Characterization of pseudoxanthoma elasticum-like lesions in the skin of patients with ?-thalassemia

Baccarani-Contri, M.; Bacchelli, Barbara; Boraldi, Federica; Quaglino, Daniela; Taparelli, F.; Carnevalia, Elena; Francomano, Maria Angela; Seidenari, Stefania; Bettoli, Vincenzo; Sanctis, Vincenzo De; Pasquali‐Ronchetti, I.

doi:10.1067/mjd.2001.110045

Cited by 78 publications

(56 citation statements)

References 28 publications

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“…It can be hypothesize that ABCC6/MRP6 deficiency would induce retention of cellular products which affect fibroblast metabolism (Boraldi et al, 2003) causing, as final consequence, extracellular matrix alterations (Neldner and Struk, 2002;Gheduzzi et al, 2003). Therefore, the relevant heterogeneity in clinical manifestations between relatives may suggest that, apart from PXE causative mutations, other genes and/or metabolic pathways that may have overall influence on the clinical expression of the disorder, as also suggested in a 20% of beta-thalassemia patients with PXE-like alterations (Baccarani-Contri et al, 2001). Furthermore, a large number of polymorphisms have been found in the ABCC6 gene that are not disease associated, but which could have a functional effect, similar to what observed for other ABC transporters (Ito el al., 2001;Rowntree and Harris, 2003).…”

Section: Genotype-phenotype Correlationmentioning

confidence: 99%

ABCC6 mutations in Italian families affected by pseudoxanthoma elasticum (PXE)

et al. 2004

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Pseudoxanthoma elasticum (PXE) is a genetic disorder, characterized by cutaneous, ocular and cardiovascular clinical symptoms, caused by mutations in a gene (ABCC6) that encodes for MRP6 (Multidrug Resistance associated Protein 6), an ATP-binding cassette membrane transporter. The ABCC6 gene was sequenced in 38 unrelated PXE Italian families. The mutation detection rate was 82.9%. Mutant alleles occurred in homozygous, compound heterozygous and heterozygous forms, however the great majority of patients were compound heterozygotes. Twenty-three different mutations were identified, among which 11 were new. Fourteen were missense (61%); five were nonsense (22%); two were frameshift (8.5%) and two were putative splice site mutations (8.5%). The great majority of mutations were located from exon 24 to 30, exon 24 being the most affected. Among the others, exons 9 and 12 were particularly involved. Almost all mutations were located in the intracellular site of MRP6. A positive correlation was observed between patient's age and severity of the disorder, especially for eye alterations. The relevant heterogeneity in clinical manifestations between patients with identical ABCC6 mutations, even within the same family, seems to indicate that, apart from PXE causative mutations, other genes and/or metabolic pathways might influence the clinical expression of the disorder.

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Section: Genotype-phenotype Correlationmentioning

confidence: 99%

ABCC6 mutations in Italian families affected by pseudoxanthoma elasticum (PXE)

et al. 2004

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“…Because PXE-like mineralization in ␤-thalassemia patients arise independently of ABCC6 mutations 16 and is clinically and structurally identical to inherited PXE, [17][18][19][20] the calcification of elastic fibers is very likely a phenocopy of inherited PXE. Therefore, we hypothesized that a converging molecular mechanism independent of genetic mutations alters the expression of ABCC6 or disrupts the biologic properties of its product in the liver and/or kidneys as a secondary consequence of the hemoglobinopathy.…”

Section: 15mentioning

confidence: 99%

A Mouse Model of β-Thalassemia Shows a Liver-Specific Down-Regulation of Abcc6 Expression

Martin

Douet

VanWart

et al. 2011

The American Journal of Pathology

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␤-Thalassemia and pseudoxanthoma elasticum (PXE) are distinct genetic disorders. Yet, a dystrophic mineralization phenotype similar to PXE has frequently been associated with ␤-thalassemia or sickle cell anemia patients of Mediterranean descent. These calcifications are clinically and structurally identical to inherited PXE. As we previously excluded the presence of PXE-causing mutations in the ABCC6 gene of ␤-thalassemia patients with PXE manifestations, we hypothesized that a molecular mechanism independent of gene mutations either altered the ABCC6 gene expression or disrupted the biologic properties of its product in the liver or kidneys, which are the tissues with the highest levels of expression. To test this possibility, we investigated Abcc6 synthesis in the liver and kidneys of a ␤-thalassemia mouse model (Hbb th3/؉ ). We found a progressive liver-specific down-regulation of the Abcc6 gene expression and protein levels by quantitative PCR, Western blotting, and immunofluorescence. The levels of Abcc6 protein decreased significantly at 6 months of age and stabilized at 10 months and older ages at ϳ25% of the wild-type protein levels. We studied the transcriptional regulation of the Abcc6 gene in wild-type and Hbb th3/؉ mice, and we identified the erythroid transcription factor NF-E2 as the main cause of the transcriptional down-regulation using transcription factor arrays and chromatin immunoprecipitation. The Hbb th3/؉ mice did not develop spontaneous calcification as seen in the Abcc6 ؊/؊ mice probably because the Abcc6 protein decrease occurred late in life and was probably insufficient to promote mineralization in the Hbb th3/؉ mouse C57BL/6J genetic background. Nevertheless, our result suggested that a similar decrease of ABCC6 expression occurs in the liver of ␤-thalassemia patients and may be responsible for their frequent PXE-like manifestations.

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“…Evidence that thalassemia-associated PXE is structurally identical to inherited PXE was derived by a recent study that compared dermal pathology between the 2 entities applying sophisticated techniques including electron microscopy and immunocytochemistry. 30 Of interest is the fact that subclinical disorders of the elastic tissue have been encountered even in the first decade of life. In a surgical series of 45 unselected patients with ␤ thalassemia major, aged between 6 and 25 years (mean, 16 years), spleen, liver, and lymph node biopsies revealed multiple defects of arterial and stromal …”

Section: Pxe-like Manifestations In ␤ Thalassemia and The Sickling Symentioning

confidence: 99%

Elastic tissue abnormalities resembling pseudoxanthoma elasticum in β thalassemia and the sickling syndromes

Aessopos

Farmakis

Loukopoulos

2002

Blood

139

124

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The development of clinical and histopathologic manifestations of a diffuse elastic tissue defect, resembling inherited pseudoxanthoma elasticum (PXE), has been encountered with a notable frequency in patients with ␤ thalassemia, sickle cell disease, and sickle thalassemia. The PXE-like clinical syndrome, consisting of skin, ocular, and vascular manifestations, has a variable severity in these hemoglobinopathies and it is age-dependent, with a generally late onset, after the second decade of life. The defect is believed to be acquired rather than inherited and related to the consequences of the primary disease. The high prevalence of the findings implicates the elastic tissue injury as one of the main comorbid abnormalities encountered in ␤ thalassemia and the sickling syndromes. In these patients a number of complications, sometimes serious, has been recognized to be related to ocular and vascular elastic tissue defects. Because several organ systems are involved, each medical specialty should be aware of the phenomenon. This coexistence, on the other hand, introduces a novel pathogenetic aspect of PXE and an important research challenge. (Blood. 2002;99:30-35)

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Characterization of pseudoxanthoma elasticum-like lesions in the skin of patients with ?-thalassemia

Cited by 78 publications

References 28 publications

ABCC6 mutations in Italian families affected by pseudoxanthoma elasticum (PXE)

ABCC6 mutations in Italian families affected by pseudoxanthoma elasticum (PXE)

A Mouse Model of β-Thalassemia Shows a Liver-Specific Down-Regulation of Abcc6 Expression

Elastic tissue abnormalities resembling pseudoxanthoma elasticum in β thalassemia and the sickling syndromes

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