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Is classical pseudoxanthoma elasticum a consequence of hepatic 'intoxication' due to ABCC6 substrate accumulation in
Mie Rostved Rasmussen1, Mette Sommerlund2, Søren Kragh Moestrup1,3
1a Department of Biomedicine, Aarhus University, Ole Worms Allé 3, 8000 Aarhus C, Denmark.
Abstract:
Pseudoxanthoma elasticum (PXE) is a serious genetic disorder with ectopic mineralization affecting the skin, the eye and the cardiovascular system. The disease is predominantly caused by mutations in the transmembrane ABC protein ABCC6, a putative small substrate transporter. Interestingly, ABCC6 seems virtually absent in the affected organs, whereas a high expression is seen in hepatocytes. This and further published experimental evidence indicate that PXE is a systemic, metabolic liver disease where circulatory changes affect the peripheral mineralization process. Owing to the well-characterized transport of organic substrates by related ABC proteins, it has been proposed that PXE is caused by impaired export of an antimineralization compound to the blood. The authors here present an alternative hypothesis that explains ectopic mineralization in PXE as a consequence of hepatic accumulation of ABCC6 substrate(s) that via gene-regulating effects leads to altered hepatic secretion and activation of antimineralization/anticalcification proteins such as fetuin-A and Gla proteins.
Insights
Pseudoxanthoma elasticum (PXE) results from ABCC6 protein mutations, causing ectopic mineralization. This study proposes PXE is a liver disease where accumulating substrates alter proteins, leading to calcification.
Area of Science:
- Biochemistry
- Genetics
- Pathology
Background:
- Pseudoxanthoma elasticum (PXE) is a genetic disorder characterized by ectopic mineralization in skin, eyes, and vasculature.
- Mutations in the ABCC6 gene, encoding a transmembrane ABC transporter, are the primary cause of PXE.
- ABCC6 is highly expressed in the liver, not affected organs, suggesting a systemic metabolic origin.
Purpose of the Study:
- To propose an alternative hypothesis for the mechanism of ectopic mineralization in PXE.
- To investigate the role of hepatic ABCC6 substrate accumulation in PXE pathogenesis.
- To explore the link between altered hepatic secretion of antimineralization proteins and PXE.
Main Methods:
- The study presents a hypothesis based on existing experimental evidence and biochemical principles.
- It discusses the proposed role of ABCC6 substrate accumulation and gene-regulatory effects.
- The hypothesis involves altered secretion and activation of key anticalcification proteins.
Main Results:
- The study hypothesizes that accumulation of ABCC6 substrates in hepatocytes leads to ectopic mineralization.
- This accumulation may trigger gene-regulatory effects altering hepatic secretion of antimineralization factors.
- Specifically, altered secretion and activation of fetuin-A and Gla proteins are implicated.
Conclusions:
- PXE may be a systemic metabolic liver disease driven by ABCC6 dysfunction.
- Hepatic accumulation of ABCC6 substrates, rather than impaired export, could be the primary driver of PXE.
- This accumulation may lead to altered expression of critical anticalcification proteins, causing ectopic mineralization.