Novel ABCC6 Mutations in Pseudoxanthoma Elasticum

Abstract

Pseudoxanthoma elasticum (PXE) is a heritable connective tissue disorder caused by mutations in an ABC (ATP-Binding Cassette) transporter gene (ABCC6), which manifests with cutaneous, ophthalmologic, and cardiovascular findings. We studied a cohort of 19 families with PXE, and identified 16 different mutations, nine of which were novel variants. The mutation detection rate was about 77%. We found that arginine codon 518 was, with the previously described R1141X and EX23_29del, a recurrently mutated amino acid (11.5% of the mutations detected for each variant R518Q and R518X). No clear delineation of genotype/phenotype correlation was identified, and marked intra-familial variability of the disease was seen in one family. One family with pseudodominant inheritance displayed three distinct ABCC6 mutations, providing further evidence for the probable exclusive recessive transmission of PXE. These data contribute to the expanding database of ABCC6 mutations, to the description of phenotypic variability, and inheritance in PXE, and should be helpful for genetic counselling.

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

“…Performing mutational analysis, we identified 42 different PXE mutations and among these 10 were novel. The frequencies of these mutations were similar to those reported in previous European studies, in which the nonsense mutation p.R1141X and the large deletion Ex23_Ex29del were described as frequent ABCC6 mutations in French, Italian and Dutch PXE patients and most of the further ABCC6 alterations were determined as unique mutations (Chassaing et al, 2004;Gheduzzi et al, 2004;Hu et al, 2004). In contrast to these reports, we found that the splice site mutation c.2787+1G>T is a new recurrent mutation in German PXE families.…”

“…In contrast to these reports, we found that the splice site mutation c.2787+1G>T is a new recurrent mutation in German PXE families. The disease-causing mutations p.R518Q and p.R518X that were frequently found in French, Italian and Swiss PXE patients (Chassaing et al, 2004;Gheduzzi et al, 2004;Miksch et al, 2005), rarely occurred in our PXE cohort and were not found in PXE families of Dutch origin . This suggests that the observed heterogeneous distribution of ABCC6 mutations in PXE patients could be due to ethnic or national differences.…”

“…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).…”

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

“…The most frequent p.R1141X PXE-related allele shared a common haplotype identical-by-descent in seven Italian families homozygous for this mutation. Moreover, comparison of haplotype analyses in Italian and in French PXE families (Chassaing et al, 2004) may suggest the presence of a common ancestor. Our results revealed a distribution of mutations along the ABCC6 gene similar to those published for other European Countries (Le Saux et al, 2001;Hu et al, 2003;Chassaing et al, 2004).…”

“…Recent reports suggest its implication in the cell extrusion of glutathionated metabolites (Belinsky et al, 2002;Ilias et al, 2002). To date, more than 60 causative mutations for PXE have been reported (Hu et al, 2003;Chassaing et al, 2004). Irrespective of the geographic origin of affected individuals, the great majority of mutations have been found between exons 24 and 30 of the ABCC6 gene (Le Saux et al, 2001;Meloni et al, 2001;Pulkkinen et al, 2001).…”