Mutations of the gene encoding the transmembrane transporter protein ABC-C6 cause pseudoxanthoma elasticum

Struk, Berthold; Cai, Li; Zäch, Stéphanie; Ji, Wan; Chung, Joon Yong; Lumsden, Amanda L.; Stümm, Markus; Huber, Marcel; Schaen, Lori; Kim, Chung-Ah; Goldsmith, Lowell A.; Viljoen, Denis; Figuera, Luis E.; Fuchs, W.K.; Munier, Francis L.; Ramesar, Raj; Hohl, Daniel; Richards, Robert I.; Neldner, Kenneth H.; Lindpaintner, Klaus

doi:10.1007/s001090000114

Cited by 122 publications

(87 citation statements)

References 7 publications

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“…Among the 42 different ABCC6 mutations detected in our PXE cohort, 32 had been described elsewhere (Bergen et al, 2000;Germain et al, 2000;Ringpfeil et al, 2000;Struk et al, 2000;Cai et al, 2001;Le Saux et al, 2001;Pulkkinen et al, 2001;Hu et al, 2003;Chassaing et al, 2004;Gheduzzi et al, 2004;Götting et al, 2004;Hendig et al, 2005;Schulz et al, 2005a;Schulz et al, 2005b), and 10 were novel DNA variations, namely c.37-1G>A, p.W38S, p.L252F, p.V415A, p.R487Q, p.N497K, c.1574_1575insG, p.S1049A, p.L1063R and c.3505_3506+2delAGGT. The mutations occurred in 10 PXE patients from 9 unrelated families and were not present in normal healthy controls (Tables 1 and 2).…”

Section: Novel Pxe Mutationsmentioning

confidence: 97%

“…The splice site mutation c.37-1G>A occurred in a homozygous form in one PXE patient and the missense mutations p.W38S and p.N497K were found in a heterozygous state in 2 patients where no further PXE mutations could be identified ( Table 2). The other 7 PXE patients were compound heterozygous for the novel DNA variations p.L252F, p.V415A, p.R487Q, p.S1049A, p.L1063R, c.1574_1575insG and c.3505_3506+2delAGGT, as well as for the known PXE-causing mutations p.R765Q, p.R1141X, p.L851P, c.3736-1G>A and p.S1403R (Bergen et al, 2000;Germain et al, 2000;Ringpfeil et al, 2000;Struk et al, 2000;Le Saux et al, 2001;Hendig et al, 2005). The majority of the new DNA alterations occurred in cytoplasmic regions of the MRP6 protein (Fig.…”

Section: Novel Pxe Mutationsmentioning

confidence: 99%

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Mutational analysis of theABCC6 gene and the proximalABCC6 gene promoter in German patients with pseudoxanthoma elasticum (PXE)

et al. 2006

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Pseudoxanthoma elasticum (PXE) is a genetic disorder characterized by calcification of elastic fibers in dermal, ocular, and cardiovascular tissues. Recently, ABCC6 mutations were identified as causing PXE. In this follow-up study we report the investigation of 61German PXE patients from 53 families, hitherto the largest cohort of German PXE patients screened for the complete ABCC6 gene. In addition, we characterized the proximal ABCC6 promoter of PXE patients according to mutation. In this study we identified 32 disease-causing ABCC6 variants, which had been described previously by us and others, and 10 novel mutations (eight missense mutations and two splice site alterations). The mutation detection rate among index patients was 87.7%. Frequent alterations were the PXE-mutations p.R1141X, Ex23,_Ex29del, and c.2787+1G>T. In the ABCC6 promoter we found the polymorphisms c.-127C>T, c.-132C>T, and c.-219A>C. The difference in the c.-219A>C frequencies between PXE patients and controls were determined as statistically significant. Interestingly, c.-219A>C is located in a transcriptional activator sequence of the ABCC6 promoter and occurred in a binding site for a transcriptional repressor, predominantly found in genes that participate in lipid metabolism. Obtaining these genetic data signifies our contribution to elucidating the pathogenetics of PXE.

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Section: Novel Pxe Mutationsmentioning

confidence: 97%

Section: Novel Pxe Mutationsmentioning

confidence: 99%

Mutational analysis of theABCC6 gene and the proximalABCC6 gene promoter in German patients with pseudoxanthoma elasticum (PXE)

et al. 2006

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“…6,7 These segregation patterns may result from pseudodominant inheritance, as a result of parental consanguinity, or (mild) manifestation of the disease in heterozygotes. [36][37][38][39] On the other hand, the presence of rare ABCC6/MRP6 mutations resulting in a true ad disease and inheritance pattern cannot be ruled out completely. In this study, we presented a novel family with an R1459C ABCC6/MRP6 mutation, in which ad segregation of PXE on the basis of clinical, molecular, and genealogical data, is the most likely explanation for our results.…”

Section: Molecular Pathology Of Pxementioning

confidence: 99%

ABCC6/MRP6 mutations: further insight into the molecular pathology of pseudoxanthoma elasticum

Plomp

Wijnholds

et al. 2003

Eur J Hum Genet

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Pseudoxanthoma elasticum (PXE) is a hereditary disease characterized by progressive dystrophic mineralization of the elastic fibres. PXE patients frequently present with skin lesions and visual acuity loss. Recently, we and others showed that PXE is caused by mutations in the ABCC6/MRP6 gene. However, the molecular pathology of PXE is complicated by yet unknown factors causing the variable clinical expression of the disease. In addition, the presence of ABCC6/MRP6 pseudogenes and multiple ABCC6/MRP6-associated deletions complicate interpretation of molecular genetic studies. In this study, we present the mutation spectrum of ABCC6/MRP6 in 59 PXE patients from the Netherlands. We detected 17 different mutations in 65 alleles. The majority of mutations occurred in the NBF1 (nucleotide binding fold) domain, in the eighth cytoplasmatic loop between the 15th and 16th transmembrane regions, and in NBF2 of the predicted ABCC6/MRP6 protein. The R1141X mutation was by far the most common mutation identified in 19 (32.2%) patients. The second most frequent mutation, an intragenic deletion from exon 23 to exon 29 in ABCC6/MRP6, was detected in 11 (18.6%) of the patients. Our data include 11 novel ABCC6/MRP6 mutations, as well as additional segregation data relevant to the molecular pathology of PXE in a limited number of patients and families. The consequences of our data for the molecular pathology of PXE are discussed.

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“…In 2000, multiple research groups reported that PXE is caused by inactivating mutations in the ATP-binding cassette sub-family C member 6 (ABCC6) gene (4)(5)(6)(7). ABCC6, also known as multidrug resistance-associated protein 6 (MRP6), is a member of the C branch of the superfamily of ATP-binding cassette (ABC)-transporters, which use the energy provided by the hydrolysis of ATP to transport substrates across a membrane (8).…”

mentioning

confidence: 99%

ABCC6 prevents ectopic mineralization seen in pseudoxanthoma elasticum by inducing cellular nucleotide release

Jansen

Küçükosmanoğlu

Haas

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

223

310

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Pseudoxanthoma elasticum (PXE) is an autosomal recessive disease characterized by progressive ectopic mineralization of the skin, eyes, and arteries, for which no effective treatment exists. PXE is caused by inactivating mutations in the gene encoding ATPbinding cassette sub-family C member 6 (ABCC6), an ATP-dependent efflux transporter present mainly in the liver. Abcc6 −/− mice have been instrumental in demonstrating that PXE is a metabolic disease caused by the absence of an unknown factor in the circulation, the presence of which depends on ABCC6 in the liver. Why absence of this factor results in PXE has remained a mystery. Here we report that medium from HEK293 cells overexpressing either human or rat ABCC6 potently inhibits mineralization in vitro, whereas medium from HEK293 control cells does not. Untargeted metabolomics revealed that cells expressing ABCC6 excrete large amounts of nucleoside triphosphates, even though ABCC6 itself does not transport nucleoside triphosphates. Extracellularly, ectonucleotidases hydrolyze the excreted nucleoside triphosphates to nucleoside monophosphates and inorganic pyrophosphate (PPi), a strong inhibitor of mineralization that plays a pivotal role in several mineralization disorders similar to PXE. The in vivo relevance of our data are demonstrated in Abcc6 −/− mice, which had plasma PPi levels <40% of those found in WT mice. This study provides insight into how ABCC6 affects PXE. Our data indicate that the factor that normally prevents PXE is PPi, which is provided to the circulation in the form of nucleoside triphosphates via an asyet unidentified but ABCC6-dependent mechanism.ATP secretion | ectopic calcification | MRP6 | ENPP1

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Mutations of the gene encoding the transmembrane transporter protein ABC-C6 cause pseudoxanthoma elasticum

Cited by 122 publications

References 7 publications

Mutational analysis of theABCC6 gene and the proximalABCC6 gene promoter in German patients with pseudoxanthoma elasticum (PXE)

Mutational analysis of theABCC6 gene and the proximalABCC6 gene promoter in German patients with pseudoxanthoma elasticum (PXE)

ABCC6/MRP6 mutations: further insight into the molecular pathology of pseudoxanthoma elasticum

ABCC6 prevents ectopic mineralization seen in pseudoxanthoma elasticum by inducing cellular nucleotide release

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