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

Pseudoxanthoma elasticum (PXE) is an inherited systemic disorder of connect ive tissue, characterized by progressive calcification of the elastic fiber s in the eye, the skin, and the cardiovascular system, resulting in decreas ed vision, skin lesions, and life-threatening vascular disease, with highly variable phenotypic expression. The PXE locus has been mapped to chromosom e 16p13.1, and was recently further refined to a 500 kb-region, containing two pseudogenes and four candidate genes. In a comprehensive mutational scr eening, we were able to exclude the responsibility of pM5, UNK, and MRP1 ge nes, candidate on the basis of their genetic localization, Conversely, we h ave found pathogenetic mutations in the MRP6 gene, in patients affected wit h PXE, indicating that human MRP6, which encodes a 1503 amino-acids membran e protein, member of the human ATP binding cassette (ABC) transporters supe rfamily, is the gene responsible for PXE. In one large PXE pedigree for whi ch we had identified a nonsense mutation (R1141X), we came across a G to A transition at position 3803 of the MRP6 cDNA sequence (R1268Q). Astonishing ly, this latter variant was found at the homozygous state in the proband's unaffected husband. We investigated the R1268Q mutation, and found the Q126 8 allele at a relatively high frequency (0.19) in a Caucasian control popul ation (n = 62 subjects). Genotype frequencies were in Hardyn-Teinberg equil ibrium, 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 fou nd in compound heterozygotes. (C) 2000 Academic Press.