title: Identification of novel polymorphisms in the pM5 and MRP1 (ABCC1) genes at locus 16p13.1 and exclusion of both genes as responsible for pseudoxanthoma elasticum.
abstract: 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. The PXE locus has been mapped to chromosome 16p13.1, and was recently further refined to a 500 kb-region, containing four candidate genes : MRP1 (ABCC1), MRP6 (ABCC6), pM5, and two copies of an unknown gene, the later we subsequently found to be identical to the gene encoding the Nuclear Pore Interacting Protein (NPIP). In a comprehensive mutational screening, we have analysed the entire coding region of the pM5, MRP1, and NPIP genes in 7 patients affected with pseudoxanthoma elasticum, but failed to find evidence of disease-causing defects in any of these three genes. Five synonymous (G232G, P395P, A862A, G912G, D1106D), and five non synonymous (V404I, N458K, D490N, F1141I, G1195R) polymorphisms were found in the pM5 gene, for which we also corrected errors in the published cDNA sequence. Analysis of the MRP1 transcript lead to the discovery of two polymorphisms (T117M, S1512L). No variant was evidenced during our screening of the NPIP gene. Our data exclude the responsibility of the pM5, MRP1 and NPIP genes in PXE, and strongly suggest that mutations in the last remaining candidate gene, MRP6, which encodes a 1503 amino-acid ABC membrane transporter, are the genetic defect responsible for PXE.
authors.affiliation: Département de Génétique, Hôpital Broussais, Paris, France.
authors.forename: J
authors.initials: J
authors.lastname: Perdu
authors.forename: D P
authors.initials: DP
authors.lastname: Germain
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D019943:Amino Acid Substitution / Q000235:genetics; D002478:Cells, Cultured; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D018432:Drug Resistance, Multiple; D006580:Genetic Carrier Screening; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009154:Mutation / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D018807:Polymorphism, Single-Stranded Conformational; D011561:Pseudoxanthoma Elasticum / Q000235:genetics*
chemical_list: D018528:ATP-Binding Cassette Transporters; D027425:ATP-Binding Cassette, Sub-Family C Proteins