Histological skin changes in heterozygote carriers of mutations in <i>ABCC6</i>, the gene causing pseudoxanthoma elasticum

Martin, Ludovic; Chassaing, Nicolas; D, Delaite; Estève, É.; Maître, F; Bert, Marc Le

doi:10.1111/j.1468-3083.2006.01940.x

Cited by 17 publications

(11 citation statements)

References 31 publications

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“…It should also be noted that PXE is an autosomal recessive disease, although heterozygous carriers of a mutation in one of the ABCC6 alleles have been suggested to demonstrate subclinical findings in the eyes in terms of angioid streaks and presence of subtle histopathologic changes in the skin without overt cutaneous phenotype (Martin et al , 2007, 2008). The morpholino “knock-down” resulted in 54–81% reduction in abcc6a expression, as determined at the mRNA level.…”

Section: Discussionmentioning

confidence: 99%

The abcc6a Gene Expression Is Required for Normal Zebrafish Development

Sadowski

Frank

et al. 2010

Journal of Investigative Dermatology

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Pseudoxanthoma elasticum (PXE) is caused by mutations in the ABCC6 gene, which encodes a putative efflux pump, ABCC6. The zebrafish (Danio rerio) has two ABCC6-related sequences. To study the function of abcc6 during zebrafish development, the mRNA expression levels were measured using RT-PCR and in situ hybridization. The abcc6a showed a relatively high level of expression at 5 days post-fertilization (dpf) and the expression was specific to the Kupffer’s vesicles. The abcc6b expression was evident at 6 hpf and remained high up to 8 dpf, corresponding to embryonic kidney proximal tubules. Morpholinos were designed to both genes to block translation and to prevent pre-mRNA splicing. Injection of the abcc6a morpholinos into 1–4 cell zebrafish embryos decreased gene expression by 54 to 81%, and induced a phenotype, cardiac edema and curled tail associated with death at around 8 dpf. Microinjecting zebrafish embryos with full-length mouse Abcc6 mRNA together with the morpholino completely rescued this phenotype. No phenotypic changes were observed when the abcc6b gene morpholino was injected to embryos, with knock-down efficiency of 100%. These results suggest that abcc6a is an essential gene for normal zebrafish development and provide novel insight into the function of ABCC6, the gene mutated in PXE.

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Section: Discussionmentioning

confidence: 99%

The abcc6a Gene Expression Is Required for Normal Zebrafish Development

Sadowski

Frank

et al. 2010

Journal of Investigative Dermatology

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“…It should be noted that there are no fully documented reports of PXE in three subsequent generations, refuting the existence of classic Mendelian autosomal dominant inheritance. 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).…”

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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“…14 Histopathologic abnormalities were found in skin biopsies from some probably heterozygous first-degree relatives of patients with PXE. 13,34,35 Most frequent abnormalities were increase and fragmentation of elastin, which were found less frequently in controls, but which we consider aspecific for PXE. In some biopsies, calcification of elastic fibers was present, but no clumping was mentioned.…”

Section: Phenotype In Carriers Of Pxementioning

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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Histological skin changes in heterozygote carriers of mutations in ABCC6, the gene causing pseudoxanthoma elasticum

Cited by 17 publications

References 31 publications

The abcc6a Gene Expression Is Required for Normal Zebrafish Development

The abcc6a Gene Expression Is Required for Normal Zebrafish Development

Pseudoxanthoma Elasticum: Molecular Genetics and Putative Pathomechanisms

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

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