Pseudoxanthoma elasticum: Mutations in the MRP6 gene encoding a transmembrane ATP-binding cassette (ABC) transporter

Abstract

Pseudoxanthoma elasticum (PXE), the prototypic heritable connective tissue disorder affecting the elastic structures in the body, manifests with cutaneous, ophthalmologic, and cardiovascular findings, with considerable morbidity and mortality. The molecular basis of PXE has remained unknown, but the disease locus has recently been mapped to an Ϸ500-kb interval on chromosome 16p13.1, without evidence for locus heterogeneity. In this study, we report pathogenetic mutations in MRP6, a member of the ABC transporter gene family, in eight kindreds with PXE. The mutation detection strategy consisted of heteroduplex scanning of coding sequences in the MRP6 gene, which were amplified by PCR by using genomic DNA as template, followed by direct nucleotide sequencing. A total of 13 mutant MRP6 alleles were disclosed in the eight probands with PXE. These genetic lesions consisted of either single base pair substitutions resulting in missense, nonsense, or splice site mutations, or large deletions resulting in allelic loss of the MRP6 locus. Examination of clinically unaffected family members in four multiplex families identified heterozygous carriers, consistent with an autosomal recessive inheritance pattern. Collectively, identification of mutations in the MRP6 gene provides the basis to examine the pathomechanisms of PXE and allows development of DNA-based carrier detection, prenatal testing, and preimplantation genetic diagnosis in families with a history of this disease.

Mutational analysis of theABCC6 gene and the proximalABCC6 gene promoter in German patients with pseudoxanthoma elasticum (PXE)

“…Among the 42 different ABCC6 mutations detected in our PXE cohort, 32 had been described elsewhere (Bergen et al, 2000;Germain et al, 2000;Ringpfeil et al, 2000;Struk et al, 2000;Cai et al, 2001;Le Saux et al, 2001;Pulkkinen et al, 2001;Hu et al, 2003;Chassaing et al, 2004;Gheduzzi et al, 2004;Götting et al, 2004;Hendig et al, 2005;Schulz et al, 2005a;Schulz et al, 2005b), and 10 were novel DNA variations, namely c.37-1G>A, p.W38S, p.L252F, p.V415A, p.R487Q, p.N497K, c.1574_1575insG, p.S1049A, p.L1063R and c.3505_3506+2delAGGT. The mutations occurred in 10 PXE patients from 9 unrelated families and were not present in normal healthy controls (Tables 1 and 2).…”

“…The splice site mutation c.37-1G>A occurred in a homozygous form in one PXE patient and the missense mutations p.W38S and p.N497K were found in a heterozygous state in 2 patients where no further PXE mutations could be identified ( Table 2). The other 7 PXE patients were compound heterozygous for the novel DNA variations p.L252F, p.V415A, p.R487Q, p.S1049A, p.L1063R, c.1574_1575insG and c.3505_3506+2delAGGT, as well as for the known PXE-causing mutations p.R765Q, p.R1141X, p.L851P, c.3736-1G>A and p.S1403R (Bergen et al, 2000;Germain et al, 2000;Ringpfeil et al, 2000;Struk et al, 2000;Le Saux et al, 2001;Hendig et al, 2005). The majority of the new DNA alterations occurred in cytoplasmic regions of the MRP6 protein (Fig.…”

Novel deletions causing pseudoxanthoma elasticum underscore the genomic instability of the ABCC6 region

“…DISCUSSION PXE, a heritable disorder affecting the skin, eyes and the cardiovascular system, is caused by mutations in the ABCC6 gene. 3,10,20,21 Of the various techniques applied to mutation analysis of ABCC6, the currently prevailing and most efficient technique is direct sequencing, with a mutation detection rate of about 90%. Various deletions involving parts or the whole ABCC6 gene have been reported earlier.…”

ABCC6 mutations in Italian families affected by pseudoxanthoma elasticum (PXE)

“…It consists of 31 exons spanning approximately 73kb and encodes for a protein (MRP6, Multidrug Resistance associated Protein 6) belonging to the ATP-binding cassette sub-family C of membrane transporters (Bergen et al, 2000;Le Saux et al, 2000;Ringpfeil et al, 2000). The precise localization in human tissues and the physiological role of MRP6 are still unknown (Scheffer et al, 2002).…”