Contribution ofABCC6 genomic rearrangements to the diagnosis of pseudoxanthoma elasticum in French patients

Abstract

Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder of connective tissues, which manifests with cutaneous, ophthalmologic and cardiovascular findings. PXE is caused by mutations in ABCC6 encoding a multidrug resistance protein (ABCC6, also known as MRP6). ABCC6 mutation detection rate ranges from 55% to 97% and it has been suggested that some of the remaining unidentified mutant alleles could correspond to large genomic rearrangements. In our cohort of 65 French PXE patients analysed for ABCC6 mutations, we identified two novel homozygous ABCC6 exonic deletions (deletions of exons 9-10 and exons 24-27). In order to systematically search for heterozygous genomic rearrangements, we have developed a quantitative multiplex PCR of short fluorescent fragments (QMPSF) approach that screens the 31 exons of ABCC6. We used QMPSF to analyse 13 PXE carrying at least one unidentified mutant, corresponding to 18 unidentified mutated alleles. This led to the detection of three large ABCC6 deletions, and two deletions of a single exon (exon 1 and exon 21). Thus QMPSF identified the causative mutation in 28% (5/18) of the uncharacterized ABCC6 mutant alleles in this cohort.