Compound heterozygosity for a recurrent 16.5-kb Alu-mediated deletion mutation and single-base-pair substitutions in the ABCC6 gene results in pseudoxanthoma elasticum

Pseudoxanthoma elasticum (PXE) is a systemic heritable disorder affecting t he elastic structures in the skin, eyes, and cardiovascular system, with co nsiderable morbidity and mortality. Recently, mutations in the ABCC6 gene ( also referred to as "MRP6" or "eMOAT") encoding multidrug-resistance protei n 6 (MRP6), a putative transmembrane ABC transporter protein of unknown fun ction, have been disclosed. Most of the genetic lesions delineated thus far consist of single-base-pair substitutions resulting in nonsense, missense, or splice-site mutations. In this study, we examined four multiplex famili es with PXE inherited in an autosomal recessive pattern. In each family, th e proband was a compound heterozygote for a single-base-pair-substitution m utation and a novel, similar to 16.5-kb deletion mutation spanning the site of the single-base-pair substitution in trans. The deletion mutation was s hown to extend from intron 22 to intron 29, resulting in out-of-frame delet ion of 1,213 nucleotides from the corresponding mRNA and causing eliminatio n of 505 amino acids from the MRP6 polypeptide. The deletion breakpoints we re precisely the same in all four families, which were of different ethnic backgrounds, and haplotype analysis by 13 microsatellite markers suggested that the deletion had occurred independently. Deletion breakpoints within i ntrons 22 and 29 were embedded within AluSx repeat sequences, specifically in a 16-bp segment of DNA, suggesting Alu-mediated homologous recombination as a mechanism.