Heterozygosity for a Single Mutation in the ABCC6 Gene May Closely Mimic PXE

Martin, Ludovic; Maître, F; Bonicel, P.; Daudon, P.; Verny, Christophe; Bonneau, Dominique; Saux, Olivier Le; Chassaing, Nicolas

doi:10.1001/archderm.144.3.301

Cited by 37 publications

(10 citation statements)

References 22 publications

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“…Obligate heterozygote carriers have essentially normal or very limited clinical phenotype but some cases have been reported to show microscopic changes of mineralization in the elastic fibers (Martin et al , 2007). A recent study has suggested that heterozygous carriers may occasionally have serious manifestations, particularly affecting the eyes (Martin et al , 2008). The carrier individuals may also be at increased risk for premature coronary artery disease (Trip et al , 2002).…”

Section: Phenotypic Spectrum Of Pxementioning

confidence: 99%

Pseudoxanthoma Elasticum: Molecular Genetics and Putative Pathomechanisms

Uitto

Jiang

2010

Journal of Investigative Dermatology

132

148

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Pseudoxanthoma elasticum (PXE), a prototypic heritable disorder with ectopic mineralization, manifests with characteristic skin findings, ocular involvement and cardiovascular problems, with considerable morbidity and mortality. The classic forms of PXE are due to loss-of-function mutations in the ABCC6 gene, which encodes ABCC6, a transmembrane efflux transporter expressed primarily in the liver. Several lines of evidence suggest that PXE is a primary metabolic disorder which, in the absence of ABCC6 transporter activity, displays reduced plasma anti-mineralization capacity due to reduced fetuin-A and matrix gla-protein (MGP) levels. MGP requires to be activated by γ-glutamyl carboxylation, a vitamin K-dependent reaction, to serve in anti-mineralization role in the peripheral connective tissue cells. While the molecules transported from the hepatocytes to circulation by ABCC6 in vivo remain unidentified, it has been hypothesized that a critical vitamin K derivative, such as reduced vitamin K conjugated with glutathione, is secreted to circulation physiologically, but not in the absence of ABCC6 transporter activity. As a result, activation of MGP by γ-glutamyl carboxylase is diminished, allowing slow, yet progressive, mineralization of connective tissues characteristic of PXE. Understanding of the pathomechanistic details of PXE provides a basis for development of targeted molecular therapies for this, currently intractable, disease.

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Section: Phenotypic Spectrum Of Pxementioning

confidence: 99%

Pseudoxanthoma Elasticum: Molecular Genetics and Putative Pathomechanisms

Uitto

Jiang

2010

Journal of Investigative Dermatology

132

148

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“…The causality of mutations of the ABCC6 gene in PXE was demonstrated in 2000 [2], [3], [5] and since then the clinico-genetic characteristics of the disease have been established [7], [8]. Interestingly, heterozygous carriers of ABCC6 mutant alleles present an increased susceptibility to cardiovascular diseases [9], [10], [11]. The transcriptional regulation of the gene [6], [12], [13] and the biochemical characteristics of the ABCC6 protein have been well defined [14].…”

Section: Introductionmentioning

confidence: 99%

Expression and In Vivo Rescue of Human ABCC6 Disease-Causing Mutants in Mouse Liver

et al. 2011

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Loss-of-function mutations in ABCC6 can cause chronic or acute forms of dystrophic mineralization described in disease models such as pseudoxanthoma elasticum (OMIM 26480) in human and dystrophic cardiac calcification in mice. The ABCC6 protein is a large membrane-embedded organic anion transporter primarily found in the plasma membrane of hepatocytes. We have established a complex experimental strategy to determine the structural and functional consequences of disease-causing mutations in the human ABCC6. The major aim of our study was to identify mutants with preserved transport activity but failure in intracellular targeting. Five missense mutations were investigated: R1138Q, V1298F, R1314W, G1321S and R1339C. Using in vitro assays, we have identified two variants; R1138Q and R1314W that retained significant transport activity. All mutants were transiently expressed in vivo, in mouse liver via hydrodynamic tail vein injections. The inactive V1298F was the only mutant that showed normal cellular localization in liver hepatocytes while the other mutants showed mostly intracellular accumulation indicating abnormal trafficking. As both R1138Q and R1314W displayed endoplasmic reticulum localization, we tested whether 4-phenylbutyrate (4-PBA), a drug approved for clinical use, could restore their intracellular trafficking to the plasma membrane in MDCKII and mouse liver. The cellular localization of R1314W was significantly improved by 4-PBA treatment, thus potentially rescuing its physiological function. Our work demonstrates the feasibility of the in vivo rescue of cellular maturation of some ABCC6 mutants in physiological conditions very similar to the biology of the fully differentiated human liver and could have future human therapeutic application.

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“…One of the issues raised regarding the clinical presentation of PXE is the question whether heterozygous carriers depict mild or subclinical phenotypes (7, 8). In our study, members in the Family 3 (I-2) and Family 4 (II-5 and II-6) were suggested to have PXE due to limited skin involvement and intermittent claudication.…”

Section: Discussionmentioning

confidence: 99%