Functional Assessment of Missense Variants in the ABCC6 gene Implicated in Pseudoxanthoma Elasticum, a Heritable Ectopic Mineralization Disorder

2021 ◽  
Author(s):  
Luke Kowal ◽  
Jianhe Huang ◽  
Hongbin Luo ◽  
Jagmohan Singh ◽  
Adam E. Snook ◽  
...  
Keyword(s):  
Functional Assessment ◽  
Pseudoxanthoma Elasticum ◽  
Missense Variants ◽  
Ectopic Mineralization ◽  
Abcc6 Gene

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 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.

scholarly journals Targeted Ablation of the Abcc6 Gene Results in Ectopic Mineralization of Connective Tissues

2005 ◽  
Vol 25 (18) ◽  
pp. 8299-8310 ◽  
Author(s):  
John F. Klement ◽  
Yasushi Matsuzaki ◽  
Qiu-Jie Jiang ◽  
Joseph Terlizzi ◽  
Hae Young Choi ◽  
...  
Keyword(s):  
Complex Disease ◽  
Soft Tissues ◽  
Subcutaneous Tissue ◽  
Pseudoxanthoma Elasticum ◽  
Connective Tissues ◽  
Alizarin Red ◽  
Arterial Blood ◽  
Ectopic Mineralization ◽  
Abcc6 Gene ◽  
Total Body

ABSTRACT Pseudoxanthoma elasticum (PXE), characterized by connective tissue mineralization of the skin, eyes, and cardiovascular system, is caused by mutations in the ABCC6 gene. ABCC6 encodes multidrug resistance-associated protein 6 (MRP6), which is expressed primarily in the liver and kidneys. Mechanisms producing ectopic mineralization as a result of these mutations remain unclear. To elucidate this complex disease, a transgenic mouse was generated by targeted ablation of the mouse Abcc6 gene. Abcc6 null mice were negative for Mrp6 expression in the liver, and complete necropsies revealed profound mineralization of several tissues, including skin, arterial blood vessels, and retina, while heterozygous animals were indistinguishable from the wild-type mice. Particularly striking was the mineralization of vibrissae, as confirmed by von Kossa and alizarin red stains. Electron microscopy revealed mineralization affecting both elastic structures and collagen fibers. Mineralization of vibrissae was noted as early as 5 weeks of age and was progressive with age in Abcc6 −/− mice but was not observed in Abcc6 +/− or Abcc6 +/+ mice up to 2 years of age. A total body computerized tomography scan of Abcc6 −/− mice revealed mineralization in skin and subcutaneous tissue as well as in the kidneys. These data demonstrate aberrant mineralization of soft tissues in PXE-affected organs, and, consequently, these mice recapitulate features of this complex disease.

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 166 Functional characterization of missense variants in ABCC6, the gene responsible for pseudoxanthoma elasticum

2021 ◽  
Vol 141 (5) ◽  
pp. S29
Author(s):  
J. Huang ◽  
L. Kowal ◽  
J. Singh ◽  
A.E. Snook ◽  
J. Uitto ◽  
...  
Keyword(s):  
Functional Characterization ◽  
Pseudoxanthoma Elasticum ◽  
Missense Variants

scholarly journals Structural and Functional Characterization of the ABCC6 Transporter in Hepatic Cells: Role on PXE, Cancer Therapy and Drug Resistance

2021 ◽  
Vol 22 (6) ◽  
pp. 2858
Author(s):  
Faustino Bisaccia ◽  
Prashant Koshal ◽  
Vittorio Abruzzese ◽  
Maria Antonietta Castiglione Morelli ◽  
Angela Ostuni
Keyword(s):  
Cancer Therapy ◽  
Functional Characterization ◽  
Physiological Role ◽  
Pseudoxanthoma Elasticum ◽  
Connective Tissues ◽  
Functional Studies ◽  
Extracellular Milieu ◽  
Hepatic Cells ◽  
Ectopic Mineralization ◽  
Anti Cancer

Pseudoxanthoma elasticum (PXE) is a complex autosomal recessive disease caused by mutations of ABCC6 transporter and characterized by ectopic mineralization of soft connective tissues. Compared to the other ABC transporters, very few studies are available to explain the structural components and working of a full ABCC6 transporter, which may provide some idea about its physiological role in humans. Some studies suggest that mutations of ABCC6 in the liver lead to a decrease in some circulating factor and indicate that PXE is a metabolic disease. It has been reported that ABCC6 mediates the efflux of ATP, which is hydrolyzed in PPi and AMP; in the extracellular milieu, PPi gives potent anti-mineralization effect, whereas AMP is hydrolyzed to Pi and adenosine which affects some cellular properties by modulating the purinergic pathway. Structural and functional studies have demonstrated that silencing or inhibition of ABCC6 with probenecid changed the expression of several genes and proteins such as NT5E and TNAP, as well as Lamin, and CDK1, which are involved in cell motility and cell cycle. Furthermore, a change in cytoskeleton rearrangement and decreased motility of HepG2 cells makes ABCC6 a potential target for anti-cancer therapy. Collectively, these findings suggested that ABCC6 transporter performs functions that modify both the external and internal compartments of the cells.

scholarly journals Pseudoxanthoma Elasticum as a Paradigm of Heritable Ectopic Mineralization Disorders

2019 ◽  
Vol 189 (2) ◽  
pp. 216-225 ◽  
Author(s):  
Qiaoli Li ◽  
Koen van de Wetering ◽  
Jouni Uitto
Keyword(s):  
Pseudoxanthoma Elasticum ◽  
Ectopic Mineralization

scholarly journals ABCC6 Gene Analysis in 20 Japanese Patients with Angioid Streaks Revealing Four Frequent and Two Novel Variants and Pseudodominant Inheritance

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Satoshi Katagiri ◽  
Yuya Negishi ◽  
Kei Mizobuchi ◽  
Mitsuyoshi Urashima ◽  
Tadashi Nakano ◽  
...  
Keyword(s):  
Medical Records ◽  
Sanger Sequencing ◽  
Pseudoxanthoma Elasticum ◽  
Japanese Patients ◽  
Compound Heterozygous ◽  
Angioid Streaks ◽  
Dermatological Examination ◽  
Abcc6 Gene ◽  
Novel Variants ◽  
Unknown Significance

Purpose. To report the spectrum of ABCC6 variants in Japanese patients with angioid streaks (AS). Patients and Methods. This was a single-center cohort study. The medical records of 20 patients with AS from 18 unrelated Japanese families were retrospectively reviewed. Screening of the ABCC6 gene (exons 1 to 31) was performed using PCR-based Sanger sequencing. Results. Eight ABCC6 variants were identified as candidate disease-causing variants. These eight variants included five known variants (p.Q378X, p.R419Q, p.V848CfsX83, p.R1114C, and p.R1357W), one previously reported variant (p.N428S) of unknown significance, and two novel variants (c.1939C>T [p.H647Y] and c.3374C>T [p.S1125F]); the three latter variants were determined to be variants of significance. The following four variants were frequently identified: p.V848CfsX83 (14/40 alleles, 35.0%), p.Q378X (7/40 alleles, 17.5%), p.R1357W (6/40 alleles, 15.0%), and p.R419Q (4/40 alleles, 10.0%). The ABCC6 variants were identified in compound heterozygous or homozygous states in 13 of 18 probands. Two families showed a pseudodominant inheritance pattern. Pseudoxanthoma elasticum was seen in 15 of 17 patients (88.2%) who underwent dermatological examination. Conclusions. We identified disease-causing ABCC6 variants that were in homozygous or compound heterozygous states in 13 of 18 families (72.2%). Our results indicated that ABCC6 variants play a significant role in patients with AS in the Japanese population.

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