Analysis of Sequence Variations in the &lt;i&gt;ABCC6&lt;/i&gt; Gene among Patients with Abdominal Aortic Aneurysm and Pseudoxanthoma Elasticum

Schulz, Veronika; Hendig, Doris; Schillinger, Martin; Exner, Markus; Domanovits, Hans; Raith, Marianne; Szliska, Christiane; Kleesiek, Knut; Götting, Christian

doi:10.1159/000087900

Cited by 19 publications

(9 citation statements)

References 84 publications

(80 reference statements)

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“…Furthermore, a haplotype analysis was performed. ABCC6 sequence variations detected in selected exons in a subgroup of 53 patients were described in other publications by our group (Götting et al, 2004;Hendig et al, 2005;Schulz et al 2005a;Schulz et al 2005b). The diagnosis of PXE in all patients was consistent with the reported consensus criteria (Christiano et al, 1992;Lebwohl et al, 1994) taking into account that these consensus criteria do not provide golden standards for PXE diagnosis or the minimal diagnostic criteria of this disease.…”

Section: Patients and Controlssupporting

confidence: 83%

“…This is so far the largest cohort of German PXE families which has been scanned for the complete ABCC6 gene. The present investigation is a follow-up study of our previous studies (Götting et al, 2004;Hendig et al, 2005;Schulz et al 2005a;Schulz et al 2005b) which now includes the complete analysis of all ABCC6 exons, the adjacent introns, the sequence of the putative proximal promoter and the haplotypes in a larger number of patients. Performing mutational analysis, we identified 42 different PXE mutations and among these 10 were novel.…”

Section: Novel Pxe Mutationsmentioning

confidence: 99%

“…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: 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: Patients and Controlssupporting

confidence: 83%

Section: Novel Pxe Mutationsmentioning

confidence: 99%

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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“…ABCC6 mutations were found in a minority of non-PXE patients (5/133) with abdominal aortic aneurysms (Schulz et al, 2005), but this was not statistically significantly different from healthy controls and could not be considered as a genetic risk factor for aortic aneurysms. Aorto-coronary aneurysm has also been reported (Heno et al, 1998) but seems not specific to PXE as it has also been reported in other PXE-like syndromes, such as beta-thalassemia (Farmakis et al, 2004).…”

Section: Clinical Expression Of the Vascular Pxe Phenotypementioning

confidence: 86%

The vascular phenotype in Pseudoxanthoma elasticum and related disorders: contribution of a genetic disease to the understanding of vascular calcification

Lefthériotis¹,

Omarjee²,

Saux³

et al. 2013

Front. Gene.

100

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Vascular calcification is a complex and dynamic process occurring in various physiological conditions such as aging and exercise or in acquired metabolic disorders like diabetes or chronic renal insufficiency. Arterial calcifications are also observed in several genetic diseases revealing the important role of unbalanced or defective anti- or pro-calcifying factors. Pseudoxanthoma elasticum (PXE) is an inherited disease (OMIM 264800) characterized by elastic fiber fragmentation and calcification in various soft conjunctive tissues including the skin, eyes, and arterial media. The PXE disease results from mutations in the ABCC6 gene, encoding an ATP-binding cassette transporter primarily expressed in the liver, kidneys suggesting that it is a prototypic metabolic soft-tissue calcifying disease of genetic origin. The clinical expression of the PXE arterial disease is characterized by an increased risk for coronary (myocardial infarction), cerebral (aneurysm and stroke), and lower limb peripheral artery disease. However, the structural and functional changes in the arterial wall induced by PXE are still unexplained. The use of a recombinant mouse model inactivated for the Abcc6 gene is an important tool for the understanding of the PXE pathophysiology although the vascular impact in this model remains limited to date. Overlapping of the PXE phenotype with other inherited calcifying diseases could bring important informations to our comprehension of the PXE disease.

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“…It is, therefore, plausible that this gene might play a role also in AAA 57. One study investigated ABCC6 polymorphisms in 133 AAA patients and 910 controls, detected only five genetic variants (missense or silent amino acid variants) in the 133 AAA cases, and no significant associations 57…”

Section: Candidate Gene Studies (Tables I–v)mentioning

confidence: 99%

Genes and Abdominal Aortic Aneurysm

Hinterseher

Tromp

Kuivaniemi

2011

Annals of Vascular Surgery

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Abdominal aortic aneurysm (AAA) is a multifactorial disease with a strong genetic component. Since first candidate gene studies were published 20 years ago, nearly 100 genetic association studies using single nucleotide polymorphisms (SNPs) in biologically relevant genes have been reported on AAA. The studies investigated SNPs in genes of the extracellular matrix, the cardiovascular system, the immune system, and signaling pathways. Very few studies were large enough to draw firm conclusions and very few results could be replicated in another sample set. The more recent unbiased approaches are family-based DNA linkage studies and genome-wide genetic association studies, which have the potential of identifying the genetic basis for AAA, if appropriately powered and well-characterized large AAA cohorts are used. SNPs associated with AAA have already been identified in these large multicenter studies. One significant association was of a variant in a gene called CNTN3 which is located on chromosome 3p12.3. Two follow-up studies, however, could not replicate the association. Two other SNPs, which are located on chromosome 9p21 and 9q33 were replicated in other samples. The two genes with the strongest supporting evidence of contribution to the genetic risk for AAA are the CDKN2BAS gene, also known as ANRIL, which encodes an antisense RNA that regulates expression of the cyclindependent kinase inhibitors CDKN2A and CDKN2B, and DAB2IP, which encodes an inhibitor of cell growth and survival. Functional studies are now needed to establish the mechanisms by which these genes contribute to AAA pathogenesis.

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Analysis of Sequence Variations in the <i>ABCC6</i> Gene among Patients with Abdominal Aortic Aneurysm and Pseudoxanthoma Elasticum

Cited by 19 publications

References 84 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)

The vascular phenotype in Pseudoxanthoma elasticum and related disorders: contribution of a genetic disease to the understanding of vascular calcification

Genes and Abdominal Aortic Aneurysm

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