Oral supplementation of inorganic pyrophosphate in pseudoxanthoma elasticum

2021 ◽  
Author(s):  
Eszter Kozák ◽  
Krisztina Fülöp ◽  
Natália Tőkési ◽  
Nidhi Rao ◽  
Qiaoli Li ◽  
...  
Keyword(s):  
Pseudoxanthoma Elasticum ◽  
Inorganic Pyrophosphate ◽  
Oral Supplementation

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 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 Plasma inorganic pyrophosphate and alkaline phosphatase in patients with pseudoxanthoma elasticum

2019 ◽  
Vol 7 (24) ◽  
pp. 798-798 ◽  
Author(s):  
Ana María Sánchez-Tévar ◽  
María García-Fernández ◽  
Belén Murcia-Casas ◽  
José Rioja-Villodres ◽  
Juan Luis Carrillo ◽  
...  
Keyword(s):  
Alkaline Phosphatase ◽  
Pseudoxanthoma Elasticum ◽  
Inorganic Pyrophosphate

scholarly journals Nonlinear optical microscopy is a novel tool for the analysis of cutaneous alterations in pseudoxanthoma elasticum

2020 ◽  
Vol 35 (8) ◽  
pp. 1821-1830 ◽  
Author(s):  
Norbert Kiss ◽  
Luca Fésűs ◽  
Szabolcs Bozsányi ◽  
Flóra Szeri ◽  
Matthias Van Gils ◽  
...  
Keyword(s):  
Early Diagnosis ◽  
Nonlinear Optical ◽  
Second Harmonic ◽  
Histopathological Examination ◽  
Pseudoxanthoma Elasticum ◽  
Calcium Deposition ◽  
Inorganic Pyrophosphate ◽  
Ectopic Mineralization ◽  
New Variant ◽  
Cardiovascular Assessment

Abstract Pseudoxanthoma elasticum (PXE, OMIM 264800) is a rare autosomal recessive disorder with ectopic mineralization and fragmentation of elastin fibers. It is caused by mutations of the ABCC6 gene that leads to decreased serum levels of inorganic pyrophosphate (PPi) anti-mineralization factor. The occurrence of severe complications among PXE patients highlights the importance of early diagnosis so that prompt multidisciplinary care can be provided to patients. We aimed to examine dermal connective tissue with nonlinear optical (NLO) techniques, as collagen emits second-harmonic generation (SHG) signal, while elastin can be excited by two-photon excitation fluorescence (TPF). We performed molecular genetic analysis, ophthalmological and cardiovascular assessment, plasma PPi measurement, conventional histopathological examination, and ex vivo SHG and TPF imaging in five patients with PXE and five age- and gender-matched healthy controls. Pathological mutations including one new variant were found in the ABCC6 gene in all PXE patients and their plasma PPi level was significantly lower compared with controls. Degradation and mineralization of elastin fibers and extensive calcium deposition in the mid-dermis was visualized and quantified together with the alterations of the collagen structure in PXE. Our data suggests that NLO provides high-resolution imaging of the specific histopathological features of PXE-affected skin. In vivo NLO may be a promising tool in the assessment of PXE, promoting early diagnosis and follow-up.

scholarly journals The pathogenic p.(R391G) ABCC6 displays incomplete penetrance implying the necessity of an interacting partner for the development of pseudoxanthoma elasticum

2020 ◽  
Author(s):  
Flora Szeri ◽  
Agnes Miko ◽  
Nastassia Navasiolava ◽  
Ambrus Kaposi ◽  
Shana Verschuere ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Pseudoxanthoma Elasticum ◽  
Reference Population ◽  
Pathogenic Variant ◽  
Ectopic Calcification ◽  
Incomplete Penetrance ◽  
Sequence Variant ◽  
Primary Role ◽  
Inorganic Pyrophosphate ◽  
Pathogenic Variants

AbstractABCC6 encodes a transmembrane transporter playing a primary role in the efflux of ATP from hepatocytes to the bloodstream. ATP is then cleaved to AMP and inorganic pyrophosphate, a major inhibitor of ectopic calcification. Pathogenic variants of ABCC6 cause pseudoxanthoma elasticum, a multisystemic recessive ectopic calcification disease of variable severity. One of the mechanisms influencing the heterogeneity of a disorder is the penetrance of pathogenic variants. The penetrance of a sequence variant shows the proportion of individuals developing the expected phenotype in the presence of the variant. Incomplete penetrance indicates that the disease does not develop in all the cases when the pathogenic variant is present. Here, we investigated whether incomplete penetrance participates in the heterogeneity of pseudoxanthoma elasticum. By integrating the clinical and genetic data of 590 patients, we created the largest European pseudoxanthoma elasticum cohort. We identified two incomplete penetrant pathogenic variants, p.(V787I) and p.(R391G), based on their allele frequencies in our cohort and in the European reference population of gnomAD. The detailed characterization of the frequent p.(R391G) pathogenic variant suggested only 2% penetrance with an unaltered severity of the clinical phenotype. Based on our biochemical analysis, we hypothesize that the variant becomes deleterious only if an interacting partner is mutated simultaneously. These data point to new molecular mechanisms by revealing the potential existence of the first interacting partner of ABCC6. Our data are important for genetic counseling of pseudoxanthoma elasticum, suggesting a much lower disease heritability of these pathogenic variants.

Crystal structures of plant inorganic pyrophosphatase, an enzyme with a moonlighting autoproteolytic activity

2019 ◽  
Vol 476 (16) ◽  
pp. 2297-2319 ◽  
Author(s):  
Marta Grzechowiak ◽  
Milosz Ruszkowski ◽  
Joanna Sliwiak ◽  
Kamil Szpotkowski ◽  
Michal Sikorski ◽  
...  
Keyword(s):  
Site Directed Mutagenesis ◽  
Size Exclusion ◽  
Inorganic Pyrophosphatase ◽  
Prolonged Storage ◽  
Mitochondrial Targeting ◽  
Cleavage Rate ◽  
Inorganic Pyrophosphate ◽  
Putative Signal Peptide ◽  
Targeting Peptide

Abstract Inorganic pyrophosphatases (PPases, EC 3.6.1.1), which hydrolyze inorganic pyrophosphate to phosphate in the presence of divalent metal cations, play a key role in maintaining phosphorus homeostasis in cells. DNA coding inorganic pyrophosphatases from Arabidopsis thaliana (AtPPA1) and Medicago truncatula (MtPPA1) were cloned into a bacterial expression vector and the proteins were produced in Escherichia coli cells and crystallized. In terms of their subunit fold, AtPPA1 and MtPPA1 are reminiscent of other members of Family I soluble pyrophosphatases from bacteria and yeast. Like their bacterial orthologs, both plant PPases form hexamers, as confirmed in solution by multi-angle light scattering and size-exclusion chromatography. This is in contrast with the fungal counterparts, which are dimeric. Unexpectedly, the crystallized AtPPA1 and MtPPA1 proteins lack ∼30 amino acid residues at their N-termini, as independently confirmed by chemical sequencing. In vitro, self-cleavage of the recombinant proteins is observed after prolonged storage or during crystallization. The cleaved fragment corresponds to a putative signal peptide of mitochondrial targeting, with a predicted cleavage site at Val31–Ala32. Site-directed mutagenesis shows that mutations of the key active site Asp residues dramatically reduce the cleavage rate, which suggests a moonlighting proteolytic activity. Moreover, the discovery of autoproteolytic cleavage of a mitochondrial targeting peptide would change our perception of this signaling process.

Epigenetic control of TNAP expression in Pseudoxanthoma elasticum fibroblasts

2012 ◽  
Author(s):  
Angela Ostuni ◽  
Vittoria Infantino ◽  
Antonella Salvia ◽  
Rocchina Miglionico ◽  
Federica Boraldi ◽  
...  
Keyword(s):  
Pseudoxanthoma Elasticum ◽  
Epigenetic Control

Placental Transfer of Vitamin K1 and Its Implications in Fetal Hemostasis

1988 ◽  
Vol 60 (01) ◽  
pp. 039-043 ◽  
Author(s):  
L Mandelbrot ◽  
M Guillaumont ◽  
M Leclercq ◽  
J J Lefrère ◽  
D Gozin ◽  
...  
Keyword(s):  
Vitamin K ◽  
High Performance ◽  
Ultrasound Guidance ◽  
Placental Transfer ◽  
Vitamin K1 ◽  
Vitamin K Deficiency ◽  
Prothrombin Activity ◽  
Oral Supplementation ◽  
K Deficiency ◽  
The Mean

SummaryVitamin K status was evaluated using coagulation studies and/ or vitamin IQ assays in a total of 53 normal fetuses and 47 neonates. Second trimester fetal blood samples were obtained for prenatal diagnosis under ultrasound guidance. Endogenous vitamin K1 concentrations (determined by high performance liquid chromatography) were substantially lower than maternal levels. The mean maternal-fetal gradient was 14-fold at mid trimester and 18-fold at birth. Despite low vitamin K levels, descarboxy prothrombin, detected by a staphylocoagulase assay, was elevated in only a single fetus and a single neonate.After maternal oral supplementation with vitamin K1, cord vitamin K1 levels were boosted 30-fold at mid trimester and 60 fold at term, demonstrating placental transfer. However, these levels were substantially lower than corresponding supplemented maternal levels. Despite elevated vitamin K1 concentrations, supplemented fetuses and neonates showed no increase in total or coagulant prothrombin activity. These results suggest that the low prothrombin levels found during intrauterine life are not due to vitamin K deficiency.

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