Publications (52) View all
-
Article: Acute Aortic Dissection Determines the Fate of Initially Untreated Aortic Segments in Marfan Syndrome.
[show abstract] [hide abstract]
ABSTRACT: BACKGROUND: Aim of the current study was to investigate incidence and etiology of surgical interventions in primarily non-treated aortic segments after previous aortic repair in patients with Marfan syndrome (MFS). METHODS AND RESULTS: Retrospective analysis of 86 consecutive MFS patients fulfilling Ghent criteria that underwent 136 aortic surgeries and were followed at this institution in the past 15 years. Mean follow-up was 8.8±6.8y. Thirty-day, 6-months, 1-year and overall mortality was 3.5%, 5.8%, 7.0% and 12.8%, respectively. Ninety-two percent of patients initially presented with aortic root, ascending aortic or arch lesions, whereas 8% presented with descending aortic or thoraco-abdominal lesions. Primary presentation was acute aortic dissection (AAD) in 36% [77% type A, 23% type B] and aneurismal disease in 64%. Secondary complete arch replacement had to be performed in only 6% of patients without AAD, but in 36% with AAD (p=0.0005). In patients without AAD, 11% required surgery on primarily non-treated aortic segments [5 out of 6 patients suffered from type B dissection during follow-up], whereas in patients after AAD, 48% underwent surgery of initially non-treated aortic segments [42% of patients with type A and 86% of those with type B dissection] (p=0.0002). CONCLUSIONS: The need for surgery in primarily non-treated aortic segments is precipitated by an initial presentation with AAD. Early elective surgery is associated with low mortality and re-intervention rates. Type B dissection in patients with MFS is associated with a high need for extensive aortic repair even if the dissection is being considered uncomplicated by conventional criteria.Circulation 03/2013; · 14.74 Impact Factor -
Article: Hemizygous deletion of COL3A1, COL5A2, and MSTN causes a complex phenotype with aortic dissection: a lesson for and from true haploinsufficiency.
[show abstract] [hide abstract]
ABSTRACT: Aortic dilatation/dissection (AD) can occur spontaneously or in association with genetic syndromes, such as Marfan syndrome (MFS; caused by FBN1 mutations), MFS type 2 and Loeys-Dietz syndrome (associated with TGFBR1/TGFBR2 mutations), and Ehlers-Danlos syndrome (EDS) vascular type (caused by COL3A1 mutations). Although mutations in FBN1 and TGFBR1/TGFBR2 account for the majority of AD cases referred to us for molecular genetic testing, we have obtained negative results for these genes in a large cohort of AD patients, suggesting the involvement of additional genes or acquired factors. In this study we assessed the effect of COL3A1 deletions/duplications in this cohort. Multiplex ligation-dependent probe amplification (MLPA) analysis of 100 unrelated patients identified one hemizygous deletion of the entire COL3A1 gene. Subsequent microarray analyses and sequencing of breakpoints revealed the deletion size of 3,408,306 bp at 2q32.1q32.3. This deletion affects not only COL3A1 but also 21 other known genes (GULP1, DIRC1, COL5A2, WDR75, SLC40A1, ASNSD1, ANKAR, OSGEPL1, ORMDL1, LOC100129592, PMS1, MSTN, C2orf88, HIBCH, INPP1, MFSD6, TMEM194B, NAB1, GLS, STAT1, and STAT4), mutations in three of which (COL5A2, SLC40A1, and MSTN) have also been associated with an autosomal dominant disorder (EDS classical type, hemochromatosis type 4, and muscle hypertrophy). Physical and laboratory examinations revealed that true haploinsufficiency of COL3A1, COL5A2, and MSTN, but not that of SLC40A1, leads to a clinical phenotype. Our data not only emphasize the impact/role of COL3A1 in AD patients but also extend the molecular etiology of several disorders by providing hitherto unreported evidence for true haploinsufficiency of the underlying gene.European journal of human genetics: EJHG 12/2010; 18(12):1315-21. · 3.56 Impact Factor -
Article: Loss of dermatan-4-sulfotransferase 1 function results in adducted thumb-clubfoot syndrome.
[show abstract] [hide abstract]
ABSTRACT: Adducted thumb-clubfoot syndrome is an autosomal-recessive disorder characterized by typical facial appearance, wasted build, thin and translucent skin, congenital contractures of thumbs and feet, joint instability, facial clefting, and coagulopathy, as well as heart, kidney, or intestinal defects. We elucidated the molecular basis of the disease by using a SNP array-based genome-wide linkage approach that identified distinct homozygous nonsense and missense mutations in CHST14 in each of four consanguineous families with this disease. The CHST14 gene encodes N-acetylgalactosamine 4-O-sulfotransferase 1 (D4ST1), which catalyzes 4-O sulfation of N-acetylgalactosamine in the repeating iduronic acid-alpha1,3-N-acetylgalactosamine disaccharide sequence to form dermatan sulfate. Mass spectrometry of glycosaminoglycans from a patient's fibroblasts revealed absence of dermatan sulfate and excess of chondroitin sulfate, showing that 4-O sulfation by CHST14 is essential for dermatan sulfate formation in vivo. Our results indicate that adducted thumb-clubfoot syndrome is a disorder resulting from a defect specific to dermatan sulfate biosynthesis and emphasize roles for dermatan sulfate in human development and extracellular-matrix maintenance.The American Journal of Human Genetics 12/2009; 85(6):873-82. · 10.60 Impact Factor -
Article: Evidence for a role of sphingosine-1 phosphate in cardiovascular remodelling in Fabry disease.
[show abstract] [hide abstract]
ABSTRACT: A hallmark of Fabry disease is the concomitant development of left-ventricular hypertrophy and arterial intima-media thickening, the pathogenesis of which is thought to be related to the presence of a plasmatic circulating growth-promoting factor. We therefore characterized the plasma of patients with Fabry disease in order to identify this factor. Using a classical biochemical strategy, we isolated and identified sphingosine-1 phosphate (S1P) as a proliferative factor present in the plasma of patients with Fabry disease. Plasma S1P levels were significantly higher in 17 patients with Fabry disease compared with 17 healthy controls (225 +/- 40 vs. 164 +/- 17 ng/mL; P = 0.005). There was a positive correlation between plasma S1P levels and both common carotid artery intima-media thickness and left-ventricular mass index (r(2) = 0.47; P = 0.006 and r(2) = 0.53; P = 0.0007, respectively). In an experimental model, mice treated with S1P developed cardiovascular remodelling similar to that observed in patients with Fabry disease. Sphingosine-1 phosphate participates in cardiovascular remodelling in Fabry disease. Our findings have implications for the treatment of cardiovascular involvement in Fabry disease.European Heart Journal 09/2009; 31(1):67-76. · 10.48 Impact Factor -
Article: Quantitative sequence analysis of FBN1 premature termination codons provides evidence for incomplete NMD in leukocytes.
[show abstract] [hide abstract]
ABSTRACT: We improved, evaluated, and used Sanger sequencing for quantification of single nucleotide polymorphism (SNP) variants in transcripts and gDNA samples. This improved assay resulted in highly reproducible relative allele frequencies (e.g., for a heterozygous gDNA 50.0+/-1.4%, and for a missense mutation-bearing transcript 46.9+/-3.7%) with a lower detection limit of 3-9%. It provided excellent accuracy and linear correlation between expected and observed relative allele frequencies. This sequencing assay, which can also be used for the quantification of copy number variations (CNVs), methylations, mosaicisms, and DNA pools, enabled us to analyze transcripts of the FBN1 gene in fibroblasts and blood samples of patients with suspected Marfan syndrome not only qualitatively but also quantitatively. We report a total of 18 novel and 19 known FBN1 sequence variants leading to a premature termination codon (PTC), 26 of which we analyzed by quantitative sequencing both at gDNA and cDNA levels. The relative amounts of PTC-containing FBN1 transcripts in fresh and PAXgene-stabilized blood samples were significantly higher (33.0+/-3.9% to 80.0+/-7.2%) than those detected in affected fibroblasts with inhibition of nonsense-mediated mRNA decay (NMD) (11.0+/-2.1% to 25.0+/-1.8%), whereas in fibroblasts without NMD inhibition no mutant alleles could be detected. These results provide evidence for incomplete NMD in leukocytes and have particular importance for RNA-based analyses not only in FBN1 but also in other genes.Human Mutation 06/2009; 30(9):1355-64. · 5.69 Impact Factor
