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Open AccessArticle

Signaling Cascade Involved in Rapid Stimulation of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) by Dexamethasone

by Miriam Bossmann, Benjamin W. Ackermann, Ulrich H. Thome and Mandy Laube

Int. J. Mol. Sci. 2017, 18(8), 1807; https://doi.org/10.3390/ijms18081807 - 19 Aug 2017

Cited by 6 | Viewed by 6208

Abstract

Impairment of mucociliary clearance with reduced airway fluid secretion leads to chronically inflamed airways. Cystic fibrosis transmembrane conductance regulator (CFTR) is crucially involved in airway fluid secretion and dexamethasone (dexa) has previously been shown to elevate CFTR activity in airway epithelial cells. However, [...] Read more.

Impairment of mucociliary clearance with reduced airway fluid secretion leads to chronically inflamed airways. Cystic fibrosis transmembrane conductance regulator (CFTR) is crucially involved in airway fluid secretion and dexamethasone (dexa) has previously been shown to elevate CFTR activity in airway epithelial cells. However, the pathway by which dexa increases CFTR activity is largely unknown. We aimed to determine whether the increase of CFTR activity by dexa is achieved by non-genomic signaling and hypothesized that the phosphoinositide 3-kinase (PI3K) pathway is involved in CFTR stimulation. Primary rat airway epithelial cells and human bronchial submucosal gland-derived Calu-3 cells were analyzed in Ussing chambers and kinase activation was determined by Western blots. Results demonstrated a critical involvement of PI3K and protein kinase B (AKT) signaling in the dexa-induced increase of CFTR activity, while serum and glucocorticoid dependent kinase 1 (SGK1) activity was not essential. We further demonstrated a reduced neural precursor cell expressed, developmentally downregulated 4-like (NEDD4L) ubiquitin E3 ligase activity induced by dexa, possibly responsible for the elevated CFTR activity. Finally, increases of CFTR activity by dexa were demonstrated within 30 min accompanied by rapid activation of AKT. In conclusion, dexa induces a rapid stimulation of CFTR activity which depends on PI3K/AKT signaling in airway epithelial cells. Glucocorticoids might thus represent, in addition to their immunomodulatory actions, a therapeutic strategy to rapidly increase airway fluid secretion. Full article

(This article belongs to the Special Issue Physiological and Pathological Roles of ABC Transporters)

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Open AccessArticle

Increased Expression of Plasma-Induced ABCC1 mRNA in Cystic Fibrosis

by Justin E. Ideozu, Xi Zhang, Amy Pan, Zainub Ashrafi, Katherine J. Woods, Martin J. Hessner, Pippa Simpson and Hara Levy

Int. J. Mol. Sci. 2017, 18(8), 1752; https://doi.org/10.3390/ijms18081752 - 11 Aug 2017

Cited by 9 | Viewed by 4664

Abstract

The ABCC1 gene is structurally and functionally related to the cystic fibrosis transmembrane conductance regulator gene (CFTR). Upregulation of ABCC1 is thought to improve lung function in patients with cystic fibrosis (CF); the mechanism underlying this effect is unknown. We analyzed [...] Read more.

The ABCC1 gene is structurally and functionally related to the cystic fibrosis transmembrane conductance regulator gene (CFTR). Upregulation of ABCC1 is thought to improve lung function in patients with cystic fibrosis (CF); the mechanism underlying this effect is unknown. We analyzed the ABCC1 promoter single nucleotide polymorphism (SNP rs504348), plasma-induced ABCC1 mRNA expression levels, and ABCC1 methylation status and their correlation with clinical variables among CF subjects with differing CFTR mutations. We assigned 93 CF subjects into disease severity groups and genotyped SNP rs504348. For 23 CF subjects and 7 healthy controls, donor peripheral blood mononuclear cells (PBMCs) stimulated with plasma underwent gene expression analysis via qRT-PCR. ABCC1 promoter methylation was analyzed in the same 23 CF subjects. No significant correlation was observed between rs504348 genotypes and CF disease severity, but pancreatic insufficient CF subjects showed increased colonization with any form of Pseudomonas aeruginosa (OR = 3.125, 95% CI: 1.192–8.190) and mucoid P. aeruginosa (OR = 5.075, 95% CI: 1.307–28.620) compared to the pancreatic sufficient group. A significantly higher expression of ABCC1 mRNA was induced by CF plasma compared to healthy control plasma (p < 0.001). CF subjects with rs504348 (CC/CG) also had higher mRNA expression compared to those with the ancestral GG genotype (p < 0.005). ABCC1 promoter was completely unmethylated; therefore, we did not detect any association between methylation and CF disease severity. In silico predictions suggested that histone modifications are crucial for regulating ABCC1 expression in PBMCs. Our results suggest that ABCC1 expression has a role in CFTR activity thereby increasing our understanding of the molecular underpinnings of the clinical heterogeneity in CF. Full article

(This article belongs to the Special Issue Physiological and Pathological Roles of ABC Transporters)

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Open AccessArticle

Predictive Structure and Topology of Peroxisomal ATP-Binding Cassette (ABC) Transporters

by Pierre Andreoletti, Quentin Raas, Catherine Gondcaille, Mustapha Cherkaoui-Malki, Doriane Trompier and Stéphane Savary

Int. J. Mol. Sci. 2017, 18(7), 1593; https://doi.org/10.3390/ijms18071593 - 22 Jul 2017

Cited by 15 | Viewed by 7462

Abstract

The peroxisomal ATP-binding Cassette (ABC) transporters, which are called ABCD1, ABCD2 and ABCD3, are transmembrane proteins involved in the transport of various lipids that allow their degradation inside the organelle. Defective ABCD1 leads to the accumulation of very long-chain fatty acids and is [...] Read more.

The peroxisomal ATP-binding Cassette (ABC) transporters, which are called ABCD1, ABCD2 and ABCD3, are transmembrane proteins involved in the transport of various lipids that allow their degradation inside the organelle. Defective ABCD1 leads to the accumulation of very long-chain fatty acids and is associated with a complex and severe neurodegenerative disorder called X-linked adrenoleukodystrophy (X-ALD). Although the nucleotide-binding domain is highly conserved and characterized within the ABC transporters family, solid data are missing for the transmembrane domain (TMD) of ABCD proteins. The lack of a clear consensus on the secondary and tertiary structure of the TMDs weakens any structure-function hypothesis based on the very diverse ABCD1 mutations found in X-ALD patients. Therefore, we first reinvestigated thoroughly the structure-function data available and performed refined alignments of ABCD protein sequences. Based on the 2.85 Å resolution crystal structure of the mitochondrial ABC transporter ABCB10, here we propose a structural model of peroxisomal ABCD proteins that specifies the position of the transmembrane and coupling helices, and highlight functional motifs and putative important amino acid residues. Full article

(This article belongs to the Special Issue Physiological and Pathological Roles of ABC Transporters)

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Open AccessArticle

Quantitative Evaluation of Drug Resistance Profile of Cells Expressing Wild-Type or Genetic Polymorphic Variants of the Human ABC Transporter ABCC4

by Megumi Tsukamoto, Shiori Sato, Kazuhiro Satake, Mizuki Miyake and Hiroshi Nakagawa

Int. J. Mol. Sci. 2017, 18(7), 1435; https://doi.org/10.3390/ijms18071435 - 4 Jul 2017

Cited by 14 | Viewed by 4455

Abstract

Broad-spectrum resistance in cancer cells is often caused by the overexpression of ABC transporters; which varies across individuals because of genetic single-nucleotide polymorphisms (SNPs). In the present study; we focused on human ABCC4 and established cells expressing the wild-type (WT) or SNP variants [...] Read more.

Broad-spectrum resistance in cancer cells is often caused by the overexpression of ABC transporters; which varies across individuals because of genetic single-nucleotide polymorphisms (SNPs). In the present study; we focused on human ABCC4 and established cells expressing the wild-type (WT) or SNP variants of human ABCC4 using the Flp-In™ system (Invitrogen, Life Technologies Corp, Carlsbad, CA, USA) based on Flp recombinase-mediated transfection to quantitatively evaluate the effects of nonsynonymous SNPs on the drug resistance profiles of cells. The mRNA levels of the cells expressing each ABCC4 variant were comparable. 3-(4,5-Dimethyl-2-thiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay clearly indicated that the EC₅₀ values of azathioprine against cells expressing ABCC4 (WT) were 1.4–1.7-fold higher than those against cells expressing SNP variants of ABCC4 (M184K; N297S; K304N or E757K). EC₅₀ values of 6-mercaptopurine or 7-Ethyl-10-hydroxy-camptothecin (SN-38) against cells expressing ABCC4 (WT) were also 1.4–2.0- or 1.9-fold higher than those against cells expressing the SNP variants of ABCC4 (K304N or E757K) or (K304N; P403L or E757K); respectively. These results indicate that the effects of nonsynonymous SNPs on the drug resistance profiles of cells expressing ABCC4 can be quantitatively evaluated using the Flp-In™ system. Full article

(This article belongs to the Special Issue Physiological and Pathological Roles of ABC Transporters)

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Open AccessCommunication

Clinical and Molecular Evidence of ABCC11 Protein Expression in Axillary Apocrine Glands of Patients with Axillary Osmidrosis

by Yu Toyoda, Tappei Takada, Tsuneaki Gomi, Hiroshi Nakagawa, Toshihisa Ishikawa and Hiroshi Suzuki

Int. J. Mol. Sci. 2017, 18(2), 417; https://doi.org/10.3390/ijms18020417 - 15 Feb 2017

Cited by 21 | Viewed by 6814

Abstract

Accumulating evidence suggests that the risk of axillary osmidrosis is governed by a non-synonymous single nucleotide polymorphism (SNP) 538G>A in human ATP-binding cassette C11 (ABCC11) gene. However, little data are available for the expression of ABCC11 protein in human axillary apocrine [...] Read more.

Accumulating evidence suggests that the risk of axillary osmidrosis is governed by a non-synonymous single nucleotide polymorphism (SNP) 538G>A in human ATP-binding cassette C11 (ABCC11) gene. However, little data are available for the expression of ABCC11 protein in human axillary apocrine glands that produce apocrine sweat—a source of odor from the armpits. To determine the effect of the non-synonymous SNP ABCC11 538G>A (G180R) on the ABCC11 in vivo, we generated transiently ABCC11-expressing transgenic mice with adenovirus vector, and examined the protein levels of each ABCC11 in the mice with immunoblotting using an anti-ABCC11 antibody we have generated in the present study. Furthermore, we examined the expression of ABCC11 protein in human axillary apocrine glands extracted from axillary osmidrosis patients carrying each ABCC11 genotype: 538GG, GA, and AA. Analyses of transiently ABCC11-expressing transgenic mice showed that ABCC11 538G>A diminishes the ABCC11 protein levels in vivo. Consistently, ABCC11 protein was detected in the human axillary apocrine glands of the 538GG homozygote or 538GA heterozygote, not in the 538AA homozygote. These findings would contribute to a better understanding of the molecular basis of axillary osmidrosis. Full article

(This article belongs to the Special Issue Physiological and Pathological Roles of ABC Transporters)

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Review

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Open AccessReview

Obstacles to Brain Tumor Therapy: Key ABC Transporters

by Juwina Wijaya, Yu Fukuda and John D. Schuetz

Int. J. Mol. Sci. 2017, 18(12), 2544; https://doi.org/10.3390/ijms18122544 - 27 Nov 2017

Cited by 67 | Viewed by 9084

Abstract

The delivery of cancer chemotherapy to treat brain tumors remains a challenge, in part, because of the inherent biological barrier, the blood–brain barrier. While its presence and role as a protector of the normal brain parenchyma has been acknowledged for decades, it is [...] Read more.

The delivery of cancer chemotherapy to treat brain tumors remains a challenge, in part, because of the inherent biological barrier, the blood–brain barrier. While its presence and role as a protector of the normal brain parenchyma has been acknowledged for decades, it is only recently that the important transporter components, expressed in the tightly knit capillary endothelial cells, have been deciphered. These transporters are ATP-binding cassette (ABC) transporters and, so far, the major clinically important ones that functionally contribute to the blood–brain barrier are ABCG2 and ABCB1. A further limitation to cancer therapy of brain tumors or brain metastases is the blood–tumor barrier, where tumors erect a barrier of transporters that further impede drug entry. The expression and regulation of these two transporters at these barriers, as well as tumor derived alteration in expression and/or mutation, are likely obstacles to effective therapy. Full article

(This article belongs to the Special Issue Physiological and Pathological Roles of ABC Transporters)

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Open AccessReview

ABC Transporters in Cancer Stem Cells: Beyond Chemoresistance

by Romana-Rea Begicevic and Marco Falasca

Int. J. Mol. Sci. 2017, 18(11), 2362; https://doi.org/10.3390/ijms18112362 - 8 Nov 2017

Cited by 274 | Viewed by 16244

Abstract

The efficacy of chemotherapy is one of the main challenges in cancer treatment and one of the major obstacles to overcome in achieving lasting remission and a definitive cure in patients with cancer is the emergence of cancer resistance. Indeed, drug resistance is [...] Read more.

The efficacy of chemotherapy is one of the main challenges in cancer treatment and one of the major obstacles to overcome in achieving lasting remission and a definitive cure in patients with cancer is the emergence of cancer resistance. Indeed, drug resistance is ultimately accountable for poor treatment outcomes and tumour relapse. There are various molecular mechanisms involved in multidrug resistance, such as the change in the activity of membrane transporters primarily belonging to the ATP binding cassette (ABC) transporter family. In addition, it has been proposed that this common feature could be attributed to a subpopulation of slow-cycling cancer stem cells (CSCs), endowed with enhanced tumorigenic potential and multidrug resistance. CSCs are characterized by the overexpression of specific surface markers that vary in different cancer cell types. Overexpression of ABC transporters has been reported in several cancers and more predominantly in CSCs. While the major focus on the role played by ABC transporters in cancer is polarized by their involvement in chemoresistance, emerging evidence supports a more active role of these proteins, in which they release specific bioactive molecules in the extracellular milieu. This review will outline our current understanding of the role played by ABC transporters in CSCs, how their expression is regulated and how they support the malignant metabolic phenotype. To summarize, we suggest that the increased expression of ABC transporters in CSCs may have precise functional roles and provide the opportunity to target, particularly these cells, by using specific ABC transporter inhibitors. Full article

(This article belongs to the Special Issue Physiological and Pathological Roles of ABC Transporters)

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Open AccessReview

The ABCC6 Transporter: A New Player in Biomineralization

by Guillaume Favre, Audrey Laurain, Tamas Aranyi, Flora Szeri, Krisztina Fulop, Olivier Le Saux, Christophe Duranton, Gilles Kauffenstein, Ludovic Martin and Georges Lefthériotis

Int. J. Mol. Sci. 2017, 18(9), 1941; https://doi.org/10.3390/ijms18091941 - 11 Sep 2017

Cited by 32 | Viewed by 6244

Abstract

Pseudoxanthoma elasticum (PXE) is an inherited metabolic disease with autosomal recessive inheritance caused by mutations in the ABCC6 gene. Since the first description of the disease in 1896, alleging a disease involving the elastic fibers, the concept evolved with the further discoveries of [...] Read more.

Pseudoxanthoma elasticum (PXE) is an inherited metabolic disease with autosomal recessive inheritance caused by mutations in the ABCC6 gene. Since the first description of the disease in 1896, alleging a disease involving the elastic fibers, the concept evolved with the further discoveries of the pivotal role of ectopic mineralization that is preponderant in the elastin-rich tissues of the skin, eyes and blood vessel walls. After discovery of the causative gene of the disease in 2000, the function of the ABCC6 protein remains elusive. More than 300 mutations have been now reported and the concept of a dermal disease has progressively evolved toward a metabolic disorder resulting from the remote effects caused by lack of a circulating anti-mineralization factor. Very recently, evidence has accumulated that this anti-mineralizing factor is inorganic pyrophosphate (PPi). This leads to decreased PPi/Pi (inorganic phosphate) ratio that results from the lack of extracellular ATP release by hepatocytes and probably renal cells harboring the mutant ABCC6 protein. However, the mechanism by which ABCC6 dysfunction causes diminished ATP release remains an enigma. Studies of other ABC transporters, such as ABCC7 or ABCC1 could help our understanding of what ABCC6 exact function is. Data and a hypothesis on the possible roles of ABCC6 in acquired metabolic diseases are also discussed. Full article

(This article belongs to the Special Issue Physiological and Pathological Roles of ABC Transporters)

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Implications of ABCG2 Expression on Irinotecan Treatment of Colorectal Cancer Patients: A Review

by Dorte Lisbet Nielsen, Jesper Andreas Palshof, Nils Brünner, Jan Stenvang and Birgitte Martine Viuff

Int. J. Mol. Sci. 2017, 18(9), 1926; https://doi.org/10.3390/ijms18091926 - 7 Sep 2017

Cited by 45 | Viewed by 4546

Abstract

Background: One of the main chemotherapeutic drugs used on a routine basis in patients with metastatic colorectal cancer ((m)CRC) is the topoisomerase-1 inhibitor, irinotecan. However, its usefulness is limited by the pre-existing or inevitable development of resistance. The ATP-binding cassette (ABC) transporter ABCG2/breast [...] Read more.

Background: One of the main chemotherapeutic drugs used on a routine basis in patients with metastatic colorectal cancer ((m)CRC) is the topoisomerase-1 inhibitor, irinotecan. However, its usefulness is limited by the pre-existing or inevitable development of resistance. The ATP-binding cassette (ABC) transporter ABCG2/breast cancer resistance protein (BRCP) through its function in xenobiotic clearance might play an important role in irinotecan resistance. With a goal to evaluate the clinical significance of ABCG2 measurements, we here review the current literature on ABCG2 in relation to irinotecan treatment in CRC patients. Results: Few studies have evaluated the association between ABCG2 gene or protein expression and prognosis in CRC patients. Discordant results were reported. The discrepancies might be explained by the use of different criteria for interpretation of results in the immunohistochemistry studies. Only one large study evaluated the ABCG2 protein expression and efficacy of irinotecan in mCRC (CAIRO study, n = 566). This study failed to demonstrate any correlation between ABCG2 protein expression in the primary tumor and response to irinotecan-based treatment. We recently raised questions on how to evaluate ABCG2 immunoreactivity patterns, and the results in the CAIRO study might be influenced by using a different scoring protocol than the one proposed by us. In contrast, our recent exploratory study of ABCG2 mRNA expression in 580 patients with stage III primary CRC (subgroup from the randomized PETACC-3 study) indicated that high ABCG2 tumor tissue mRNA expression might be predictive for lack of efficacy of irinotecan. Conclusion: The biological role of ABCG2 in predicting clinical irinotecan sensitivity/resistance in CRC is uncertain. In particular, the significance of ABCG2 cellular localization needs to be established. Data concerning ABCG2 mRNA expression and prediction of adjuvant irinotecan efficacy are still sparse and need to be confirmed. Full article

(This article belongs to the Special Issue Physiological and Pathological Roles of ABC Transporters)

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Open AccessReview

CFTR-NHERF2-LPA₂ Complex in the Airway and Gut Epithelia

by Weiqiang Zhang, Zhihong Zhang, Yanhui Zhang and Anjaparavanda P. Naren

Int. J. Mol. Sci. 2017, 18(9), 1896; https://doi.org/10.3390/ijms18091896 - 4 Sep 2017

Cited by 10 | Viewed by 5428

Abstract

The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP- and cGMP-regulated chloride (Cl⁻) and bicarbonate (HCO₃⁻) channel localized primarily at the apical plasma membrane of epithelial cells lining the airway, gut and exocrine glands, where it is [...] Read more.

The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP- and cGMP-regulated chloride (Cl⁻) and bicarbonate (HCO₃⁻) channel localized primarily at the apical plasma membrane of epithelial cells lining the airway, gut and exocrine glands, where it is responsible for transepithelial salt and water transport. Several human diseases are associated with altered CFTR channel function. Cystic fibrosis (CF) is caused by the absence or dysfunction of CFTR channel activity, resulting from mutations in the gene. Secretory diarrhea is caused by the hyperactivation of CFTR channel activity in the gastrointestinal tract. CFTR is a validated target for drug development to treat CF, and extensive research has been conducted to develop CFTR inhibitors for therapeutic interventions of secretory diarrhea. The intracellular processing, trafficking, apical membrane localization, and channel function of CFTR are regulated by dynamic protein–protein interactions in a complex network. In this paper, we review the current knowledge of a macromolecular complex of CFTR, Na⁺/H⁺ exchanger regulatory factor 2 (NHERF2), and lysophosphatidic acids (LPA) receptor 2 (LPA₂) at the apical plasma membrane of airway and gut epithelial cells, and discuss its relevance in human physiology and diseases. We also explore the possibilities of targeting this complex to fine tune CFTR channel activity, with a hope to open up new avenues to develop novel therapies for CF and secretory diarrhea. Full article

(This article belongs to the Special Issue Physiological and Pathological Roles of ABC Transporters)

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Critical Role of the Human ATP-Binding Cassette G1 Transporter in Cardiometabolic Diseases

by Lise M. Hardy, Eric Frisdal and Wilfried Le Goff

Int. J. Mol. Sci. 2017, 18(9), 1892; https://doi.org/10.3390/ijms18091892 - 2 Sep 2017

Cited by 39 | Viewed by 5930

Abstract

ATP-binding cassette G1 (ABCG1) is a member of the large family of ABC transporters which are involved in the active transport of many amphiphilic and lipophilic molecules including lipids, drugs or endogenous metabolites. It is now well established that ABCG1 promotes the export [...] Read more.

ATP-binding cassette G1 (ABCG1) is a member of the large family of ABC transporters which are involved in the active transport of many amphiphilic and lipophilic molecules including lipids, drugs or endogenous metabolites. It is now well established that ABCG1 promotes the export of lipids, including cholesterol, phospholipids, sphingomyelin and oxysterols, and plays a key role in the maintenance of tissue lipid homeostasis. Although ABCG1 was initially proposed to mediate cholesterol efflux from macrophages and then to protect against atherosclerosis and cardiovascular diseases (CVD), it becomes now clear that ABCG1 exerts a larger spectrum of actions which are of major importance in cardiometabolic diseases (CMD). Beyond a role in cellular lipid homeostasis, ABCG1 equally participates to glucose and lipid metabolism by controlling the secretion and activity of insulin and lipoprotein lipase. Moreover, there is now a growing body of evidence suggesting that modulation of ABCG1 expression might contribute to the development of diabetes and obesity, which are major risk factors of CVD. In order to provide the current understanding of the action of ABCG1 in CMD, we here reviewed major findings obtained from studies in mice together with data from the genetic and epigenetic analysis of ABCG1 in the context of CMD. Full article

(This article belongs to the Special Issue Physiological and Pathological Roles of ABC Transporters)

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Open AccessReview

The Mechanistic Links between Insulin and Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Cl⁻ Channel

by Yoshinori Marunaka

Int. J. Mol. Sci. 2017, 18(8), 1767; https://doi.org/10.3390/ijms18081767 - 14 Aug 2017

Cited by 9 | Viewed by 11237

Abstract

The cystic fibrosis transmembrane conductance regulator (CFTR) Cl⁻ channel belongs to the ATP-binding cassette (ABC) transporter superfamily and regulates Cl⁻ secretion in epithelial cells for water secretion. Loss-of-function mutations to the CFTR gene cause dehydrated mucus on the apical side of [...] Read more.

The cystic fibrosis transmembrane conductance regulator (CFTR) Cl⁻ channel belongs to the ATP-binding cassette (ABC) transporter superfamily and regulates Cl⁻ secretion in epithelial cells for water secretion. Loss-of-function mutations to the CFTR gene cause dehydrated mucus on the apical side of epithelial cells and increase the susceptibility of bacterial infection, especially in the airway and pulmonary tissues. Therefore, research on the molecular properties of CFTR, such as its gating mechanism and subcellular trafficking, have been intensively pursued. Dysregulated CFTR trafficking is one of the major pathological hallmarks in cystic fibrosis (CF) patients bearing missense mutations in the CFTR gene. Hormones that activate cAMP signaling, such as catecholamine, have been found to regulate the intracellular trafficking of CFTR. Insulin is one of the hormones that regulate cAMP production and promote trafficking of transmembrane proteins to the plasma membrane. The functional interactions between insulin and CFTR have not yet been clearly defined. In this review article, I review the roles of CFTR in epithelial cells, its regulatory role in insulin secretion, and a mechanism of CFTR regulation by insulin. Full article

(This article belongs to the Special Issue Physiological and Pathological Roles of ABC Transporters)

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ABCC6 and Pseudoxanthoma Elasticum: The Face of a Rare Disease from Genetics to Advocacy

by Karobi Moitra, Sonia Garcia, Michelle Jaldin, Clementine Etoundi, Donna Cooper, Anna Roland, Patrice Dixon, Sandra Reyes, Sevilay Turan, Sharon Terry and Michael Dean

Int. J. Mol. Sci. 2017, 18(7), 1488; https://doi.org/10.3390/ijms18071488 - 11 Jul 2017

Cited by 17 | Viewed by 9407

Abstract

Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder characterized by the mineralization of connective tissues in the body. Primary manifestation of PXE occurs in the tissues of the skin, eyes, and cardiovascular system. PXE is primarily caused by mutations in the ABCC6 gene. [...] Read more.

Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder characterized by the mineralization of connective tissues in the body. Primary manifestation of PXE occurs in the tissues of the skin, eyes, and cardiovascular system. PXE is primarily caused by mutations in the ABCC6 gene. The ABCC6 gene encodes the trans-membrane protein ABCC6, which is highly expressed in the kidneys and liver. PXE has high phenotypic variability, which may possibly be affected by several modifier genes. Disease advocacy organizations have had a pivotal role in bringing rare disease research to the forefront and in helping to sustain research funding for rare genetic diseases in order to help find a treatment for these diseases, pseudoxanthoma elasticum included. Because of these initiatives, individuals affected by these conditions benefit by being scientifically informed about their condition, having an effective support mechanism, and also by contributing to scientific research efforts and banking of biological samples. This rapid progress would not have been possible without the aid of disease advocacy organizations such as PXE International. Full article

(This article belongs to the Special Issue Physiological and Pathological Roles of ABC Transporters)

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