Homozygosity for the R1268Q mutation in MRP6, the pseudoxanthoma elasticum gene, is not disease-causing

Pseudoxanthoma elasticum (PXE) is an inherited systemic disorder of connective tissue, characterized by progressive calcification of the elastic fibers in the eye, the skin, and the cardiovascular system, resulting in decreased vision, skin lesions, and life-threatening vascular disease, with highly variable phenotypic expression. The PXE locus has been mapped to chromosome 16p13.1, and was recently further refined to a 500 kb-region, containing two pseudogenes and four candidate genes. In a comprehensive mutational screening, we were able to exclude the responsibility of pM5, UNK, and MRP1 genes, candidate on the basis of their genetic localization. Conversely, we have found pathogenetic mutations in the MRP6 gene, in patients affected with PXE, indicating that human MRP6, which encodes a 1503 amino-acids membrane protein, member of the human ATP binding cassette (ABC) transporters superfamily, is the gene responsible for PXE. In one large PXE pedigree for which we had identified a nonsense mutation (R1141X), we came across a G to A transition at position 3803 of the MRP6 cDNA sequence (R1268Q). Astonishingly, this latter variant was found at the homozygous state in the proband's unaffected husband. We investigated the R1268Q mutation, and found the Q1268 allele at a relatively high frequency (0.19) in a Caucasian control population (n = 62 subjects). Genotype frequencies were in Hardy-Weinberg equilibrium, and three healthy volunteers were homozygous for the Q1268 allele. These data indicate that the R1268Q variant in the MRP6 gene does not cause PXE per se. Further studies will elucidate if it may play a role when found in compound heterozygotes.