Abstract

Aims: Pseudoxanthoma elasticum (PXE), an autosomal recessive disorder with considerable phenotypic variability, mainly affects the eyes, skin and cardiovascular system, characterized by dystrophic mineralization of connective tissues. It is caused by mutations in the ABCC6 gene (ATP binding cassette family C member 6) which encodes MRP6 (multidrug resistance-associated protein 6). This study aimed to investigate the mutation spectrum of ABCC6 and possible genotype-phenotype correlations.

Patients and methods: Mutation data were collected on an international case series of 270 PXE patients (239 probands; 31 affected family members). A dHPLC-based assay was developed to screen for mutations in all 31 exons eliminating pseudogene co-amplification. In 134 patients with a known phenotype and both mutations identified, genotype-phenotype correlations were assessed.

Results: Overall 316 mutant alleles in ABCC6 were identified in 239 probands, including 39 novel mutations. Mutations were found to cluster in exons 24 and 28 corresponding to the second nucleotide binding fold and the last intracellular domain of the protein. Together with the recurrent R1141X and del23-29 mutations, these mutations accounted for 71.5% of the total individual mutations identified. Genotype-phenotype analysis failed to reveal a significant correlation between the types of mutations identified or their predicted effect on the expression of the protein and the age of onset and severity of the disease.

Conclusions: This study emphasizes the principal role of ABCC6 mutations in the pathogenesis of PXE, while the reasons for phenotypic variability remain to be explored.