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

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 Although various treatment options have emerged during the last 20 years, many are either already outdated or not yet ready to be applied generally. Clinical physicians often are left stranded while patients suffer from the consequences of outdated therapies, or feel unrecognized by their attending doctors who may feel uncertain about using new therapeutic approaches or not even know about them.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.

Download Full-text

Pseudoxanthoma elasticum with prominent arterial calcifications evoking CD73 deficiency

Vascular Medicine ◽

10.1177/1358863x19853360 ◽

2019 ◽

Vol 24 (5) ◽

pp. 461-464 ◽

Cited By ~ 4

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.

Download Full-text

Dysregulation of gene expression in ABCC6 knockdown HepG2 cells

Cellular & Molecular Biology Letters ◽

10.2478/s11658-014-0208-2 ◽

2014 ◽

Vol 19 (4) ◽

Cited By ~ 17

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.

Download Full-text

Zebrafish enpp1 mutants exhibit pathological mineralization, mimicking features of generalized arterial calcification of infancy (GACI) and pseudoxanthoma elasticum (PXE)

Disease Models & Mechanisms ◽

10.1242/dmm.015693 ◽

2014 ◽

Vol 7 (7) ◽

pp. 811-822 ◽

Cited By ~ 30

Author(s):

A. Apschner ◽

L. F. A. Huitema ◽

B. Ponsioen ◽

J. Peterson-Maduro ◽

S. Schulte-Merker

Keyword(s):

Pseudoxanthoma Elasticum ◽

Arterial Calcification

Download Full-text

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

Journal of Ophthalmology ◽

10.1155/2017/1079687 ◽

2017 ◽

Vol 2017 ◽

pp. 1-7 ◽

Cited By ~ 1

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.

Download Full-text