The Multifaceted Complexity of Genetic Diseases: A Lesson from Pseudoxanthoma Elasticum

Quaglino, Daniela; Boraldi, Federica; Annovi, Giulia; Ronchetti, Ivonne Pasquali

doi:10.5772/22161

Cited by 19 publications

(30 citation statements)

References 131 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Despite the well-known limits provided by the simplifications usually associated with in vitro models, nevertheless, studies on cultured human dermal fibroblasts that, isolated from healthy subjects as well as from PXE patient's, maintain in vitro several characteristics related to their pathologic phenotype (Quaglino et al, 2011), allow direct investigation of the response of human peripheral mesenchymal cells, avoiding interferences caused by dietary absorption properties and/or transport capabilities in the circulation. From in vivo studies on the PXE animal model, it was suggested that, because of still elusive mechanisms, availability of vit K is not a limiting factor in the pathology of PXE and/or that vit K-dependent inhibition of calcification may not be preponderant in the development of the disease (Brampton et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…Pseudoxanthoma elasticum (PXE) is a genetic disorder associated with mutations in the ABCC6 gene (Le Saux et al, 2000) and characterized by progressive mineralization of elastic fibers affecting skin, eyes, and the cardiovascular system (Quaglino et al, 2011). Compared with controls, fibroblasts from PXE patients exhibit similar in vitro and in vivo matrix gla protein (MGP) expression, but with a significant reduction in carboxylated MGP (cMGP; Gheduzzi et al, 2007), a well-known endogenous inhibitor of soft tissue calcification .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Matrix Gla Protein and Alkaline Phosphatase Are Differently Modulated in Human Dermal Fibroblasts from PXE Patients and Controls

Boraldi

Annovi

Vermeer

et al. 2013

Journal of Investigative Dermatology

Self Cite

View full text Add to dashboard Cite

Mineralization of elastic fibers in pseudoxanthoma elasticum (PXE) has been associated with low levels of carboxylated matrix gla protein (MGP), most likely as a consequence of reduced vitamin K (vit K) availability. Unexpectedly, vit K supplementation does not exert beneficial effects on soft connective tissue mineralization in the PXE animal model. To understand the effects of vit K supplementation and in the attempt to interfere with pathways leading to the accumulation of calcium and phosphate within PXE-mineralized soft connective tissues, we have conducted in vitro studies on dermal fibroblasts isolated from control subjects and from PXE patients. Cells were cultured in standard conditions and in calcifying medium (CM) in the presence of vit K1 and K2, or levamisole, an alkaline phosphatase (ALP) inhibitor. Control and PXE fibroblasts were characterized by a similar dose-dependent uptake of both vit K1 and vit K2, thus promoting a significant increase of total protein carboxylation in all cell lines. Nevertheless, MGP carboxylation remained much less in PXE fibroblasts. Interestingly, PXE fibroblasts exhibited a significantly higher ALP activity. Consistently, the mineralization process induced in vitro by a long-term culture in CM appeared unaffected by vit K, whereas it was abolished by levamisole.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Matrix Gla Protein and Alkaline Phosphatase Are Differently Modulated in Human Dermal Fibroblasts from PXE Patients and Controls

Boraldi

Annovi

Vermeer

et al. 2013

Journal of Investigative Dermatology

Self Cite

View full text Add to dashboard Cite

show abstract

“…It should be noted, however, that the hypothesis presented above may be only one aspect of the multifaceted complexity of PXE [39].…”

Section: Cardiovascular Mineralizationmentioning

confidence: 90%

Pseudoxanthoma elasticum: the paradigm of ectopic mineralization disorders – diagnosis and treatment

Uitto¹,

Jiang

2013

Expert Review of Dermatology

View full text Add to dashboard Cite

“…Furthermore, ectopic calcification occurs in a number of genetic diseases as in Pseudoxanthoma elasticum (PXE), a rare autosomal recessive disorder characterized by progressive mineralization of elastic fibers within soft connective tissues [1], mainly affecting skin, vascular walls and eyes [2]. In PXE, vessel alterations primarily consist of mineral plaques accumulating inside elastic fibers of medium sized arteries and veins.…”

Section: Introductionmentioning

confidence: 99%

“…In PXE, vessel alterations primarily consist of mineral plaques accumulating inside elastic fibers of medium sized arteries and veins. Therefore, the most common cardiovascular complications are: diminished or absent peripheral vascular pulses, mitral valve prolapse, arterial hypertension, angina pectoris, early intermittent claudication (often regarded as the first sign of accelerated atherosclerosis), arteriosclerosis and increased risk of myocardial and cerebral infarction [2], [3], [4], [5]. The age-dependent progression and severity of pathologic manifestations are very heterogeneous, thus suggesting that, beside ABCC6 causative mutations [6], [7], [8], other genes and/or polymorphisms contribute to the clinical phenotype [9], [10], [11], [12].…”

Section: Introductionmentioning

confidence: 99%

Can APOE and MTHFR polymorphisms have an influence on the severity of cardiovascular manifestations in Italian Pseudoxanthoma elasticum affected patients?

Boraldi

Costa

Rabacchi

et al. 2014

Molecular Genetics and Metabolism Reports

Self Cite

View full text Add to dashboard Cite

BackgroundThe clinical phenotype of Pseudoxanthoma elasticum (PXE) affected patients, although progressive with age, is very heterogeneous, even in the presence of identical ABCC6 mutations, thus suggesting the occurrence of modifier genes. Beside typical skin manifestations, the cardiovascular (CV) system, and especially the peripheral vasculature, is frequently and prematurely compromised.Methods and resultsA cohort of 119 Italian PXE patients has been characterized for apolipoprotein E (APOE) and methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms by PCR. The severity of the clinical phenotype has been quantified according to the Phenodex PXE International score system. Statistical analysis (chi2 test, odd ratio, regression analysis, analysis of variance) were done by GraphPad. Data demonstrate that the frequency of APOE alleles is similar in PXE patients and in healthy subjects and that the allelic variant E2 confers a protection against the age-related increase of CV manifestations. By contrast, PXE patients are characterized by high frequency of the MTHFR-T677T polymorphism. With age, CV manifestations in T677T, but also in C677T, patients are more severe than those associated with the C677C genotype. Interestingly, compound heterozygosity for C677T and A1298C polymorphisms is present in 70% of PXE patients.ConclusionsPXE patients may be screened for these polymorphisms in order to support clinicians for a better management of disease-associated CV complications.

show abstract

The Multifaceted Complexity of Genetic Diseases: A Lesson from Pseudoxanthoma Elasticum

Cited by 19 publications

References 131 publications

Matrix Gla Protein and Alkaline Phosphatase Are Differently Modulated in Human Dermal Fibroblasts from PXE Patients and Controls

Matrix Gla Protein and Alkaline Phosphatase Are Differently Modulated in Human Dermal Fibroblasts from PXE Patients and Controls

Pseudoxanthoma elasticum: the paradigm of ectopic mineralization disorders – diagnosis and treatment

Can APOE and MTHFR polymorphisms have an influence on the severity of cardiovascular manifestations in Italian Pseudoxanthoma elasticum affected patients?

Contact Info

Product

Resources

About