Chassaing N, Martin L, Calvas P, Le Bert M, Hovnanian APseudoxanthoma elasticum: a clinical, pathophysiological and genetic update including 11 novel ABCC6 mutations. J Med Genet 42:881-892

French National Centre for Scientific Research, Lutetia Parisorum, Île-de-France, France
Journal of Medical Genetics (Impact Factor: 6.34). 01/2006; 42(12):881-92. DOI: 10.1136/jmg.2004.030171
Source: PubMed


Pseudoxanthoma elasticum (PXE) is an inherited systemic disease of connective tissue primarily affecting the skin, retina, and cardiovascular system. It is characterised pathologically by elastic fibre mineralisation and fragmentation (so called "elastorrhexia"), and clinically by high heterogeneity in age of onset and the extent and severity of organ system involvement. PXE was recently associated with mutations in the ABCC6 (ATP binding cassette subtype C number 6) gene. At least one ABCC6 mutation is found in about 80% of patients. These mutations are identifiable in most of the 31 ABCC6 exons and consist of missense, nonsense, frameshift mutations, or large deletions. No correlation between the nature or location of the mutations and phenotype severity has yet been established. Recent findings support exclusive recessive inheritance. The proposed prevalence of PXE is 1/25,000, but this is probably an underestimate. ABCC6 encodes the protein ABCC6 (also known as MRP6), a member of the large ATP dependent transmembrane transporter family that is expressed predominantly in the liver and kidneys, and only to a lesser extent in tissues affected by PXE. The physiological substrates of ABCC6 remain to be determined, but the current hypothesis is that PXE should be considered to be a metabolic disease with undetermined circulating molecules interacting with the synthesis, turnover, or maintenance of elastic fibres.

Download full-text


Available from: Marc Le Bert,
  • Source
    • "PXE is a connective tissue disorder of broken elastic fibers and localized calcification due to deficiency of ABCC6, which is a membrane transporter whose ligand is unknown. The most common problems occur in the eyes and skin, and later in blood vessels in the form of premature atherosclerosis [49]. Calcification of elastic fibers plays a critical role in the pathology of PXE, which involves small vessels and the possibility of a circulating factor. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Ecto-5'-nucleotidase (e5NT, CD73) is an enzyme that is highly expressed in endothelium and is involved in the extracellular nucleotide catabolism. CD73 converts AMP to adenosine that via specific subtypes of P1 receptor mediates cytoprotection involving diverse mechanisms such as vasodilatation, suppression of inflammation, inhibition of thrombosis and anti-adrenergic effect. Physiological intravascular concentration of adenosine is in nanomolar range, but could become micromolar in response to various forms of stress. Endothelium is a major site for both CD73 mediated production of adenosine and its cytoprotective effect. Nucleotides (predominantly ATP or ADP) that could be released from different cells via controlled specific of unspecific mechanisms constitute a major source of substrate for adenosine production via CD73. Direct effects of extracellular nucleotides (mediated by P2 receptors) are typically opposite to adenosine P1 mediated activities. Retention of nucleotides and decreased adenosine production due to loss of CD73 function may have negative implications and could be important cause of various pathologies. Protective role of CD73 was indicated in ectopic calcification, atherosclerosis, rejection after xenotransplantation and thrombosis. Reduced activity of CD73 due to lymphocyte contact with endothelium increases its permeability that leads to enhanced leukocyte transmigration. Upregulation of endothelial CD73 may therefore be protective in a number of cardiovascular pathologies. Such effect has been confirmed for some common drugs such as statins and it could be part of its pleiotropic portfolio. Activation of CD73 could be a new target for specific treatment strategy that in particular will enhance endothelial protection. Copyright © 2015. Published by Elsevier Urban & Partner Sp. z o.o.
    Pharmacological reports: PR 05/2015; 67(4). DOI:10.1016/j.pharep.2015.05.002 · 1.93 Impact Factor
  • Source
    • "PXE is caused by mutations in the ABCC6 gene which encodes a putative efflux transporter, ABCC6 (ATP-binding cassette family C member 6), primarily expressed in liver and kidney, and mediates ATP release from the liver (Jansen et al., 2014). Over 1000 mutant alleles have been identified in patients with PXE from varied ancestral and ethnic backgrounds (Chassaing et al, 2005; Miksch et al, 2005; Pfendner et al, 2007). Besides the presence of two pseudogenes (ABCC6-ψ1 and ABCC6-ψ2) containing sequences highly homologous to the 5'-end of ABCC6, the molecular diagnosis of PXE is becoming increasingly challenging as the molecular etiology of the disease becomes more complex (Pulkkinen et al, 2001). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The molecular etiology of pseudoxanthoma elasticum (PXE), an autosomal recessive connective tissue disorder, has become increasingly complex as not only mutations in ABCC6 but also ENPP1 and GGCX can cause resembling phenotypes. Identification of modifier genes, such as VEGFA, has further contributed to the molecular heterogeneity of PXE. In such heterogeneous diseases, Next Generation Sequencing allows to perform mutation screening of several genes in a single reaction. We explored whole exome sequencing (WES) as an efficient diagnostic tool to identify the causal mutations in ABCC6, GGCX, ENPP1 and VKORC1, in 16 PXE patients. WES identified a causal ABCC6 mutation in 30 out of 32 alleles and one GGCX mutation, whereas no causal mutations in ENPP1 or VKORC1 were detected. Exomes with insufficient reads (≤20 depth) for the 4 genes and patients with single mutations were further evaluated by Sanger sequencing (SS) but no additional mutations were found. The potential of WES compared to targeted NGS, is the ease to examine target genes and the opportunity to search for novel genes when targeted analysis is negative. Together with low cost, rapid and less laborious workflow, we conclude that WES complemented with SS can provide a tiered approach to molecular diagnostics of PXE.Journal of Investigative Dermatology accepted article preview online, 29 September 2014; doi:10.1038/jid.2014.421.
    Journal of Investigative Dermatology 09/2014; 135(4). DOI:10.1038/jid.2014.421 · 7.22 Impact Factor
  • Source
    • "The first clinical description of the disease was done in 1881 by Rigal, and in 1896 Darier adopted the term pseudoxanthoma elasticum after observing typical dermal histopathological alterations of the process. Ocular involvement was observed for the first time in 1929 by Grönblad and Strandberg, while early atheromatosis, the last component of the disease, was described in 1944, occasion in which Carlbord reported calcification of vessel walls in 29 patients with pseudoxanthoma elasticum.1 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Pseudoxanthoma elasticum is a rare inherited multisystem disorder that is characterized by a pathological mineralization of the elastic connective tissue, which involves predominantly the skin, eyes and cardiovascular system. Its cause lies on mutations in the ABCC6 gene, which lead to reduction or absence of the transmembrane transport ADP dependent protein (MRP6), causing an accumulation of extracellular material and subsequent deposition of calcium and other minerals in the elastic tissue. The authors report two cases of pseudoxanthoma elasticum, emphasizing its major clinical features and the importance of early diagnosis of the disorder, aiming for adequate therapeutic management of associated complications.
    Anais brasileiros de dermatologia 09/2014; 89(5):812-5. DOI:10.1590/abd1806-4841.20143144 · 0.72 Impact Factor
Show more