Pseudoxanthoma elasticum: molecular investigations in a consanguineous family further supports the existence of pseudogenes (ψABCC6) homologous to the ABCC6 gene

Pseudoxanthoma elasticum (PXE) is an inherited systemic disorder of connective tissue, affecting the skin, the eyes, and the vascular system in a highly variable phenotypic expression. The PXE locus has been mapped to chromosome 16p13.1 and mutations in the ABCC6 gene (previously known as MRP6 or eMOAT), encoding a 1503 amino acids putative membrane transporter of unknown function, have recently been disclosed as the genetic defect responsible for PXE. We have identified a heterozygous missense mutation (G226R) in exon 7 of the ABCC6 gene in a PXE female patient, born from parents who were second cousins. Despite complete scanning of the gene, no further mutation was evident. A heterozygous profile was also found in the proband's unaffected children, the mutant peak being of much lower amplitude. However, haplotype homozygosity was confirmed at locus 16p13.1, using both, extragenic microsatellites (D16S3017 and D16S3060) and intragenic polymorphisms (V614A in exon 14 and R1268Q in exon 27) located 3′ from mutation G226R, in agreement with the known consanguinity in the family. Taken together, our data indicate that PCR products of exon 7 of the ABCC6 gene were amplified from more than two genomic copies. This further supports the existence of ABCC6 pseudogene(s) (ψABCC6) highly homologous to the 5′ end (exons 1−9) of the human ABCC6 gene. These results will prove invaluable when genotyping patients affected with PXE.