gene have been described, of all types (missense, nonsense, splice alteration, insertion, small deletion or large deletion). Although there have been reports of autosomal dominant inheritance, the inheritance is typically autosomal recessive (both parents need to be carriers, and there is a 25% chance that a child will inherit both abnormal copies of the gene and therefore develop the condition).

Strong genetic linkage was found with mutations in the ABCC6 gene, which codes for the MRP6 protein, but the exact mechanism by which this protein (which is a membrane transporter from the large ATP-binding cassette transporter family) influences the disease course is unknown; the protein is expressed in most organs, but mainly in the liver and kidney. It is unclear in what way this would lead to abnormalities in skin, eyes and blood vessels. It is thought that particular mutations do not cause a more severe or less severe form of the disease. Given the variations in age of onset and severity it is likely that other unknown risk factors (genetic and dietary) may be involved. One study suggested that mutations causing total absence of an MRP6 protein caused a more severe disease, but this could not be confirmed in a subsequent case series.

Premature atherosclerosis is also associated with mutations in the ABCC6 gene, even in those without PXE. A syndrome almost indistinguishable from hereditary PXE has been described in patients with hemoglobinopathies (sickle-cell disease and thalassemia) through a poorly understood mechanism. In addition, there appears to be another PXE-like syndrome with a similar phenotype but as a result of problems with another gene, gamma-glutamyl carboxylase.