Serum Factors from Pseudoxanthoma Elasticum Patients Alter Elastic Fiber Formation In Vitro

Saux, Olivier Le; Bunda, Severa; VanWart, Christopher M.; Douet, Vanessa; Got, Laurence; Martin, Ludovic; Hinek, Aleksander

doi:10.1038/sj.jid.5700201

Cited by 75 publications

(64 citation statements)

References 42 publications

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“…Also, Maccari et al recently reported abnormal excretion of glycoaminoglycans in the urine of PXE patients, which may indicate abnormal kidney functions [24]. Furthermore, we recently reported that metabolites present in serum of PXE patients interfered with the assembly of elastic fibers produced by skin fibroblasts and aortic smooth muscle cells [25]. All these results do support the notion that the pathology of PXE may indeed derives from the lack of ABCC6 function in either liver or kidney or both.…”

Section: Introductionsupporting

confidence: 77%

HNF4α and NF-E2 are key transcriptional regulators of the murine Abcc6 gene expression

Douet

VanWart

Heller

et al. 2006

Biochimica et Biophysica Acta (BBA) - Gene Structure and Expres

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SUMMARYMutations in an ABC transporter gene called ABCC6 are responsible for pseudoxanthoma elasticum (PXE), a rare heritable disease characterized by elastic fiber calcification in skin, ocular and vascular tissues. The presumed function of this ABC transporter is to export metabolites from polarized cells. However, the endogenous substrate(s) are unknown and the exact relationship with elastic fibers is unclear. As ABCC6 is expressed at high level only in liver and kidneys, tissues seemingly unrelated to the PXE phenotype, we explored the transcriptional regulation of the murine Abcc6 gene to define transcriptional regulation conferring tissue specificity and to gather clues on its possible biological function. We cloned 2.9 kb of the mAbcc6 5′-flanking region and several deletion constructs linked to a luciferase reporter gene. We delineated a proximal promoter and a liver-specific enhancer region. We also demonstrated that the proximal region is a TATA-less promoter requiring an intact CCAATbox and Sp1 binding for its basal activity. By using reporter assays and chromatin immunoprecipitations, we showed that HNF4α and surprinsingly, NF-E2, enhanced the mAbcc6 promoter activity. The involvement of both HNF4α and NF-E2 in the mAbcc6 gene regulation suggests that Abcc6 might be involved in a detoxification processes related to hemoglobin or heme.

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Section: Introductionsupporting

confidence: 77%

HNF4α and NF-E2 are key transcriptional regulators of the murine Abcc6 gene expression

Douet

VanWart

Heller

et al. 2006

Biochimica et Biophysica Acta (BBA) - Gene Structure and Expres

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“…The substrate(s) transported by ABCC6 is unknown, and PXE is now considered a metabolic disease. 4,5 At present, 4200 different ABCC6 mutations have been identified. These are primarily located at the 3¢ end of ABCC6 between exons 24 and 30.…”

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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“…25 These cells have been shown to synthesize abnormal proteoglycans and to exhibit a higher expression of elastin (ELN), which was further associated with pathological assembly of elastic fibers when cultured in the presence of PXE sera. 16, 26 Quaglino et al 27 reported that PXE fibroblasts have a raised matrix metallopeptidase 2 mRNA and protein expression. In addition, a mild oxidative stress was observed in PXE fibroblasts with higher malondialdehyde levels, increased superoxide dismutase 2 and reduced catalase and glutathione peroxidase activities.…”

mentioning

confidence: 99%

“…12,13 Indeed, several studies reported alterations in systemic blood components in PXE patients and mouse models due to MRP6 deficiency. [14][15][16][17][18][19][20] Accordingly, PXE was assumed to be primarily a metabolic disorder. 12,[21][22][23] In contrast, results of several studies also point to a local role for ABCC6/MRP6 as expression of the protein was detected in dermal fibroblasts from healthy controls whereas it was found to be absent in fibroblasts from PXE patients.…”

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confidence: 99%

Gene expression profiling of ABC transporters in dermal fibroblasts of pseudoxanthoma elasticum patients identifies new candidates involved in PXE pathogenesis

Hendig

Langmann

Kocken

et al. 2008

Laboratory Investigation

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Mutations in the ABCC6 gene, encoding the multidrug resistance-associated protein 6 (MRP6), cause pseudoxanthoma elasticum (PXE). This heritable disorder leads to pathological alterations in connective tissues. The implication of MRP6 deficiency in PXE is still unknown. Moreover, nothing is known about a possible compensatory expression of other ATP binding-cassette (ABC) transporter proteins in MRP6-deficient cells. We investigated the gene expression profile of 47 ABC transporters in human dermal fibroblasts of healthy controls (n ¼ 2) and PXE patients (n ¼ 4) by TaqMan low-density array. The analysis revealed the expression of 37 ABC transporter genes in dermal fibroblasts. ABCC6 gene expression was not quantifiable in fibroblasts derived from PXE patients. Seven genes (ABCA6, ABCA9, ABCA10, ABCB5, ABCC2, ABCC9 and ABCD2) were induced, whereas the gene expression of one gene (ABCA3) was decreased, comparing controls and PXE patients (with at least twofold changes). We reanalyzed the gene expression of selected ABC transporters in a larger set of dermal fibroblasts from controls and PXE patients (n ¼ 6, each). Reanalysis showed high interindividual variability between samples, but confirmed the results obtained in the array analysis. The gene expression of ABC transporter genes, as well as lineage markers of PXE, was further examined after inhibition of ABCC6 gene expression by using specific small-interfering RNA. These experiments corroborated the observed gene expression alterations, most notably in the ABCA subclass (up to fourfold, Po0.05). We therefore conclude that MRP6-deficient dermal fibroblasts exhibit a distinct gene expression profile of ABCA transporters, potentially to compensate for MRP6 deficiency. Moreover, our results point to a function for ABCC6/MRP6 in sterol transport, as sterols are preferential regulators of ABCA transporter activity and expression. Further studies are now required to uncover the role of ABCA transporters in PXE.

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Serum Factors from Pseudoxanthoma Elasticum Patients Alter Elastic Fiber Formation In Vitro

Cited by 75 publications

References 42 publications

HNF4α and NF-E2 are key transcriptional regulators of the murine Abcc6 gene expression

HNF4α and NF-E2 are key transcriptional regulators of the murine Abcc6 gene expression

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

Gene expression profiling of ABC transporters in dermal fibroblasts of pseudoxanthoma elasticum patients identifies new candidates involved in PXE pathogenesis

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