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The ABCC6 Transporter as a Paradigm for Networking from an Orphan Disease to Complex Disorders.

De Vilder EY, Hosen MJ, Vanakker OM - Biomed Res Int (2015)

Bottom Line: The knowledge on the genetic etiology of complex disorders largely results from the study of rare monogenic disorders.While during the last decade the awareness of the wide ramifications of ABCC6 has increased significantly, the gene itself and the transmembrane transporter it encodes have not unveiled all of the mysteries that surround them.In this review, we summarize the network approaches used to study ABCC6 and the role of this gene in several complex diseases.

View Article: PubMed Central - PubMed

Affiliation: Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium ; Department of Ophthalmology, Ghent University Hospital, 9000 Ghent, Belgium.

ABSTRACT
The knowledge on the genetic etiology of complex disorders largely results from the study of rare monogenic disorders. Often these common and rare diseases show phenotypic overlap, though monogenic diseases generally have a more extreme symptomatology. ABCC6, the gene responsible for pseudoxanthoma elasticum, an autosomal recessive ectopic mineralization disorder, can be considered a paradigm gene with relevance that reaches far beyond this enigmatic orphan disease. Indeed, common traits such as chronic kidney disease or cardiovascular disorders have been linked to the ABCC6 gene. While during the last decade the awareness of the wide ramifications of ABCC6 has increased significantly, the gene itself and the transmembrane transporter it encodes have not unveiled all of the mysteries that surround them. To gain more insights, multiple approaches are being used including next-generation sequencing, computational methods, and various "omics" technologies. Much effort is made to place the vast amount of data that is gathered in an integrated system-biological network; the involvement of ABCC6 in common disorders provides a good view on the wide implications and potential of such a network. In this review, we summarize the network approaches used to study ABCC6 and the role of this gene in several complex diseases.

No MeSH data available.


Related in: MedlinePlus

Review of the disorders and pathophysiological mechanisms associated with the ABCC6 transporter, which is primarily expressed in the liver and kidney. Chronic deficiency of the transporter is involved in rare disorders such as pseudoxanthoma elasticum (PXE), generalized arterial calcification of infancy (GACI), and PXE phenocopies in thalassemias. More acute ABCC6 deficiency is a susceptibility factor and/or a modifier for stroke, myocardial infarction (MI), cardiac fibrosis, peripheral artery disease (PAD), age-related macular degeneration (AMD), chronic kidney disease (CKD), nephrocalcinosis, and dyslipidemia. BMP2: bone morphogenetic protein 2; MGP: matrix Gla protein; MSX2: muscle segment homeobox 2; OC: osteocalcin; PPi: inorganic pyrophosphate; TGF: transforming growth factor [4, 7–9, 12, 14, 28–45].
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fig3: Review of the disorders and pathophysiological mechanisms associated with the ABCC6 transporter, which is primarily expressed in the liver and kidney. Chronic deficiency of the transporter is involved in rare disorders such as pseudoxanthoma elasticum (PXE), generalized arterial calcification of infancy (GACI), and PXE phenocopies in thalassemias. More acute ABCC6 deficiency is a susceptibility factor and/or a modifier for stroke, myocardial infarction (MI), cardiac fibrosis, peripheral artery disease (PAD), age-related macular degeneration (AMD), chronic kidney disease (CKD), nephrocalcinosis, and dyslipidemia. BMP2: bone morphogenetic protein 2; MGP: matrix Gla protein; MSX2: muscle segment homeobox 2; OC: osteocalcin; PPi: inorganic pyrophosphate; TGF: transforming growth factor [4, 7–9, 12, 14, 28–45].

Mentions: Despite the disadvantage of not knowing the substrates, important progress has been made in the unraveling of the mechanisms in which ABCC6 is involved (Figure 2). To this end, a combination of several approaches is being used, including next-generation sequencing, computational methods, and various “omics” technologies. In doing so, ABCC6 was found to play a role in more pathophysiological processes than could initially be envisaged based on its association with PXE. From this perspective, the ABCC6 transporter is becoming increasingly important for a growing number of diseases (Figure 3).


The ABCC6 Transporter as a Paradigm for Networking from an Orphan Disease to Complex Disorders.

De Vilder EY, Hosen MJ, Vanakker OM - Biomed Res Int (2015)

Review of the disorders and pathophysiological mechanisms associated with the ABCC6 transporter, which is primarily expressed in the liver and kidney. Chronic deficiency of the transporter is involved in rare disorders such as pseudoxanthoma elasticum (PXE), generalized arterial calcification of infancy (GACI), and PXE phenocopies in thalassemias. More acute ABCC6 deficiency is a susceptibility factor and/or a modifier for stroke, myocardial infarction (MI), cardiac fibrosis, peripheral artery disease (PAD), age-related macular degeneration (AMD), chronic kidney disease (CKD), nephrocalcinosis, and dyslipidemia. BMP2: bone morphogenetic protein 2; MGP: matrix Gla protein; MSX2: muscle segment homeobox 2; OC: osteocalcin; PPi: inorganic pyrophosphate; TGF: transforming growth factor [4, 7–9, 12, 14, 28–45].
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4555454&req=5

fig3: Review of the disorders and pathophysiological mechanisms associated with the ABCC6 transporter, which is primarily expressed in the liver and kidney. Chronic deficiency of the transporter is involved in rare disorders such as pseudoxanthoma elasticum (PXE), generalized arterial calcification of infancy (GACI), and PXE phenocopies in thalassemias. More acute ABCC6 deficiency is a susceptibility factor and/or a modifier for stroke, myocardial infarction (MI), cardiac fibrosis, peripheral artery disease (PAD), age-related macular degeneration (AMD), chronic kidney disease (CKD), nephrocalcinosis, and dyslipidemia. BMP2: bone morphogenetic protein 2; MGP: matrix Gla protein; MSX2: muscle segment homeobox 2; OC: osteocalcin; PPi: inorganic pyrophosphate; TGF: transforming growth factor [4, 7–9, 12, 14, 28–45].
Mentions: Despite the disadvantage of not knowing the substrates, important progress has been made in the unraveling of the mechanisms in which ABCC6 is involved (Figure 2). To this end, a combination of several approaches is being used, including next-generation sequencing, computational methods, and various “omics” technologies. In doing so, ABCC6 was found to play a role in more pathophysiological processes than could initially be envisaged based on its association with PXE. From this perspective, the ABCC6 transporter is becoming increasingly important for a growing number of diseases (Figure 3).

Bottom Line: The knowledge on the genetic etiology of complex disorders largely results from the study of rare monogenic disorders.While during the last decade the awareness of the wide ramifications of ABCC6 has increased significantly, the gene itself and the transmembrane transporter it encodes have not unveiled all of the mysteries that surround them.In this review, we summarize the network approaches used to study ABCC6 and the role of this gene in several complex diseases.

View Article: PubMed Central - PubMed

Affiliation: Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium ; Department of Ophthalmology, Ghent University Hospital, 9000 Ghent, Belgium.

ABSTRACT
The knowledge on the genetic etiology of complex disorders largely results from the study of rare monogenic disorders. Often these common and rare diseases show phenotypic overlap, though monogenic diseases generally have a more extreme symptomatology. ABCC6, the gene responsible for pseudoxanthoma elasticum, an autosomal recessive ectopic mineralization disorder, can be considered a paradigm gene with relevance that reaches far beyond this enigmatic orphan disease. Indeed, common traits such as chronic kidney disease or cardiovascular disorders have been linked to the ABCC6 gene. While during the last decade the awareness of the wide ramifications of ABCC6 has increased significantly, the gene itself and the transmembrane transporter it encodes have not unveiled all of the mysteries that surround them. To gain more insights, multiple approaches are being used including next-generation sequencing, computational methods, and various "omics" technologies. Much effort is made to place the vast amount of data that is gathered in an integrated system-biological network; the involvement of ABCC6 in common disorders provides a good view on the wide implications and potential of such a network. In this review, we summarize the network approaches used to study ABCC6 and the role of this gene in several complex diseases.

No MeSH data available.


Related in: MedlinePlus