title: ABCC6/MRP6 mutations: further insight into the molecular pathology of pseudoxanthoma elasticum.
abstract: Pseudoxanthoma elasticum (PXE) is a hereditary disease characterized by progressive dystrophic mineralization of the elastic fibres. PXE patients frequently present with skin lesions and visual acuity loss. Recently, we and others showed that PXE is caused by mutations in the ABCC6/MRP6 gene. However, the molecular pathology of PXE is complicated by yet unknown factors causing the variable clinical expression of the disease. In addition, the presence of ABCC6/MRP6 pseudogenes and multiple ABCC6/MRP6-associated deletions complicate interpretation of molecular genetic studies. In this study, we present the mutation spectrum of ABCC6/MRP6 in 59 PXE patients from the Netherlands. We detected 17 different mutations in 65 alleles. The majority of mutations occurred in the NBF1 (nucleotide binding fold) domain, in the eighth cytoplasmatic loop between the 15th and 16th transmembrane regions, and in NBF2 of the predicted ABCC6/MRP6 protein. The R1141X mutation was by far the most common mutation identified in 19 (32.2%) patients. The second most frequent mutation, an intragenic deletion from exon 23 to exon 29 in ABCC6/MRP6, was detected in 11 (18.6%) of the patients. Our data include 11 novel ABCC6/MRP6 mutations, as well as additional segregation data relevant to the molecular pathology of PXE in a limited number of patients and families. The consequences of our data for the molecular pathology of PXE are discussed.
authors.affiliation: Netherlands Ophthalmic Research Institute, KNAW, Amsterdam, The Netherlands.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Hu
authors.forename: Astrid
authors.initials: A
authors.lastname: Plomp
authors.forename: Jan
authors.initials: J
authors.lastname: Wijnholds
authors.forename: Jacoline
authors.initials: J
authors.lastname: Ten Brink
authors.forename: Simone
authors.initials: S
authors.lastname: van Soest
authors.forename: L Ingeborgh
authors.initials: LI
authors.lastname: van den Born
authors.forename: Anita
authors.initials: A
authors.lastname: Leys
authors.forename: Ron
authors.initials: R
authors.lastname: Peek
authors.forename: Paulus T V M
authors.initials: PT
authors.lastname: de Jong
authors.forename: Arthur A B
authors.initials: AA
authors.lastname: Bergen
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D002648:Child; D004252:DNA Mutational Analysis; D017931:DNA Primers; D017353:Gene Deletion; D015870:Gene Expression; D005787:Gene Frequency; D005820:Genetic Testing; D006801:Humans; D008969:Molecular Sequence Data; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D011487:Protein Conformation; D011561:Pseudoxanthoma Elasticum / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C102029:ABCC6 protein, human