Aneurysmatic dilatation of ascending aorta in a patient with ?-thalassemia and a pseudoxanthoma elasticum-like syndrome

Farmakis, Dimitrios; Vesleme, Vassiliki; Papadogianni, Argiroula; Tsaftaridis, Panagiotis; Kapralos, Pantelis; Aessopos, Athanasios

doi:10.1007/s00277-004-0859-6

Cited by 22 publications

(17 citation statements)

References 20 publications

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“…Fragmentation of elastic fibers is also a typical hallmark of the connective tissue disorder PXE [10], which is caused by mutations in the ABCC6 gene [19,20,21,22,23,24]. This disease mainly leads to alterations in dermal, ocular and all vascular tissues, and, in some cases, aneurysmatic dilatations were observed [41, 42]. In order to determine if the occurrence of sequence variations in the ABCC6 gene is associated with the presence of AAAs and to compare the frequencies of ABCC6 polymorphisms and mutations in AAA and PXE patients, we screened the ABCC6 exons 16–18, 24 and 28–30 from 133 unrelated patients with AAA, 54 PXE patients and 23 PXE relatives.…”

Section: Discussionmentioning

confidence: 99%

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

Schulz

Hendig

Schillinger³

et al. 2005

J Vasc Res

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Abdominal aortic aneurysm (AAA) is characterized by dilatation of arterial walls, which is accompanied by degradation of elastin and collagen molecules. Biochemical and environmental factors are known to be relevant for AAA development, and familial predisposition is well recognized. A connective tissue disorder that is also associated with fragmentation of elastic fibers is Pseudoxanthoma elasticum (PXE). PXE is caused by mutations in the ABCC6 gene and mainly affects dermal, ocular and all vascular tissues. To investigate whether variations in ABCC6 are found in AAA patients and to determine mutations in PXE patients, we analyzed seven selected ABCC6 exons of 133 AAA and 54 PXE patients subjected to mutational analysis. In our cohort of AAA patients, we found five ABCC6 alterations, which result in missense or silent amino acid variants. The allelic frequencies of these sequence variations were not significantly different between AAA patients and healthy controls. Therefore, we suggest that alterations in ABCC6 are not a genetic risk factor for AAA. Mutational screening of the PXE patients revealed 19 different ABCC6 variations, including two novel PXE-causing mutations. These results expand the ABCC6 mutation database in PXE.

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Section: Discussionmentioning

confidence: 99%

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

Schulz

Hendig

Schillinger³

et al. 2005

J Vasc Res

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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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“…24 In fact, it has been shown that 85% of patients Ͼ30 years of age who have thalassemia intermedia have at least 1 of the typical manifestations of the defect, namely, skin lesions, ocular angioid streaks, and arterial degeneration, 25 whereas subclinical pathology findings were found in 96% of young patients with thalassemia major and other hemolytic conditions. 26 This defect has been related to a number of vascular and other complications, 27,28 including pulmonary arterial lesions, hence providing a structural component to the aforementioned hemolysis-related vasculopathy. 22 A hypercoagulable state is another notable finding in hemoglobinopathies.…”

Section: Pathophysiologymentioning

confidence: 99%

Pulmonary Hypertension Associated With Hemoglobinopathies

Farmakis

Aessopos

2011

Circulation

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Aneurysmatic dilatation of ascending aorta in a patient with ?-thalassemia and a pseudoxanthoma elasticum-like syndrome

Cited by 22 publications

References 20 publications

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

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

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

Pulmonary Hypertension Associated With Hemoglobinopathies

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