title: Mutational analysis of the ABCC6 gene and the proximal ABCC6 gene promoter in German patients with pseudoxanthoma elasticum (PXE).
abstract: Pseudoxanthoma elasticum (PXE) is a genetic disorder characterized by calcification of elastic fibers in dermal, ocular, and cardiovascular tissues. Recently, ABCC6 mutations were identified as causing PXE. In this follow-up study we report the investigation of 61 German PXE patients from 53 families, hitherto the largest cohort of German PXE patients screened for the complete ABCC6 gene. In addition, we characterized the proximal ABCC6 promoter of PXE patients according to mutation. In this study we identified 32 disease-causing ABCC6 variants, 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 the ABCC6 promoter 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 the ABCC6 promoter 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.
authors.affiliation: Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen, Universitätsklinik der Ruhr-Universität Bochum, Bad Oeynhausen, Germany.
authors.forename: Veronika
authors.initials: V
authors.lastname: Schulz
authors.forename: Doris
authors.initials: D
authors.lastname: Hendig
authors.forename: Maja
authors.initials: M
authors.lastname: Henjakovic
authors.forename: Christiane
authors.initials: C
authors.lastname: Szliska
authors.forename: Knut
authors.initials: K
authors.lastname: Kleesiek
authors.forename: Christian
authors.initials: C
authors.lastname: Götting
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D002648:Child; D002851:Chromatography, High Pressure Liquid; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D005858:Germany; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000737:chemistry / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D011561:Pseudoxanthoma Elasticum / Q000235:genetics*; D022821:RNA Splice Sites; D016415:Sequence Alignment
chemical_list: D027425:ATP-Binding Cassette, Sub-Family C Proteins; D022821:RNA Splice Sites; C102029:ABCC6 protein, human