Disruption of Abcc6 in the mouse: novel insight in the pathogenesis of pseudoxanthoma elasticum

Gorgels, Theo G. M. F.; Hu, Xiaofeng; Scheffer, George L.; Wal, Allard C. van der; Toonstra, Johan; Jong, Paulus T. V. M. de; Kuppevelt, Toin H. Van; Levelt, Christiaan N.; Wolf, Anneke de; Loves, Willem J.P; Scheper, Rik J.; Peek, Ron; Bergen, Arthur A. B.

doi:10.1093/hmg/ddi183

Cited by 177 publications

(198 citation statements)

References 32 publications

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“…To date, Ϸ50 mutations of Abcc6 have been found in humans with the autosomal recessive disease, pseudoxanthoma elasticum (PXE), manifested by dystrophic calcification affecting the elastic fibers in skin, Bruch's membrane, and vessel walls with highly variable clinical manifestations (25). It is noteworthy that myocardial calcification has not been reported as a phenotype associated with either human PXE or the mouse Abcc6 knockout models (26,27). Moreover, Abcc6 knockout mice on a B6 background develop medial vascular calcification spontaneously with age, whereas the Abcc6-deficient C3H mice do not show signs of vascular calcification until challenged by hyperlipidemia (unpublished data).…”

Section: Discussionmentioning

confidence: 99%

Identification of Abcc6 as the major causal gene for dystrophic cardiac calcification in mice through integrative genomics

Meng

Vera²,

Che³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

119

130

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The genetic factors contributing to the complex disorder of myocardial calcification are largely unknown. Using a mouse model, we fine-mapped the major locus (Dyscalc1) contributing to the dystrophic cardiac calcification (DCC) to an 840-kb interval containing 38 genes. We then identified the causal gene by using an approach integrating genetic segregation and expression array analyses to identify, on a global scale, cis-acting DNA variations that perturb gene expression. By studying two intercrosses, in which the DCC trait segregates, a single candidate gene (encoding the ATPbinding cassette transporter ABCC6) was identified. Transgenic complementation confirmed Abcc6 as the underlying causal gene for Dyscalc1. We demonstrate that in the cross, the expression of Abcc6 is highly correlated with the local mineralization regulatory system and the BMP2-Wnt signaling pathway known to be involved in the systemic regulation of calcification, suggesting potential pathways for the action of Abcc6 in DCC. Our results demonstrate the power of the integrative genomics in discovering causal genes and pathways underlying complex traits.expression quantitative trait locus ͉ transgenic ͉ positional cloning ͉ osteopontin C haracterized by hydroxyapatite deposition in necrotic myocytes, myocardial calcification is common in specific forms of cardiomyopathy and in myocardial infarction. It has been estimated that Ϸ8% of patients with severe myocardial infarction develop myocardial calcification within 6 years, suggesting a genetic predisposition for postinjury healing and remodeling processes (1). Historically, dystrophic cardiac calcification (DCC) has been considered a spontaneous form of cardiomyopathy in mice, associated with a variety of predisposing factors, but with normal blood levels of calcium and phosphate. Experimentally, it can be reproducibly initiated using a transdiaphragmal freeze-thaw injury or a high-phosphorous (HP) diet (2, 3). Several inbred mouse strains, including C3H/HeJ (C3H) and DBA/2J (DBA), are highly susceptible, whereas many other inbred mouse strains, including C57BL/6J (B6), C57BL/10J (B10), A/J, MRL/MpJ, and BALB/cJ are resistant (refs. 4 and 5; X.W., T.A.D., and A.J.L., unpublished data). In DCC susceptible strains, calcification has also been observed in skeletal muscle, including in the tongue and diaphragm, and kidney, suggesting a systemic defect (2, 5).Using quantitative trait locus (QTL) analysis of an F 2 intercross between B6 and C3H mice (BxH), we previously mapped four DCC loci (6, 7). The locus on chromosome 7 (Dyscalc1), which exhibits recessive inheritance, explains 31% of the total genetic variance and is the major contributor. Dyscalc1 was confirmed by separate intercrosses of B6 and DBA mice (BxD) (5, 8). The C3H strain was originally derived from an outbreeding experiment of the DBA strain, leading us to hypothesize that the susceptible strains C3H and DBA share a common diseasecausing allele (8). To fine map the Dyscalc1 locus, we screened a panel of recombinant congenic (RC) s...

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Section: Discussionmentioning

confidence: 99%

Identification of Abcc6 as the major causal gene for dystrophic cardiac calcification in mice through integrative genomics

Meng

Vera²,

Che³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

119

130

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“…Several studies have indeed reported alterations in plasma lipoproteins or vitamin D metabolism from PXE patients [22] and the recent generation of the PXE mouse model with altered HDL and creatinine levels support these findings [23]. Also, Maccari et al recently reported abnormal excretion of glycoaminoglycans in the urine of PXE patients, which may indicate abnormal kidney functions [24].…”

Section: Introductionmentioning

confidence: 94%

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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“…Abcc6 −/− mice faithfully recapitulate most of the symptoms of PXE and have been indispensable for showing that PXE is a metabolic disease (13)(14)(15)(16). Abcc6 −/− muzzle skin that mineralizes in Abcc6 −/− mice does not mineralize when grafted onto WT mice, and muzzle skin of WT mice mineralizes only when grafted onto Abcc6 −/− mice (17).…”

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confidence: 99%

ABCC6 prevents ectopic mineralization seen in pseudoxanthoma elasticum by inducing cellular nucleotide release

Jansen

Küçükosmanoğlu

Haas

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

223

310

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Pseudoxanthoma elasticum (PXE) is an autosomal recessive disease characterized by progressive ectopic mineralization of the skin, eyes, and arteries, for which no effective treatment exists. PXE is caused by inactivating mutations in the gene encoding ATPbinding cassette sub-family C member 6 (ABCC6), an ATP-dependent efflux transporter present mainly in the liver. Abcc6 −/− mice have been instrumental in demonstrating that PXE is a metabolic disease caused by the absence of an unknown factor in the circulation, the presence of which depends on ABCC6 in the liver. Why absence of this factor results in PXE has remained a mystery. Here we report that medium from HEK293 cells overexpressing either human or rat ABCC6 potently inhibits mineralization in vitro, whereas medium from HEK293 control cells does not. Untargeted metabolomics revealed that cells expressing ABCC6 excrete large amounts of nucleoside triphosphates, even though ABCC6 itself does not transport nucleoside triphosphates. Extracellularly, ectonucleotidases hydrolyze the excreted nucleoside triphosphates to nucleoside monophosphates and inorganic pyrophosphate (PPi), a strong inhibitor of mineralization that plays a pivotal role in several mineralization disorders similar to PXE. The in vivo relevance of our data are demonstrated in Abcc6 −/− mice, which had plasma PPi levels <40% of those found in WT mice. This study provides insight into how ABCC6 affects PXE. Our data indicate that the factor that normally prevents PXE is PPi, which is provided to the circulation in the form of nucleoside triphosphates via an asyet unidentified but ABCC6-dependent mechanism.ATP secretion | ectopic calcification | MRP6 | ENPP1

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Disruption of Abcc6 in the mouse: novel insight in the pathogenesis of pseudoxanthoma elasticum

Cited by 177 publications

References 32 publications

Identification of Abcc6 as the major causal gene for dystrophic cardiac calcification in mice through integrative genomics

Identification of Abcc6 as the major causal gene for dystrophic cardiac calcification in mice through integrative genomics

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

ABCC6 prevents ectopic mineralization seen in pseudoxanthoma elasticum by inducing cellular nucleotide release

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