ABCMdb

PMID: 20075945

Costrop LM, Vanakker OO, Van Laer L, Le Saux O, Martin L, Chassaing N, Guerra D, Pasquali-Ronchetti I, Coucke PJ, De Paepe A
Novel deletions causing pseudoxanthoma elasticum underscore the genomic instability of the ABCC6 region.
J Hum Genet. 2010 Feb;55(2):112-7. Epub 2010 Jan 15., [PubMed]

Sentences

No. Mutations Sentence Comment

13 ABCC6 p.Arg1141* Two of these mutations are particularly prevalent, a deletion of exon 23-29 (del23-29) and p.R1141X (c.3421C4T).6-8 To date, only 16 different large ABCC6 deletions (entire exons, whole gene deletions) have been identified in PXE patients.7,9-14 Nevertheless, ABCC6 is extremely prone to genomic rearrangements because of the high content of repetitive elements in all introns and in the genomic sequences surrounding the gene.14 We hypothesized that because of the documented instability of the ABCC6 genomic region, the unidentified mutant alleles remaining after direct sequencing and screening for the recurrent exon 23-29 deletion, may consist of deletions and/or insertions. In this study, we aimed to screen for the presence of such deletions and/or insertions using the multiplex ligation-dependent probe amplification (MLPA) technique. Login to comment 68 ABCC6 p.Arg600Cys In contrast, a false positive MLPA result was obtained as a consequence of the presence of a known heterozygous point mutation in the probe-annealing region in patient 6 (c.1798C4T; p.R600C). Login to comment 83 ABCC6 p.Arg1141* Finally, we performed MLPA analysis in eight patients with a previously identified apparently homozygous p.R1141X mutation (exon 24) to verify whether the subjects were indeed homozygotes Patient 3 1 0.5 0 -0.5 -1 -1.5 Patient 13 1 0.5 0 -0.5 -1 -1.5 0Mb Patient 26 1 0.5 0 -0.5 -1 -1.5 Patient 34 1 0.5 0 -0.5 -1 -1.5 EXON27 EXON26 EXON25 EXON24 EXON23 16.16Mb 16.16Mb 16.16Mb 16.16Mb 16.16Mb 16.17Mb 16.17Mb 16.17Mb 9.87Mb 19.74Mb 29.61Mb 0Mb 9.87Mb 19.74Mb 29.61Mb 0Mb Chr.16 9.87Mb 19.74Mb 29.61Mb p.13.3 p.13.2 p.13.12 p.12.3 p.12.1 p.11.1 p.13.3 p.13.2 p.13.12 p.12.3 p.12.1 p.11.1p.13.3 p.13.2 p.13.12 p.12.3 p.12.1 p.11.1 Chr.16 Chr.16 Chr.16 Patient 32 0.5 0 -0.5 1 16146Kb EXON31 EXON30Chr.16 16148Kb 16150Kb 16151Kb 16153Kb 16156Kb -1 a b Figure 2 Array CGH based results. Login to comment 97 ABCC6 p.Arg1141* Surprisingly, we identified deletions removing the region of exon 24 in two of these patients, indicating that a non-negligible proportion of patients with R1141X were in fact compound heterozygous. Login to comment 112 ABCC6 p.Arg1221Cys ABCC6 p.Arg391Gly Allele 1 Allele 2 Probe/DNA similarity Long range+breakpoint determination aCGH Remark 3 p.Arg391Gly c.1171A4G 24-27 del. Identical c.3307À1006_3882+1582del Yes *, Min. (16157574À16164330) Max. (16157202À16164346) 4 p.Arg1221Cys c.3661C4T Exon 30 del. Identical c.4209À?_4403+?del - *, True positive 7 p.Arg518Stop c.1552C4T Exon 2 del. Login to comment 116 ABCC6 p.Arg518Gln )del Yes *, Min. (14956252À16213237) Max. (14852061À16807177) 28 p.Arg518Gln c.1553G4A Exon 24 del. Login to comment 118 ABCC6 p.Arg600Cys )del Yes *, Min. (15164187À17919962) Max. (15062188À18020277) 6 p.Arg600Cys c.1798C4T Exon 14 del. Login to comment 211 ABCC6 p.Gln378* 23 Cai, L., Lumsden, A., Guenther, U. P., Neldner, S. A., Zach, S., Knoblauch, H. et al. A novel Q378X mutation exists in the transmembrane transporter protein ABCC6 and its pseudogene: implications for mutation analysis in pseudoxanthoma elasticum. J. Mol. Med. 79, 536-546 (2001). Login to comment