Mutational Analysis of theABCC6Gene and the ProximalABCC6Gene Promoter in German Patients With Pseudoxanthoma Elasticum (PXE)

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Abstract

Pseudoxanthoma elasticum (PXE) is a genetic disorder characterized by calcification of elastic fibers in dermal, ocular, and cardiovascular tissues. Recently,ABCC6mutations were identified as causing PXE. In this follow-up study we report the investigation of 61German PXE patients from 53 families, hitherto the largest cohort of German PXE patients screened for the completeABCC6gene. In addition, we characterized the proximalABCC6promoter of PXE patients according to mutation. In this study we identified 32 disease-causingABCC6variants, which had been described previously by us and others, and 10 novel mutations (eight missense mutations and two splice site alterations). The mutation detection rate among index patients was 87.7%. Frequent alterations were the PXE-mutations p.R1141X, Ex23, Ex29del, and c.2787+1G>T. In theABCC6promoter we found the polymorphisms c.-127C>T, c.-132C>T, and c.-219A>C. The difference in the c.-219A>C frequencies between PXE patients and controls were determined as statistically significant. Interestingly, c.-219A>C is located in a transcriptional activator sequence of theABCC6promoter and occurred in a binding site for a transcriptional repressor, predominantly found in genes that participate in lipid metabolism. Obtaining these genetic data signifies our contribution to elucidating the pathogenetics of PXE. © 2006 Wiley-Liss, Inc.

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