A spectrum of ABCC6 mutations is responsible for pseudoxanthoma elasticum

To better understand the pathogenetics of pseudoxanthoma elasticum (PXE), w e performed a mutational analysis of ATP-binding cassette subfamily C membe r 6 (ABCC6) in 122 unrelated patients with PXE, the largest cohort of patie nts yet studied. Thirty-six mutations were characterized, and, among these, 28 were novel variants (for a total of 43 PXE mutations known to date). Tw enty-one alleles were missense variants, six were small insertions or delet ions, five were nonsense, two were alleles likely to result in aberrant mRN A splicing, and two were large deletions involving ABCC6. Although most mut ations appeared to be unique variants, two disease-causing alleles occurred frequently in apparently unrelated individuals. R1141X was found in our pa tient cohort at a frequency of 18.8% and was preponderant in European patie nts. ABCC6del23-29 occurred at a frequency of 12.9% and was prevalent in pa tients from the United States. These results suggested that R1141X and ABCC 6del23-29 might have been derived regionally from founder alleles. Putative disease-causing mutations were identified in similar to 64% of the 244 chr omosomes studied, and 85.2% of the 122 patients were found to have at least one disease-causing allele. Our results suggest that a fraction of the und etected mutant alleles could be either genomic rearrangements or mutations occurring in noncoding regions of the ABCC6 gene. The distribution pattern of ABCC6 mutations revealed a cluster of disease-causing variants within ex ons encoding a large C-terminal cytoplasmic loop and in the C-terminal nucl eotide-binding domain (NBD2). We discuss the potential structural and funct ional significance of this mutation pattern within the context of the compl ex relationship between the PXE phenotype and the function of ABCC6.