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.

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    • "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. "
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    • " connective tissue affecting pri - marily the skin , retina , and cardiovascular system . The prevalence of PXE is 1 / 25 000 , but is probably underes - timated . PXE is characterized pathologically by elastic fiber mineralization and fragmentation . It has recently been associated with mutations in the ABCC6 gene found in about 80% of patients ( Chassaing et al . , 2005 ) . Clinically , there is a high heterogeneity in age of onset and the extent and severity of organ system involvement ."
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    • "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). "
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    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.
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