Molecular genetics of pseudoxanthoma elasticum

Pseudoxanthoma elasticum (PXE), a systemic heritable connective tissue diso rder, is characterized by progressive calcification of elastic structures i n the skin, the eyes and the cardiovascular system, with considerable intra - and interfamilial phenotypic variability. Recently, underlying genetic de fects have been identified in the ABCC6 gene, which resides on the chromoso mal locus 16p13.1 and encodes the MRP6 protein, a member of the ATP-binding cassette (ABC) family of proteins. The affected individuals are homozygous or compound heterozygous for a spectrum of genetic lesions, including nons ense and missense mutations, or deletions and splice-site alterations, conf irming the autosomal recessive nature of this condition. Analysis of the de duced primary sequence suggests that MRP6 is a transmembrane transporter, b ut its function has not been delineated yet. Surprisingly, however, MRP6 is expressed primarily, if not exclusively, in the liver and the kidneys, sug gesting that PXE may be a primary metabolic disorder with secondary involve ment of elastic fibers. Identification of mutations in the ABCC6 gene in PX E provides a means for prenatal and presymptomatic testing in families at r isk for recurrence. DNA-based analyses will also identify heterozygous carr iers who may be at risk for development of limited manifestations of the di sease as a result of compounding genetic factors and/or environmental modif iers.