Pseudoxanthoma Elasticum Is a Recessive Disease Characterized by Compound Heterozygosity

Ringpfeil, Franziska; McGuigan, Kelly; Fuchsel, Lauren; Kozic, Heidi; Larralde, Margarita; Lebwohl, Mark; Uitto, Jouni

doi:10.1038/sj.jid.5700115

Cited by 69 publications

(57 citation statements)

References 19 publications

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“…After a comprehensive series of reports on the genetics of pseudoxanthoma elasticum focusing notably on identifying mutations in the ABCC6 gene [21][22][23][24][25] and the generation of mouse models [14,26], there is now a growing interest in the transcriptional regulation of ABCC6 expression. Indeed, ABCC6 and its rodent orthologs Abcc6 are primarily expressed in liver and kidneys whereas the PXE phenotype affects dermal, vascular and ocular tissues.…”

Section: Discussionmentioning

confidence: 99%

DNA methylation and Sp1 binding determine the tissue-specific transcriptional activity of the mouse Abcc6 promoter

Douet

Heller

Saux

2007

Biochemical and Biophysical Research Communications

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SummaryThe gene encoding the ABCC6 protein, an ABC transporter of the multidrug resistance-associated protein (MRP), is mainly expressed in liver and kidney. Mutations in ABCC6 are responsible for the development of the pseudoxanthoma elasticum (PXE) phenotype. PXE is a recessive disease characterized by the calcification of elastic fibers resulting in dermal, vascular and ocular clinical manifestations. The physiological function of ABCC6 and the rodent orthologs Abcc6 is unknown and their precise relationship to elastic fibers is only a matter of speculation. Despite several studies focused on the transcriptional regulation of ABCC6/Abcc6, the molecular signals conferring the tissue-specificity to the ABCC6/Abcc6 expression are not well defined. In this report, we determined the level of the mouse Abcc6 promoter methylation in tissues with low level of expression (tail extremity and skin), intermediate (kidney) and high level of expression (liver). We observed that high and moderate levels of methylation correlated with low levels of Abcc6 expression. Moreover, we determined that CpG methylation of the Abcc6 proximal promoter region was interfering with the binding of the Sp1 transcription factor thereby inhibiting Sp1-dependent transactivation. Thus, our data provides the first direct evidence that an epigenetic mechanism regulates the binding of the transcription factor Sp1 to the proximal promoter and participates in the tissue-specific expression control of the mouse Abcc6 gene.

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Section: Discussionmentioning

confidence: 99%

DNA methylation and Sp1 binding determine the tissue-specific transcriptional activity of the mouse Abcc6 promoter

Douet

Heller

Saux

2007

Biochemical and Biophysical Research Communications

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“…Consequently, the search of disease-promoting genetic cofactors has to be intensified in the future. Nevertheless, failure to detect all disease-causing alleles is a common problem in many PXE studies (Ringpfeil et al, 2006). Thus, applying other techniques for mutation detection like cDNA sequencing or direct sequencing will have to be performed for our patients where only one causative mutation was identified.…”

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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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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“…16,17 Most authors did not find a clear genotypephenotype correlation. 7,16,18 -21 The phenotype can be variable, also within families, 9,16,19,[22][23][24] but because of the genetic heterogeneity and the autosomal recessive inheritance, extended pedigrees and larger series of patients with the same genotype are rare. We examined 15 patients with homozygous PXE and 44 heterozygous relatives from a genetic isolate in the Netherlands, all of them had the same mutation, a deletion of a T in exon 27 (c.3775delT).…”

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confidence: 99%

Pseudoxanthoma elasticum: Wide phenotypic variation in homozygotes and no signs in heterozygotes for the c.3775delT mutation in ABCC6

Plomp

Bergen

Florijn

et al. 2009

Genetics in Medicine

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Purpose: Pseudoxanthoma elasticum is an autosomal recessive disorder of elastic tissue in the skin, eyes, and cardiovascular system, caused by mutations in the ABCC6 gene. The purpose of this study was to check variability in expression within one genotype and look for pseudoxanthoma elasticum signs in heterozygotes. Methods: We examined a relatively large, in comparison with the present literature, group of adult persons homozygous or heterozygous for the c.3775delT mutation in the ABCC6 gene, from a genetically isolated population in the Netherlands. All participants filled out a questionnaire and underwent standardized dermatologic and ophthalmologic examinations with photography of skin and fundus abnormalities. Skin biopsies from affected skin or a predilection site and/or a scar were examined and compared with biopsies from controls. Results: Skin abnormalities, ophthalmologic signs, and cardiovascular problems varied greatly among the 15 homozygous participants. There was no correlation among severity of skin, eyes, or cardiovascular abnormalities. None of the 44 heterozygous participants had any sign of pseudoxanthoma elasticum on dermatologic, histopathologic, and/or ophthalmologic examination, but 32% had cardiovascular disease. Conclusion: Individuals homozygous for the c.3775delT mutation can have a highly variable phenotype. We did not find pseudoxanthoma elasticum eye or skin abnormalities in the heterozygous family members. Genet Med 2009:11(12):852-858.

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Pseudoxanthoma Elasticum Is a Recessive Disease Characterized by Compound Heterozygosity

Cited by 69 publications

References 19 publications

DNA methylation and Sp1 binding determine the tissue-specific transcriptional activity of the mouse Abcc6 promoter

DNA methylation and Sp1 binding determine the tissue-specific transcriptional activity of the mouse Abcc6 promoter

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

Pseudoxanthoma elasticum: Wide phenotypic variation in homozygotes and no signs in heterozygotes for the c.3775delT mutation in ABCC6

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