Pseudoxanthoma elasticum: Point mutations in the ABCC6 gene and a large deletion including also ABCC1 and MYH11

Meloni, Ilaria; Rubegni, Pietro; Aloe, G. De; Bruttini, Mirella; Pianigiani, Elisa; Cusano, Roberto; Seri, Marco; Mondillo, Sergio; Federico, Antonio; Bardelli, A.; Andreassi, Lucio; Fimiani, Michele; Renieri, Alessandra

doi:10.1002/humu.1157

Cited by 40 publications

(23 citation statements)

References 10 publications

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“…Various deletions involving parts or the whole ABCC6 gene have been reported earlier. 7,[10][11][12][13][14] Small or large deletions are expected to make up for the bulk of the unidentified alleles because heterozygous middle-sized deletions are notoriously difficult to detect with traditional PCR-based assays. Furthermore, the presence of numerous repetitive elements makes the ABCC6 region subject to genomic rearrangements.…”

Section: Confirmation Of the Single-exon Deletionsmentioning

confidence: 99%

“…22,23 Until now, a total of 16 different large deletions (exons, whole gene deletions) have been described. 7,[9][10][11][12][13][14] Because of the wide variety of repeat elements in the ABCC6 region, we anticipated that several of the unidentified mutant alleles in our PXE cohort would consist of deletions and insertions.…”

Section: Confirmation Of the Single-exon Deletionsmentioning

confidence: 99%

“…[6][7][8] To date, only 16 different large ABCC6 deletions (entire exons, whole gene deletions) have been identified in PXE patients. 7,[9][10][11][12][13][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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2010

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Mutations in ABCC6 cause pseudoxanthoma elasticum (PXE), a heritable disease that affects elastic fibers. Thus far, 4200 mutations have been characterized by various PCR-based techniques (primarily direct sequencing), identifying up to 90% of PXE-causing alleles. This study wanted to assess the importance of deletions and insertions in the ABCC6 genomic region, which is known to have a high recombinational potential. To detect ABCC6 deletions/insertions, which can be missed by direct sequencing, multiplex ligation-dependent probe amplification (MLPA) was applied in PXE patients with an incomplete genotype. MLPA was performed in 35 PXE patients with at least one unidentified mutant allele after exonic sequencing and exclusion of the recurrent exon 23-29 deletion. Six multi-exon deletions and four single-exon deletions were detected. Using MLPA in addition to sequencing, we expanded the ABCC6 mutation spectrum with 9 novel deletions and characterized 25% of unidentified disease alleles. Our results further illustrate the instability of the ABCC6 genomic region and stress the importance of screening for deletions in the molecular diagnosis of PXE.

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Section: Confirmation Of the Single-exon Deletionsmentioning

confidence: 99%

Section: Confirmation Of the Single-exon Deletionsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2010

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“…Using a limited haplotype analysis with the microsatellite markers D16B9621 and D16S764, the five intragenic SNPs c.1841T>C, c.2490C>T, c.3803G>A, c.4404-76A>G and c.4404-31G>A and the intragenic mutation c.3421C>T, a deletion of the whole ABCC6 gene could be excluded in homozygous state in all patients and in heterozygous state in all but 2 PXE patients. Saux et al, 2001;B, Miksch et al, 2005;C, Cai et al, 2001;D, Chassaing et al, 2004;E, Meloni et al, 2001;F, Hendig et al, 2004;G, Schulz et al, 2005a;H, Hu et al, 2003;I, Uitto et al, 2001;J, Le Saux et al, 2000;K, Gheduzzi et al, 2004;L, Schulz et al, 2005b;M, Götting et al, 2004;N, Ringpfeil et al, 2000;O, Bergen et al, 2000;P, Struk et al, 2000;Q, Pulkkinen et al, 2001;R, Ringpfeil et al, 2001;S, Götting et al, 2005. F = female, M = male, wt = wild-type, hm = homozygote, ht = heterozygote, cht = compound heterozygote, nd = not determined, MSM = microsatellite marker, E = eyes, S = skin, G = gastrointestinum, H = heart, V = vascular tissue and A = arterial hypertension. a The PXE families are consecutively numbered and the affected family members are indicated by following numbers.…”

Section: Pxe Mutations Discovered By Dhplc Analysismentioning

confidence: 99%

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

et al. 2006

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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 61German 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.

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“…In our cohort of French patients this deletion represents 9/130 (7 %) of the mutated alleles. Large deletions of the entire ABCC6 gene have been reported several times (Bergen et al, 2000;Meloni et al, 2001;Miksch et al, 2005) Exonic deletions have been identified fortuitously through failure to amplify target sequences (exon 15 and 24-25 deletions) (Le Saux et al, 2001;Katona et al, 2005) or by a SNP segregation analysis study (exon 1-21 deletion) (Miksch et al, 2005). Because large genomic rearrangements of the ABCC6 gene have not readily been detectable by conventional PCR-based techniques, it has been suggested that such mutations could account for unidentified alleles.…”

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confidence: 99%

Contribution ofABCC6 genomic rearrangements to the diagnosis of pseudoxanthoma elasticum in French patients

Chassaing

Martin²,

Bourthoumieu

et al. 2007

Hum. Mutat.

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Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder of connective tissues, which manifests with cutaneous, ophthalmologic and cardiovascular findings. PXE is caused by mutations in ABCC6 encoding a multidrug resistance protein (ABCC6, also known as MRP6). ABCC6 mutation detection rate ranges from 55 % to 97 % and it has been suggested that some of the remaining unidentified mutant alleles could correspond to large genomic rearrangements. In our cohort of 65 French PXE patients analysed for ABCC6 mutations, we identified two novel homozygous ABCC6 exonic deletions (deletions of exons 9-10 and exons 24-27). In order to systematically search for heterozygous genomic rearrangements, we have developed a quantitative multiplex PCR of short fluorescent fragments (QMPSF) approach that screens the 31 exons of ABCC6. We used QMPSF to analyse 13 PXE carrying at least one unidentified mutant, corresponding to 18 unidentified mutated alleles. This led to the detection of three large ABCC6 deletions, and two deletions of a single exon (exon 1 and exon 21). Thus QMPSF identified the causative mutation in 28% (5/18) of the uncharacterized ABCC6 mutant alleles in this cohort. © 2007 Wiley-Liss, Inc. KEY WORDS: PXE; ABCC6; MRP6; QMPSF: genomic rearrangements INTRODUCTIONPseudoxanthoma elasticum (PXE; MIM# 264800) is an inherited disorder mainly involving three organ systems (cutaneous, ocular and cardiovascular) with highly variable clinical expression. Recessive and dominant inheritances have been reported (Pope, 1975;Neldner, 1988;Bergen et al., 2000) but an exclusively autosomal recessive mode of inheritance seems more likely (Chassaing et al., 2005;Ringpfeil et al., 2006). This disease is caused by mutations in the ATP-binding cassette, sub-family C, member 6 (ABCC6) gene, encoding a multidrug resistance protein (ABCC6, also known as MRP6; MIM# 603234), mostly expressed in liver and kidneys both at mRNA and protein levels (Kool et al., 1999;Scheffer et al., 2002) and to a lesser extent in tissues affected by PXE (Bergen et al., 2000). To date, more than 150 different mutations have been identified (Chassaing et al., 2005; DOI: 10.1002/humu.9509 2 Chassaing et al. Miksch et al., 2005;Schulz et al., 2006). ABCC6 molecular analysis leads to the detection of 55 % (Le Saux et al., 2001) to 97 % (Miksch et al., 2005) of mutations depending on the mutation detection methodologies used in the largest published studies. Thus, despite the extensive and enduring efforts of many groups since ABCC6 was identified as the causative gene in PXE, up to 45 % of the mutated alleles remain to be identified. In our cohort of 65 French PXE patients, we had identified 112/130 (86 %) of the mutated alleles using previously published strategy of molecular analysis (Chassaing et al., 2004). Many reasons for the lack of mutation detection in some patients have been suggested, such as splice site mutations distant from the coding sequence, mutations in the gene regulatory sequences, exonic rearrangements or genotyping of patients wit...

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Pseudoxanthoma elasticum: Point mutations in the ABCC6 gene and a large deletion including also ABCC1 and MYH11

Cited by 40 publications

References 10 publications

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

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

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

Contribution ofABCC6 genomic rearrangements to the diagnosis of pseudoxanthoma elasticum in French patients

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