scholarly journals Dysregulation of gene expression in ABCC6 knockdown HepG2 cells

2014 ◽  
Vol 19 (4) ◽  
Author(s):  
Rocchina Miglionico ◽  
Maria Armentano ◽  
Monica Carmosino ◽  
Antonella Salvia ◽  
Flavia Cuviello ◽  
...  
Keyword(s):  
Hepg2 Cells ◽  
Autosomal Recessive ◽  
Pseudoxanthoma Elasticum ◽  
Arterial Calcification ◽  
Elastic Fibers ◽  
Ectopic Calcification ◽  
Ectopic Mineralization ◽  
Abcc6 Gene ◽  
Basolateral Plasma Membrane

AbstractABCC6 protein is an ATP-dependent transporter that is mainly found in the basolateral plasma membrane of hepatocytes. ABCC6 deficiency is the primary cause of several forms of ectopic mineralization syndrome. Mutations in the human ABCC6 gene cause pseudoxanthoma elasticum (PXE), an autosomal recessive disease characterized by ectopic calcification of the elastic fibers in dermal, ocular and vascular tissues. Mutations in the mouse ABCC6 gene were also associated with dystrophic cardiac calcification. Reduced levels of ABCC6 protein were found in a β-thalassemic mouse model. Moreover, some cases of generalized arterial calcification in infancy are due to ABCC6 mutations. In order to study the role of ABCC6 in the pathogenesis of ectopic mineralization, the expressions of genes involved in this process were evaluated in HepG2 cells upon stable knockdown of ABCC6 by small hairpin RNA (shRNA) technology. ABCC6 knockdown in HepG2 cells causes a significant upregulation of the genes promoting mineralization, such as TNAP, and a parallel downregulation of genes with anti-mineralization activity, such as NT5E, Fetuin A and Osteopontin. Although the absence of ABCC6 has been already associated with ectopic mineralization syndromes, this study is the first to show a direct relationship between reduced ABCC6 levels and the expression of pro-mineralization genes in hepatocytes.

Pseudoxanthoma elasticum with prominent arterial calcifications evoking CD73 deficiency

2019 ◽  
Vol 24 (5) ◽  
pp. 461-464 ◽  
Author(s):  
Magali Devriese ◽  
Anne Legrand ◽  
Marie-Cécile Courtois ◽  
Xavier Jeunemaitre ◽  
Juliette Albuisson
Keyword(s):  
Vascular Calcification ◽  
Pseudoxanthoma Elasticum ◽  
Arterial Calcification ◽  
Elastic Fibers ◽  
Connective Tissues ◽  
Tibial Arteries ◽  
Ectopic Mineralization ◽  
Abcc6 Gene ◽  
Next Generation Sequencing Ngs ◽  
Eye Lesions

Pseudoxanthoma elasticum (PXE) is a rare disorder characterized by skin, eye, and cardiovascular lesions due to ectopic mineralization and fragmentation of elastic fibers of connective tissues. We present an atypical case of PXE with diffuse vascular calcification and negligible skin and eye lesions. The patient was a 37-year-old man suffering from severe bilateral arterial calcifications in superficial femoral and posterior tibial arteries. Eye fundoscopy and skin examination were first considered normal. This phenotype suggested first the diagnosis of Arterial Calcification due to Deficiency of CD73 (ACDC) characterized by mutations in NT5E gene. However, we found two variants in ABCC6 gene, and no variant in NT5E. Skin reexamination revealed few lateral skin papules confined to the scalp. Phenotypic overlap was described in vascular calcification disorders, between GACI and PXE phenotypes, and we discuss here expansion of this overlap, including ACDC phenotype. Identification of these expanding and overlapping phenotypes was enabled by genetic screening of the corresponding genes, in a systematic approach. We propose to create a calcification next generation sequencing (NGS) panel with NT5E, GGCX, ENPP1, and ABCC6 genes to improve the molecular diagnosis of vascular calcification.

scholarly journals ABCC6, Pyrophosphate and Ectopic Calcification: Therapeutic Solutions

2021 ◽  
Vol 22 (9) ◽  
pp. 4555
Author(s):  
Briana K. Shimada ◽  
Viola Pomozi ◽  
Janna Zoll ◽  
Sheree Kuo ◽  
Ludovic Martin ◽  
...  
Keyword(s):  
Soft Tissues ◽  
Genetic Disorders ◽  
Pseudoxanthoma Elasticum ◽  
Arterial Calcification ◽  
Ectopic Calcification ◽  
Direct Inhibition ◽  
Inorganic Pyrophosphate ◽  
Cardiovascular Tissues ◽  
Ectopic Mineralization

Pathological (ectopic) mineralization of soft tissues occurs during aging, in several common conditions such as diabetes, hypercholesterolemia, and renal failure and in certain genetic disorders. Pseudoxanthoma elasticum (PXE), a multi-organ disease affecting dermal, ocular, and cardiovascular tissues, is a model for ectopic mineralization disorders. ABCC6 dysfunction is the primary cause of PXE, but also some cases of generalized arterial calcification of infancy (GACI). ABCC6 deficiency in mice underlies an inducible dystrophic cardiac calcification phenotype (DCC). These calcification diseases are part of a spectrum of mineralization disorders that also includes Calcification of Joints and Arteries (CALJA). Since the identification of ABCC6 as the “PXE gene” and the development of several animal models (mice, rat, and zebrafish), there has been significant progress in our understanding of the molecular genetics, the clinical phenotypes, and pathogenesis of these diseases, which share similarities with more common conditions with abnormal calcification. ABCC6 facilitates the cellular efflux of ATP, which is rapidly converted into inorganic pyrophosphate (PPi) and adenosine by the ectonucleotidases NPP1 and CD73 (NT5E). PPi is a potent endogenous inhibitor of calcification, whereas adenosine indirectly contributes to calcification inhibition by suppressing the synthesis of tissue non-specific alkaline phosphatase (TNAP). At present, therapies only exist to alleviate symptoms for both PXE and GACI; however, extensive studies have resulted in several novel approaches to treating PXE and GACI. This review seeks to summarize the role of ABCC6 in ectopic calcification in PXE and other calcification disorders, and discuss therapeutic strategies targeting various proteins in the pathway (ABCC6, NPP1, and TNAP) and direct inhibition of calcification via supplementation by various compounds.

scholarly journals Role of Serum Fetuin-A, a Major Inhibitor of Systemic Calcification, in Pseudoxanthoma Elasticum

2006 ◽  
Vol 52 (2) ◽  
pp. 227-234 ◽  
Author(s):  
Doris Hendig ◽  
Veronika Schulz ◽  
Marius Arndt ◽  
Christiane Szliska ◽  
Knut Kleesiek ◽  
...  
Keyword(s):  
Blood Donors ◽  
Family Members ◽  
Gene Mutations ◽  
Pseudoxanthoma Elasticum ◽  
Elastic Fibers ◽  
Fetuin A ◽  
Cardiovascular Involvement ◽  
Abcc6 Gene ◽  
Sandwich Enzyme Immunoassay

Abstract Background: Pseudoxanthoma elasticum (PXE) is a hereditary disorder of the connective tissue affecting the skin, retina, and cardiovascular system and characterized by progressive calcification of abnormal and fragmented elastic fibers in the extracellular matrix. The aim of the present study was to investigate the association of fetuin-A, a major systemic inhibitor of calcification, with PXE. Methods: Fetuin-A was measured by quantitative sandwich enzyme immunoassay in sera from 110 German patients with PXE, 53 unaffected first-degree family members, and 80 healthy blood donors. We determined the distribution of the fetuin-A polymorphisms c.742C>T (p.T248M) and c.766C>G (p.T256S) in these same 3 groups. The occurrences of the frequent ABCC6 gene mutations c.3421C>T (p.R1141X) and c.EX23_EX29del were also assessed. Results: Serum fetuin-A concentrations in male and female PXE patients were lower than in unaffected first-degree relatives and controls [mean (SD) concentrations, 0.55 (0.11) g/L in patients; 0.70 (0.23) g/L in relatives; and 0.80 (0.23) g/L in controls (P <0.0001)]. Serum fetuin-A was higher in female PXE patients with cardiovascular involvement than in the corresponding male group (P <0.05). The fetuin-A polymorphism frequencies did not differ among PXE patients, family members, and blood donors. Conclusion: A deficiency of multidrug resistance-associated protein 6 leads to alteration of circulating substrates, e.g., inhibitors of calcification as fetuin-A, leading to progressive mineralization of elastic fibers in PXE.

scholarly journals The Role of Vitamin K and Its Related Compounds in Mendelian and Acquired Ectopic Mineralization Disorders

2019 ◽  
Vol 20 (9) ◽  
pp. 2142
Author(s):  
Lukas Nollet ◽  
Matthias Van Gils ◽  
Shana Verschuere ◽  
Olivier Vanakker
Keyword(s):  
Vitamin K ◽  
Current Knowledge ◽  
Pseudoxanthoma Elasticum ◽  
Ectopic Calcification ◽  
Multifactorial Diseases ◽  
Multiple Organs ◽  
Keutel Syndrome ◽  
Ectopic Mineralization ◽  
Related Compounds

Ectopic mineralization disorders comprise a broad spectrum of inherited or acquired diseases characterized by aberrant deposition of calcium crystals in multiple organs, such as the skin, eyes, kidneys, and blood vessels. Although the precise mechanisms leading to ectopic calcification are still incompletely known to date, various molecular targets leading to a disturbed balance between pro- and anti-mineralizing pathways have been identified in recent years. Vitamin K and its related compounds, mainly those post-translationally activated by vitamin K-dependent carboxylation, may play an important role in the pathogenesis of ectopic mineralization as has been demonstrated in studies on rare Mendelian diseases, but also on highly prevalent disorders, like vascular calcification. This narrative review compiles and summarizes the current knowledge regarding the role of vitamin K, its metabolism, and associated compounds in the pathophysiology of both monogenic ectopic mineralization disorders, like pseudoxanthoma elasticum or Keutel syndrome, as well as acquired multifactorial diseases, like chronic kidney disease. Clinical and molecular aspects of the various disorders are discussed according to the state-of-the-art, followed by a comprehensive literature review regarding the role of vitamin K in molecular pathophysiology and as a therapeutic target in both human and animal models of ectopic mineralization disorders.

scholarly journals Disruption of Abcc6 Transporter in Zebrafish Causes Ocular Calcification and Cardiac Fibrosis

2020 ◽  
Vol 22 (1) ◽  
pp. 278
Author(s):  
Jianjian Sun ◽  
Peilu She ◽  
Xu Liu ◽  
Bangjun Gao ◽  
Daqin Jin ◽  
...  
Keyword(s):  
Vitamin K ◽  
Cardiac Fibrosis ◽  
Clinical Manifestations ◽  
Pseudoxanthoma Elasticum ◽  
Matrix Gla Protein ◽  
Ectopic Calcification ◽  
Transcription Activator ◽  
Multisystem Disorder ◽  
Ectopic Mineralization ◽  
Extensive Calcification

Pseudoxanthoma elasticum (PXE), caused by ABCC6/MRP6 mutation, is a heritable multisystem disorder in humans. The progressive clinical manifestations of PXE are accompanied by ectopic mineralization in various connective tissues. However, the pathomechanisms underlying the PXE multisystem disorder remains obscure, and effective treatment is currently available. In this study, we generated zebrafish abcc6a mutants using the transcription activator-like effector nuclease (TALEN) technique. In young adult zebrafish, abcc6a is expressed in the eyes, heart, intestine, and other tissues. abcc6a mutants exhibit extensive calcification in the ocular sclera and Bruch’s membrane, recapitulating part of the PXE manifestations. Mutations in abcc6a upregulate extracellular matrix (ECM) genes, leading to fibrotic heart with reduced cardiomyocyte number. We found that abcc6a mutation reduced levels of both vitamin K and pyrophosphate (PPi) in the serum and diverse tissues. Vitamin K administration increased the gamma-glutamyl carboxylated form of matrix gla protein (cMGP), alleviating ectopic calcification and fibrosis in vertebrae, eyes, and hearts. Our findings contribute to a comprehensive understanding of PXE pathophysiology from zebrafish models.

scholarly journals Therapy of Pseudoxanthoma Elasticum: Current Knowledge and Future Perspectives

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1895
Author(s):  
Max Jonathan Stumpf ◽  
Nadjib Schahab ◽  
Georg Nickenig ◽  
Dirk Skowasch ◽  
Christian Alexander Schaefer
Keyword(s):  
Current Knowledge ◽  
Treatment Options ◽  
Pseudoxanthoma Elasticum ◽  
Skin Lesions ◽  
Arterial Calcification ◽  
Future Perspectives ◽  
Strong Inhibitor ◽  
New Therapeutic Approaches ◽  
Pathogenic Variants ◽  
Abcc6 Gene

Pseudoxanthoma elasticum (PXE) is a rare, genetic, metabolic disease with an estimated prevalence of between 1 per 25,000 and 56,000. Its main hallmarks are characteristic skin lesions, development of choroidal neovascularization, and early-onset arterial calcification accompanied by a severe reduction in quality-of-life. Underlying the pathology are recessively transmitted pathogenic variants of the ABCC6 gene, which results in a deficiency of ABCC6 protein. This results in reduced levels of peripheral pyrophosphate, a strong inhibitor of peripheral calcification, but also dysregulation of blood lipids. Although various treatment options have emerged during the last 20 years, many are either already outdated or not yet ready to be applied generally. Clinical physicians often are left stranded while patients suffer from the consequences of outdated therapies, or feel unrecognized by their attending doctors who may feel uncertain about using new therapeutic approaches or not even know about them. In this review, we summarize the broad spectrum of treatment options for PXE, focusing on currently available clinical options, the latest research and development, and future perspectives.

scholarly journals Increased Elastin Degradation in Pseudoxanthoma Elasticum Is Associated with Peripheral Arterial Disease Independent of Calcification

2020 ◽  
Vol 9 (9) ◽  
pp. 2771
Author(s):  
Jonas W. Bartstra ◽  
Wilko Spiering ◽  
Jody M. W. van den Ouweland ◽  
Willem P. T. M. Mali ◽  
Rob Janssen ◽  
...  
Keyword(s):  
Peripheral Arterial Disease ◽  
Ankle Brachial Index ◽  
Pseudoxanthoma Elasticum ◽  
Arterial Disease ◽  
Arterial Calcification ◽  
Elastin Degradation ◽  
Liquid Chromatography Tandem Mass ◽  
Peripheral Arterial ◽  
Fontaine Classification

Pseudoxanthoma elasticum (PXE) results in extensive fragmentation and calcification of elastin fibers in the peripheral arteries, which results in peripheral arterial disease (PAD). Current research focuses on the role of calcifications in the pathogenesis of PXE. Elastin degradation and calcification are shown to interact and may amplify each other. This study aims to compare plasma desmosines, a measure of elastin degradation, between PXE patients and controls and to investigate the association between desmosines and (1) arterial calcification, (2) PAD, and (3) PAD independent of arterial calcification in PXE. Plasma desmosines were quantified with liquid chromatography-tandem mass spectrometry in 93 PXE patients and 72 controls. In PXE patients, arterial calcification mass was quantified on CT scans. The ankle brachial index (ABI) after treadmill test was used to analyze PAD, defined as ABI < 0.9, and the Fontaine classification was used to distinguish symptomatic and asymptomatic PAD. Regression models were built to test the association between desmosines and arterial calcification and arterial functioning in PXE. PXE patients had higher desmosines than controls (350 (290–410) ng/L vs. 320 (280–360) ng/L, p = 0.02). After adjustment for age, sex, body mass index, smoking, type 2 diabetes mellitus, and pulmonary abnormalities, desmosines were associated with worse ABI (β (95%CI): −68 (−132; −3) ng/L), more PAD (β (95%CI): 40 (7; 73) ng/L), and higher Fontaine classification (β (95%CI): 30 (6; 53) ng/L), but not with arterial calcification mass. Lower ABI was associated with higher desmosines, independent from arterial calcification mass (β (95%CI): −0.71(−1.39; −0.01)). Elastin degradation is accelerated in PXE patients compared to controls. The association between desmosines and ABI emphasizes the role of elastin degradation in PAD in PXE. Our results suggest that both elastin degradation and arterial calcification independently contribute to PAD in PXE.

scholarly journals Therapeutics Development for Pseudoxanthoma Elasticum and Related Ectopic Mineralization Disorders: Update 2020

2020 ◽  
Vol 10 (1) ◽  
pp. 114
Author(s):  
Hongbin Luo ◽  
Qiaoli Li ◽  
Yi Cao ◽  
Jouni Uitto
Keyword(s):  
Plasma Levels ◽  
Autosomal Recessive Disorder ◽  
Pseudoxanthoma Elasticum ◽  
Calcium Hydroxyapatite ◽  
The Elderly ◽  
Arterial Calcification ◽  
Inorganic Pyrophosphate ◽  
Treatment Development ◽  
Arterial Blood ◽  
Ectopic Mineralization

Pseudoxanthoma elasticum (PXE), the prototype of heritable ectopic mineralization disorders, manifests with deposition of calcium hydroxyapatite crystals in the skin, eyes and arterial blood vessels. This autosomal recessive disorder, due to mutations in ABCC6, is usually diagnosed around the second decade of life. In the spectrum of heritable ectopic mineralization disorders are also generalized arterial calcification of infancy (GACI), with extremely severe arterial calcification diagnosed by prenatal ultrasound or perinatally, and arterial calcification due to CD73 deficiency (ACDC) manifesting with arterial and juxta-articular mineralization in the elderly; the latter disorders are caused by mutations in ENPP1 and NT5E, respectively. The unifying pathomechanistic feature in these three conditions is reduced plasma levels of inorganic pyrophosphate (PPi), a powerful endogenous inhibitor of ectopic mineralization. Several on-going attempts to develop treatments for these conditions, either with the goal to normalize PPi plasma levels or by means of preventing calcium hydroxyapatite deposition independent of PPi, are in advanced preclinical levels or in early clinical trials. This overview summarizes the prospects of treatment development for ectopic mineralization disorders, with PXE, GACI and ACDC as the target diseases, from the 2020 vantage point.

scholarly journals Mutations in the ABCC6 Gene as a Cause of Generalized Arterial Calcification of Infancy: Genotypic Overlap with Pseudoxanthoma Elasticum

2014 ◽  
Vol 134 (3) ◽  
pp. 658-665 ◽  
Author(s):  
Qiaoli Li ◽  
Jill L. Brodsky ◽  
Laura K. Conlin ◽  
Bruce Pawel ◽  
Andrew C. Glatz ◽  
...  
Keyword(s):  
Pseudoxanthoma Elasticum ◽  
Arterial Calcification ◽  
Abcc6 Gene

scholarly journals Pseudoxanthoma Elasticum, Kidney Stones and Pyrophosphate: From a Rare Disease to Urolithiasis and Vascular Calcifications

2019 ◽  
Vol 20 (24) ◽  
pp. 6353 ◽  
Author(s):  
Emmanuel Letavernier ◽  
Elise Bouderlique ◽  
Jeremy Zaworski ◽  
Ludovic Martin ◽  
Michel Daudon
Keyword(s):  
Rare Disease ◽  
Kidney Stones ◽  
Genetic Disorders ◽  
Gene Mutations ◽  
Pseudoxanthoma Elasticum ◽  
Elastic Fibers ◽  
Mendelian Disease ◽  
Vascular Calcifications ◽  
Stone Formers ◽  
Abcc6 Gene

Pseudoxanthoma elasticum is a rare disease mainly due to ABCC6 gene mutations and characterized by ectopic biomineralization and fragmentation of elastic fibers resulting in skin, cardiovascular and retinal calcifications. It has been recently described that pyrophosphate (a calcification inhibitor) deficiency could be the main cause of ectopic calcifications in this disease and in other genetic disorders associated to mutations of ENPP1 or CD73. Patients affected by Pseudoxanthoma Elasticum seem also prone to develop kidney stones originating from papillary calcifications named Randall’s plaque, and to a lesser extent may be affected by nephrocalcinosis. In this narrative review, we summarize some recent discoveries relative to the pathophysiology of this mendelian disease responsible for both cardiovascular and renal papillary calcifications, and we discuss the potential implications of pyrophosphate deficiency as a promoter of vascular calcifications in kidney stone formers and in patients affected by chronic kidney disease.

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