Pseudoxanthoma elasticum: Mutations in the MRP6 gene encoding a transmembrane ATP-binding cassette (ABC) transporter

Pseudoxanthoma elasticum (PXE), the prototypic heritable connective tissue disorder affecting the elastic structures in the body, manifests with cutan eous, ophthalmologic, and cardiovascular findings, with considerable morbid ity and mortality. The molecular basis of PXE has remained unknown, but the disease locus has recently been mapped to an approximate to 500-kb interva l on chromosome 16p13.1, without evidence for locus heterogeneity. In this study, we report pathogenetic mutations in MRP6, a member of the ABC transp orter gene family, in eight kindreds with PXE. The mutation detection strat egy consisted of heteroduplex scanning of coding sequences in the MRP6 gene , which were amplified by PCR by using genomic DNA as template, followed by direct nucleotide sequencing. A total of 13 mutant MRP6 alleles were discl osed in the eight probands with PXE. These genetic lesions consisted of eit her single base pair substitutions resulting in missense, nonsense, or spli ce site mutations, or large deletions resulting in allelic loss of the MRP6 locus. Examination of clinically unaffected family members in four multipl ex families identified heterozygous carriers, consistent with an autosomal recessive inheritance pattern. Collectively, identification of mutations in the MRP6 gene provides the basis to examine the pathomechanisms of PXE and allows development of DNA-based carrier detection, prenatal testing, and p reimplantation genetic diagnosis in families with a history of this disease .