Mutation detection in the ABCC6 gene and genotype phenotype analysis in a large international case series affected by pseudoxanthoma elasticum

Pfendner, Ellen G; Vanakker, Olivier; Terry, Sharon F.; Vourthis, Sophia; McAndrew, Patricia; McClain, Monica R.; Fratta, Sarah; Marais, Anna‐Susan; Hariri, Susan; Coucke, Paul; Ramsay, Michèle; Viljoen, Denis; Terry, Patrick F.; Paepe, Anne De; Uitto, Jouni; Bercovitch, Lionel

doi:10.1136/jmg.2007.051094

Cited by 161 publications

(231 citation statements)

References 45 publications

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“…Two of these mutations are particularly prevalent, a deletion of exon 23-29 (del23-29) and p.R1141X (c.3421C4T). [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.…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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

et al. 2010

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“…PXE is caused by mutations in the ABCC6 gene which encodes a putative transmembrane protein, MRP6, a member of the family of ATP-binding cassette (ABC) multi-drug resistance-associated proteins [3]. The ABCC6 gene is primarily expressed in the liver, to a lesser extent in the proximal tubules of kidneys, and at very low level, if at all, †Corresponding Author Jouni Uitto, M.D., Ph.D., Department of Dermatology and Cutaneous Biology, Jefferson Medical College, 233 S. 10th Street, Suite 450 BLSB, Philadelphia, PA 19107, USA, Tel: (215) 503-5785, Fax: (215) 503-5788, E-mail: E-mail: Jouni.Uitto@jefferson.edu.…”

Section: Introductionmentioning

confidence: 99%

Pseudoxanthoma elasticum: Reduced γ-glutamyl carboxylation of matrix gla protein in a mouse model (Abcc6−−)

Jiang

Schurgers

et al. 2007

Biochemical and Biophysical Research Communications

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Pseudoxanthoma elasticum (PXE), a heritable multi-system disorder manifesting with ectopic mineralization of soft connective tissues, is caused by mutations in the ABCC6/MRP6 gene/protein system, but the mechanisms how the ABCC6 mutations lead to aberrant mineralization are currently unknown. In this study, we utilized a transgenic mouse model, Abcc6 −/− , to examine the mineralization processes. We focused on matrix gla protein (MGP) which has been shown to be critical, when activated by γ-carboxylation of glutamyl residues, for prevention of unwanted mineralization. The concentration of MGP in the serum of Abcc6 −/− mice was significantly reduced when compared to wild-type controls (p<0.004). More importantly, MGP isolated from the liver of Abcc6 −/− mice was largely under-carboxylated, and therefore possesses no activity. Finally, examination of the Abcc6 −/− mice revealed association of total and under-carboxylated forms of MGP with ectopic mineralization while the γ-carboxylated form was essentially absent. These results suggest that MGP in Abcc6 −/− mice is largely in inactive form and is unable to prevent the unwanted mineralization of connective tissues in PXE.

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“…ABCC6 encodes multiresistance-associated protein 6 (MRP6), a member of the large ATP-dependent transmembrane transporter family. The majority of ABCC6 mutations are inactivating mutations leading to the absence of functional MRP6 [4][5][6][7][8]. To date, no correlation has been reported between the nature or position of the mutations and the phenotype, suggesting the role of modifier genes and environmental factors.…”

Section: Pxe Is a Metabolic Diseasementioning

confidence: 99%

Modifier genes in pseudoxanthoma elasticum: novel insights from the Ggcx mouse model

Hovnanian

2010

J Mol Med

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Mutation detection in the ABCC6 gene and genotype phenotype analysis in a large international case series affected by pseudoxanthoma elasticum

Abstract: This study emphasises the principal role of ABCC6 mutations in the pathogenesis of PXE, but the reasons for phenotypic variability remain to be explored.

Cited by 161 publications

References 45 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

Pseudoxanthoma elasticum: Reduced γ-glutamyl carboxylation of matrix gla protein in a mouse model (Abcc6−−)

Modifier genes in pseudoxanthoma elasticum: novel insights from the Ggcx mouse model

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