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Dianna M. Milewicz - One of the best experts on this subject based on the ideXlab platform.
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fbn2 mutation associated with manifestations of marfan syndrome and congenital contractural arachnodactyly
Journal of Medical Genetics, 2004Co-Authors: Prateek Gupta, Debra D Wallis, T O Chin, H Northrup, Van Tranfadulu, Jeffrey A Towbin, Dianna M. MilewiczAbstract:Congenital contractures involving multiple joints and a crumpled appearance of the helix of the ear are more common in CCA than MFS. Ectopia lentis is a complication present in approximately half of patients with MFS. The most common cardiovascular complication in patients with MFS is pro- gressive dilatation of the ascending aorta, initially involving the sinuses of Valsalva. 6 Although patients affected with CCA were initially felt not to have aortic involvement, three children under 6 years of age with CCA have had dilated aortic roots, further blurring the clinical distinction between the two syndromes. 5 The overlap in the clinical features has a molecular basis; CCA and MFS result from mutations in two homologous genes, FBN2 and FBN1, respectively. 5 7-9
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association of fibrillin 1 single nucleotide polymorphism haplotypes with systemic sclerosis in choctaw and japanese populations
Arthritis & Rheumatism, 2001Co-Authors: Ning Wang, Dianna M. Milewicz, Ranajit Chakraborty, Masataka Kuwana, Constantin A Bona, Frank C ArnettAbstract:Objective Previously, we demonstrated with the use of microsatellite markers that a 2-cM haplotype on chromosome 15q containing the fibrillin 1 gene (FBN1) was strongly associated with systemic sclerosis (SSc) in the Choctaw, a population with high SSc prevalence. In this study, all 69 known FBN1 exons were sequenced to ascertain the presence of changes that might show associations with SSc in the Choctaw and Japanese SSc patients and controls. Methods Screening of FBN1 exons was accomplished by polymerase chain reaction–based fluorescence sequencing of genomic DNA using single-nucleotide polymorphism (SNP) haplotypes, and their frequencies were determined with a new algorithm that recognizes past recombination events between sites. Haplotype phylogenies were inferred using the median-joining network analysis. Results Five SNPs were identified in FBN1. They are located in the 5′-untranslated region (SNP-1), exon 15 (SNP-2), intron 17 (SNP-3), exon 27 (SNP-4), and intron 27 (SNP-5). Only SNP-1 (TC) demonstrated an association with SSc in the Choctaw. Eleven FBN1 SNP haplotypes were ascertained in the Choctaw population, 2 of which (SNPs 5 and 6) were found only in the SSc patients. These same FBN1 SNP haplotypes were associated with SSc in the Japanese. Conclusion A SNP in the 5′-untranslated region of FBN1 (SNP-1, C allele) was strongly associated with SSc in the Choctaw. Furthermore, this polymorphism is present on 2 unique FBN1 haplotypes found only in Choctaw SSc patients. The same 2 haplotypes demonstrate associations with SSc in the Japanese. These data extend the earlier microsatellite studies and are consistent with the hypothesis that FBN1 or a nearby gene on chromosome 15q is involved in SSc susceptibility in the Choctaw and the Japanese.
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clustering of fbn2 mutations in patients with congenital contractural arachnodactyly indicates an important role of the domains encoded by exons 24 through 34 during human development
American Journal of Medical Genetics, 1998Co-Authors: Eun Sook Park, Elizabeth A Putnam, David Chitayat, Anne H Child, Dianna M. MilewiczAbstract:Congenital contractural arachnodactyly (CCA) is an autosomal dominant condition phenotypically related to Marfan syndrome (MFS). CCA is caused by mutations in FBN2, whereas MFS results from mutations in FBN1. FBN2 mRNA extracted from 12 unrelated CCA patient cell strains was screened for mutations, and FBN2 mutations were identified in six of these samples. All of the identified FBN2 mutations cluster in a limited region of the gene, a region where mutations in FBN1 produce the severe, congenital form of MFS (so-called neonatal MFS). Furthermore, three of the identified mutations occur in the FBN2 locations exactly corresponding to FBN1 mutations that have been reported in cases of neonatal MFS. These mutations indicate that this central region of both of the fibrillins plays a critical role in human embryogenesis. The limited region of FBN2 that can be mutated to cause CCA may also help to explain the rarity of CCA compared to MFS. Am. J. Med. Genet. 78:350–355, 1998. © 1998 Wiley-Liss, Inc.
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fibrillin 1 FBN1 mutations in patients with thoracic aortic aneurysms
Circulation, 1996Co-Authors: Dianna M. Milewicz, Kristi Michael, Nancy Fisher, Thomas Markello, Joseph S. Coselli, Alan BiddingerAbstract:Background Mutations in the FBN1 gene are the cause of the Marfan syndrome, an autosomal dominant disorder with skeletal, ocular, and cardiovascular complications. Aneurysms or dissections of the ascending thoracic aorta are the major cardiovascular complications of the disorder. We tested the hypothesis that FBN1 mutations cause thoracic aortic aneurysms or dissections in patients who do not have the Marfan syndrome. Methods and Results The FBN1 gene was screened for mutations by use of genomic DNA from two patients with thoracic aortic aneurysms who did not have the Marfan syndrome. Individual FBN1 exons were amplified with intron-based exon-specific primers; the DNA fragments were screened for mutations using single-stranded conformational polymorphism analysis; and aberrantly migrating bands were sequenced directly. We identified a missense mutation in one patient, D1155N in exon 27. Dermal fibroblasts from the affected individual were used to study the effect of the missense mutation D1155N on fibril...
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fibrillin 2 fbn2 mutations result in the marfan like disorder congenital contractural arachnodactyly
Nature Genetics, 1995Co-Authors: Elizabeth A Putnam, Dianna M. Milewicz, Francesco Ramirez, Hui ZhangAbstract:Congenital contractural arachnodactyly (CCA) is an autosomal dominant disorder that is phenotypically similar to Marfan syndrome (MFS) and characterized by arachnodactyly, dolichostenomelia, scoliosis, multiple congenital contractures and abnormalities of the external ears1. In contrast to MFS, CCA does not affect the aorta or the eyes. Two closely related genes, FBN1 located on chromosome 15q15–21.3 and FBN2 located at 5q23–31, encode large fibrillin proteins found in extracellular matrix structures called microfibrils2–4. The MFS is caused by mutations in FBN1, while CCA has been genetically linked to FBN2 (refs 2, 5, 6). We now describe a pair of FBN2 missense mutations in two CCA patients that cause substitution of distinct cysteine residues in separate epidermal growth-factor-like (EGF) repeats. Our study provides final proof of the association between FBN2 mutations and CCA pathology, thus establishing the role of the fibrillin-2 in extracellular matrix physiology and pathology.
Francesco Ramirez - One of the best experts on this subject based on the ideXlab platform.
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fibrillin 1 microfibrils influence adult bone marrow hematopoiesis
Matrix Biology, 2016Co-Authors: Silvia Smaldone, Carolina L Bigarella, Maria Del Solar, Saghi Ghaffari, Francesco RamirezAbstract:Abstract We have recently demonstrated that fibrillin-1 assemblies regulate the fate of skeletal stem cells (aka, mesenchymal stem cells [MSCs]) by modulating TGFβ activity within the microenvironment of adult bone marrow niches. Since MSCs can also influence hematopoietic stem cell (HSC) activities, here we investigated adult hematopoiesis in mice with Cre-mediated inactivation of the fibrillin-1 ( FBN1 ) gene in the mesenchyme of the forming limbs ( FBN1 Prx1 − / − mice). Analyses of 3-month-old FBN1 Prx1 − / − mice revealed a statistically significant increase of circulating red blood cells, which a differentiation assay correlated with augmented erythropoiesis. This finding, together with evidence of fibrillin-1 deposition in erythroblastic niches, supported the notion that this extracellular matrix protein normally restricts differentiation of erythroid progenitors. Whereas flow cytometry measurements identified a decreased HSC frequency in mutant relative to wild type mice, no appreciable differences were noted with regard to the relative abundance and differentiation potential of myeloid progenitor cells. Together these findings implied that fibrillin-1 normally promotes HSC expansion but does not influence cell lineage commitment. Since local TGFβ hyperactivity has been associated with abnormal osteogenesis in FBN1 Prx1 − / − mice, 1-month-old mutant and wild type animals were systemically treated for 8 weeks with either a pan-TGF-β-neutralizing antibody or an antibody of the same IgG1 isotype. The distinct outcomes of these pharmacological interventions strongly suggest that fibrillin-1 differentially modulates TGFβ activity in HSC vs. erythroid niches.
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losartan attenuates degradation of aorta and lung tissue micromechanics in a mouse model of severe marfan syndrome
Annals of Biomedical Engineering, 2016Co-Authors: Francesco Ramirez, Jiajye Lee, Josephine Galatioto, Satish Rao, Kevin D CostaAbstract:Marfan syndrome (MFS) is an autosomal dominant disease of the connective tissue due to mutations in the fibrillin-1 gene (FBN1). This study aimed at characterizing microelastic properties of the ascending aortic wall and lung parenchyma tissues from wild type (WT) and age-matched FBN1 hypomorphic mice (FBN1(mgR/mgR) mice) to identify tissue-specific biomechanical effects of aging and disease in MFS. Atomic force microscopy was used to indent lung parenchyma and aortic wall tissues, using Hybrid Eshelby Decomposition analysis to extract layer-specific properties of the intima and media. The intima stiffened with age and was not different between WT and FBN1(mgR/mgR) tissues, whereas the media layer of MFS aortas showed progressive structural and mechanical degradation with a modulus that was 50% softer than WT by 3.5 months of age. Similarly, MFS mice displayed progressive structural and mechanical deterioration of lung tissue, which was over 85% softer than WT by 3.5 months of age. Chronic treatment with the angiotensin type I receptor antagonist, losartan, attenuated the aorta and lung tissue degradation, resulting in structural and mechanical properties not significantly different from age-matched WT controls. By revealing micromechanical softening of elastin-rich aorta and lung tissues with disease progression in fibrillin-1 deficient mice, our findings support the use of losartan as a prophylactic treatment that may abrogate the life-threatening symptoms of MFS.
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Establishment of fibrillin-deficient osteoprogenitor cell lines identifies molecular abnormalities associated with extracellular matrix perturbation of osteogenic differentiation
Cell and Tissue Research, 2011Co-Authors: Silvia Smaldone, Luca Carta, Francesco RamirezAbstract:Fibrillin-1 and fibrillin-2 are structural components of the extracellular matrix which are also involved in modulating local TGFβ and BMP bioavailability. Loss of fibrillin-1 or fibrillin-2 is associated with perturbed osteoblast maturation principally as the result of unbalanced TGFβ and BMP signaling. Here, we demonstrated that stable expression of small hairpin RNAs against fibrillin-1(FBN1) or fibrillin-2 (Fbn2) transcripts in the clonal osteoprogenitor cell line Kusa-A1 led to the same phenotypic and molecular manifestations as germline FBN1- or Fbn2-null mutations in primary calvarial osteoblast cultures. Proof-of-concept experiments are also presented showing that FBN1- or Fbn2-silenced Kusa-A1 cell lines are suitable models to identify candidate determinants of osteogenesis which are under the control of extracellular microfibrils. Specific findings included: the inference of a potential role for fibrillin-1-mediated cell–matrix interactions in regulating Kusa-A1 proliferation; the possibility of fibrillin-2 involvement in modulating the activity of transcription factor Runx2 by restricting microRNA expression and/or processing; and the suggestion that fibrillin-1 and fibrillin-2 influence Notch signaling indirectly by differentially regulating BMP signaling. Collectively, the data reiterated the notion that fibrillin-1 and fibrillin-2 exert opposite effects on osteoblast differentiation through the discrete modulation of a broad network of interacting signaling molecules.
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fibrillin 1 genetic deficiency leads to pathological ageing of arteries in mice
The Journal of Pathology, 2011Co-Authors: Boubacar Mariko, Mylene Pezet, Jeanpierre Andrieu, Stéphanie Bouillot, Philippe Huber, Daniela Quaglino, Barry Starcher, Mariepaule Jacob, Brigitte Escoubet, Francesco RamirezAbstract:Fibrillin-1, the major component of extracellular microfibrils that associate with insoluble elastin in elastic fibres, is mainly synthesized during development and postnatal growth and is believed to guide elastogenesis. Mutations in the fibrillin-1 gene cause Marfan syndrome, a multisystem disorder characterized by aortic aneurysms and dissections. The recent finding that early deficiency of elastin modifies vascular ageing has raised the possibility that fibrillin-1 deficiency could also contribute to late-onset pathology of vascular remodelling. To address this question, we examined cardiovascular function in 3-week-old, 6-month-old, and 24-month-old mice that are heterozygous for a hypomorphic structural mutation of fibrillin-1 (FBN1 mice). Our results indicate that FBN1 mice, particularly those that are 24 months old, are slightly more hypotensive than wild-type littermates. Additionally, aneurysm and aortic insufficiency were more frequently observed in ageing FBN1 mice than in the wild-type counterparts. We also noted substantial fragmentation and decreased number of elastic lamellae in the aortic wall of FBN1 mice, which were correlated with an increase in aortic stiffness, a decrease in vasoreactivity, altered expression of elastic fibre-related genes, including fibrillin-1 and elastin, and a decrease in the relative ratio between tissue elastin and collagen. Collectively, our findings suggest that the heterozygous mgΔ mutation accelerates some aspects of vascular ageing and eventually leads to aortic manifestations resembling those of Marfan syndrome. Importantly, our data also indicate that vascular abnormalities in FBN1 mice are opposite to those induced by elastin haploinsufficiency during ageing that affect blood pressure, vascular dimensions, and number of elastic lamellae. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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extracellular microfibrils control osteoblast supported osteoclastogenesis by restricting tgfβ stimulation of rankl production
Journal of Biological Chemistry, 2010Co-Authors: Harikiran Nistala, Sui Leearteaga, Silvia Smaldone, Gabriella Siciliano, Francesco RamirezAbstract:Mutations in fibrillin-1 or fibrillin-2, the major structural components of extracellular microfibrils, cause pleiotropic manifestations in Marfan syndrome and congenital contractural arachnodactyly, respectively. We recently found that fibrillin-1 and fibrillin-2 control bone formation by regulating osteoblast differentiation through the differential modulation of endogenous TGFβ and bone morphogenetic protein signals. Here, we describe in vivo and ex vivo experiments that implicate the fibrillins as negative regulators of bone resorption. Adult Fbn2−/− mice display a greater than normal osteolytic response to locally implanted lipopolysaccharide-coated titanium particles. Although isolated cultures of Fbn2−/− preosteoclasts exhibited normal differentiation and activity, these features were substantially augmented when mutant or wild-type preosteoclasts were co-cultured with Fbn2−/− but not wild-type osteoblasts. Greater osteoclastogenic potential of Fbn2−/− osteoblasts was largely accounted for by up-regulation of the Rankl gene secondary to heightened TGFβ activity. This conclusion was based on the findings that blockade of TGFβ signaling blunts Rankl up-regulation in Fbn2−/− osteoblasts and bones and that systemic TGFβ antagonism improves locally induced osteolysis in Fbn2−/− mice. Abnormally high Rankl expression secondary to elevated TGFβ activity was also noted in cultured osteoblasts from FBN1−/− mice. Collectively our data demonstrated that extracellular microfibrils balance local catabolic and anabolic signals during bone remodeling in addition to implying distinct mechanisms of bone loss in Marfan syndrome and congenital contractural arachnodactyly.
Bart Loeys - One of the best experts on this subject based on the ideXlab platform.
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an FBN1 deep intronic mutation in a familial case of marfan syndrome an explanation for genetically unsolved cases
Human Mutation, 2014Co-Authors: Elisabeth Gillis, Bart Loeys, Marlies Kempers, Simone Salemink, Janneke Timmermans, Emile C Cheriex, Sebastiaan C A M Bekkers, Erik Fransen, Christine E M De DiesmuldersAbstract:Marfan syndrome (MFS) is caused by mutations in the FBN1 (fibrillin-1) gene, but approximately 10% of MFS cases remain genetically unsolved. Here, we report a new FBN1 mutation in an MFS family that had remained negative after extensive molecular genomic DNA FBN1 testing, including denaturing high-performance liquid chromatography, Sanger sequencing, and multiplex ligation-dependent probe amplification. Linkage analysis in the family and cDNA sequencing of the proband revealed a deep intronic point mutation in intron 56 generating a new splice donor site. This mutation results in the integration of a 90-bp pseudo-exon between exons 56 and 57 containing a stop codon, causing nonsense-mediated mRNA decay. Although more than 90% of FBN1 mutations can be identified with regular molecular testing at the genomic level, deep intronic mutations will be missed and require cDNA sequencing or whole-genome sequencing.
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circulating transforming growth factor beta in marfan syndrome
Circulation, 2009Co-Authors: Peter Matt, Florian Schoenhoff, Jennifer Habashi, Tammy M Holm, David Loch, Olga D Carlson, Benjamin F Griswold, Qin Fu, Julie De Backer, Bart LoeysAbstract:BACKGROUND: Marfan syndrome (MFS) is caused by mutations in the fibrillin-1 gene and dysregulation of transforming growth factor-beta (TGF-beta). Recent evidence suggests that losartan, an angiotensin II type 1 blocker that blunts TGF-beta activation, may be an effective treatment for MFS. We hypothesized that dysregulation of TGF-beta might be mirrored in circulating TGF-beta concentrations. METHODS AND RESULTS: Serum obtained from MFS mutant mice (FBN1(C1039G/+)) treated with losartan was analyzed for circulating TGF-beta1 concentrations and compared with those from placebo-treated and wild-type mice. Aortic root size was measured by echocardiography. Data were validated in patients with MFS and healthy individuals. In mice, circulating total TGF-beta1 concentrations increased with age and were elevated in older untreated FBN1(C1039G/+) mice compared with wild-type mice (P=0.01; n=16; mean+/-SEM, 115+/-8 ng/mL versus n=17; mean+/-SEM, 92+/-4 ng/mL). Losartan-treated FBN1(C1039G/+) mice had lower total TGF-beta1 concentrations compared with age-matched FBN1(C1039G/+) mice treated with placebo (P=0.01; n=18; 90+/-5 ng/mL), and circulating total TGF-beta1 levels were indistinguishable from those of age-matched wild-type mice (P=0.8). Correlation was observed between circulating TGF-beta1 levels and aortic root diameters in FBN1(C1039G/+) and wild-type mice (P=0.002). In humans, circulating total TGF-beta1 concentrations were elevated in patients with MFS compared with control individuals (P<0.0001; n=53; 15+/-1.7 ng/mL versus n=74; 2.5+/-0.4 ng/mL). MFS patients treated with losartan (n=55) or beta-blocker (n=80) showed significantly lower total TGF-beta1 concentrations compared with untreated MFS patients (P< or =0.05). CONCLUSIONS: Circulating TGF-beta1 concentrations are elevated in MFS and decrease after administration of losartan, beta-blocker therapy, or both and therefore might serve as a prognostic and therapeutic marker in MFS.
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contribution of molecular analyses in diagnosing marfan syndrome and type i fibrillinopathies an international study of 1009 probands
Journal of Medical Genetics, 2008Co-Authors: Laurence Faivre, Bart Loeys, Anne H Child, Gwenaelle Collodberoud, Bert Callewaert, Christine Binquet, Elodie Gautier, Eloisa Arbustini, Karin Mayer, Mine ArslankirchnerAbstract:BACKGROUND: The diagnosis of Marfan syndrome (MFS) is usually initially based on clinical criteria according to the number of major and minor systems affected following international nosology. The number of FBN1 mutation carriers, at risk of aortic complications who would not be properly diagnosed based only on clinical grounds, is of growing importance owing to the increased availability of molecular screening. The aim of the study was to identify patients who should be considered for FBN1 mutation screening. METHODS: Our international series included 1009 probands with a known FBN1 mutation. Patients were classified as either fulfilling or not fulfilling "clinical" criteria. In patients with unfulfilled "clinical" criteria, we evaluated the percentage of additional patients who became positive for international criteria when the FBN1 mutation was considered. The aortic risk was evaluated and compared in patients fulfilling or not fulfilling the "clinical" international criteria. RESULTS: Diagnosis of MFS was possible on clinical grounds in 79% of the adults, whereas 90% fulfilled the international criteria when including the FBN1 mutation. Corresponding figures for children were 56% and 85%, respectively. Aortic dilatation occurred later in adults with unfulfilled "clinical criteria" when compared to the Marfan syndrome group (44% vs 73% at 40 years, p<0.001), but the lifelong risk for ascending aortic dissection or surgery was not significantly different in both groups. CONCLUSIONS: Because of its implications for aortic follow-up, FBN1 molecular analysis is recommended in newly suspected MFS when two systems are involved with at least one major system affected. This is of utmost importance in patients without aortic dilatation and in children.
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Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study.
American Journal of Human Genetics, 2007Co-Authors: Laurence Faivre, Bart Loeys, Gwenaëlle Collod-béroud, Anne Child, Bert Callewaert, Christine Binquet, Elodie Gautier, Eloisa Arbustini, Karin Mayer, Mine Arslan-kirchnerAbstract:Mutations in the fibrillin-1 (FBN1) gene cause Marfan syndrome (MFS) and have been associated with a wide range of overlapping phenotypes. Clinical care is complicated by variable age at onset and the wide range of severity of aortic features. The factors that modulate phenotypical severity, both among and within families, remain to be determined. The availability of international FBN1 mutation Universal Mutation Database (UMD-FBN1) has allowed us to perform the largest collaborative study ever reported, to investigate the correlation between the FBN1 genotype and the nature and severity of the clinical phenotype. A range of qualitative and quantitative clinical parameters (skeletal, cardiovascular, ophthalmologic, skin, pulmonary, and dural) was compared for different classes of mutation (types and locations) in 1,013 probands with a pathogenic FBN1 mutation. A higher probability of ectopia lentis was found for patients with a missense mutation substituting or producing a cysteine, when compared with other missense mutations. Patients with an FBN1 premature termination codon had a more severe skeletal and skin phenotype than did patients with an inframe mutation. Mutations in exons 24-32 were associated with a more severe and complete phenotype, including younger age at diagnosis of type I fibrillinopathy and higher probability of developing ectopia lentis, ascending aortic dilatation, aortic surgery, mitral valve abnormalities, scoliosis, and shorter survival; the majority of these results were replicated even when cases of neonatal MFS were excluded. These correlations, found between different mutation types and clinical manifestations, might be explained by different underlying genetic mechanisms (dominant negative versus haploinsufficiency) and by consideration of the two main physiological functions of fibrillin-1 (structural versus mediator of TGF beta signalling). Exon 24-32 mutations define a high-risk group for cardiac manifestations associated with severe prognosis at all ages.
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comprehensive molecular screening of the FBN1 gene favors locus homogeneity of classical marfan syndrome
Human Mutation, 2004Co-Authors: Bart Loeys, Gerard Pals, Lieve Nuytinck, J De Backer, P Van Acker, K Wettinck, Paul Coucke, A De PaepeAbstract:In order to estimate the contribution of mutations at the fibrillin-1 locus (FBN1) to classical Marfan syndrome (MFS) and to study possible phenotypic differences between patients with an FBN1 mutation vs. without, a comprehensive molecular study of the FBN1 gene in a cohort of 93 MFS patients fulfilling the clinical diagnosis of MFS according to the Ghent nosology was performed. The initial mutation screening by CSGE/SSCP allowed identification of an FBN1-mutation in 73 patients. Next, sequencing of all FBN1-exons was performed in 11 mutation-negative patients, while in nine others, DHPLC was used. This allowed identification of seven and five additional mutations, respectively. Southern blot analysis revealed an abnormal hybridization pattern in one more patient. A total of 23 out of the 85 mutations identified here are reported for the first time. Phenotypic comparison of MFS patients with cysteine-involving mutations vs. premature termination mutations revealed significant differences in ocular and skeletal involvement. The phenotype of the eight patients without proven FBN1 mutation did not differ from the others with respect to the presence of major cardiac, ocular, and skeletal manifestations or positive familial history. Most likely, a portion of FBN1-mutations remains undetected because of technical limitations. In conclusion, the involvement of the FBN1-gene could be demonstrated in at least 91% of all MFS patients (85/93), which strongly suggests that this gene is the predominant, if not the sole, locus for MFS.
Peter N Robinson - One of the best experts on this subject based on the ideXlab platform.
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comprehensive analysis of dural ectasia in 150 patients with a causative FBN1 mutation
Clinical Genetics, 2014Co-Authors: C. Sondermann, Meike Rybczynski, Harald Kaemmerer, T. S. Mir, A. Staebler, L. Brockstaedt, C R Habermann, Peter N RobinsonAbstract:The purpose of this study was to perform a comprehensive study of dural ectasia (DE) related to FBN1 mutations. We performed a database analysis of two German metropolitan regions of 150 patients (68 men, 82 women; mean age 35 ± 16 years). All patients had a FBN1 mutation and underwent dural magnetic resonance imaging. Age was 35 in 36 patients. Prevalence of dural ectasia was 89% with criteria of Oosterhof and Habermann, 83% with Fattori, 78% with Lundby, and 59% with Ahn. DE was less frequent in patients <16 years with Ahn and Fattori. DE related to skeletal manifestations with all criteria, to aortic Z-scores and mitral valve prolapse with criteria of Habermann and Lundby, and to age with criteria of Fattori. The Fattori-grade of DE increased with age, aortic Z-scores, and skeletal score points. There was no consistent relationship of DE with any type of FBN1 mutation. DE is frequent in patients with FBN1 mutations irrespective of age and its severity increases during life. Criteria of Oosterhof and Habermann yielded most consistent diagnostic results. DE relates to skeletal involvement, aortic Z-scores, and mitral valve prolapse.
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regulation of fibrillin 1 gene expression by sp1
Gene, 2013Co-Authors: Christian Rodelsperger, Peter N Robinson, Martin DigweedAbstract:Abstract Mutations in the fibrillin-1 gene ( FBN1 ) cause Marfan Syndrome (MFS), a hereditary disorder of connective tissue. The transcription of FBN1 has been reported to be driven by a short ultraconserved region (SUPR) in the 5′ untranslated exon A of FBN1 , but the nature of other factors involved in FBN1 gene regulation has not been clarified. In this study, we characterized the transcription factors involved in FBN1 gene regulation. The results show that Sp1 protein binds to two putative binding sites in the promoter of FBN1 . Overexpression of Sp1 resulted in a significant increase in both promoter activity and FBN1 mRNA level in HEK 293 cells, whereas inhibition or knockdown of Sp1 decreased FBN1 gene expression. In addition, we found that Poly [ADP-ribose] polymerase 1 (PARP1) binds to the palindromic sequence TCTCGCGAGA in the ultraconserved region of the FBN1 promoter and that the regulation of FBN1 expression by PARP1 is dependent on Sp1. These results indicate that both Sp1 and PARP1 contribute to FBN1 gene expression. These observations add to our understanding of the transcriptional regulation of FBN1 gene expression.
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progeroid facial features and lipodystrophy associated with a novel splice site mutation in the final intron of the FBN1 gene
American Journal of Medical Genetics Part A, 2011Co-Authors: Denise Horn, Peter N RobinsonAbstract:The association of progeroid features and lipodystrophy was very recently described in a female adult with additional manifestations of Marfan syndrome. Mutation analysis of the fibrillin I (FBN1) gene revealed a novel heterozygous frameshift mutation at the 3′ end in that patient. Here, we report on a 3.5-year-old girl with progeroid facial signs of neonatal onset, lipodystrophy, large head circumference with corresponding hydrocephaly, and tall stature at the end of infancy. Her facial appearance showed convincing clinical similarities to the above-mentioned case. We identified a novel heterozygous de novo splice site mutation c.8226+1G>T affecting the last intron of FBN1. We suggest a specific clinical entity characterized by progeroid facial features, lipodystrophy, and at least some clinical signs of Marfan syndrome is associated with a subset of mutations located at the 3′ end of FBN1. This phenotype which is different from that of classical Marfan syndrome could be caused by a truncated FBN1 protein which could escape nonsense-mediated RNA decay. © 2011 Wiley-Liss, Inc.
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the molecular genetics of marfan syndrome and related microfibrillopathies
Journal of Medical Genetics, 2000Co-Authors: Peter N Robinson, Maurice GodfreyAbstract:Mutations in the gene for fibrillin-1 ( FBN1 ) have been shown to cause Marfan syndrome, an autosomal dominant disorder of connective tissue characterised by pleiotropic manifestations involving primarily the ocular, skeletal, and cardiovascular systems. Fibrillin-1 is a major component of the 10-12 nm microfibrils, which are thought to play a role in tropoelastin deposition and elastic fibre formation in addition to possessing an anchoring function in some tissues. Fibrillin-1 mutations have also been found in patients who do not fulfil clinical criteria for the diagnosis of Marfan syndrome, but have related disorders of connective tissue, such as isolated ectopia lentis, familial aortic aneurysm, and Marfan-like skeletal abnormalities, so that Marfan syndrome may be regarded as one of a range of type 1 fibrillinopathies. There appear to be no particular hot spots since mutations are found throughout the entire fibrillin-1 gene. However, a clustering of mutations associated with the most severe form of Marfan syndrome, neonatal Marfan syndrome, has been noted in a region encompassing exons 24 to 32. The gene for fibrillin-2 ( FBN2 ) is highly homologous to FBN1 , and mutations in FBN2 have been shown to cause a phenotypically related disorder termed congenital contractural arachnodactyly. Since mutations in the fibrillin genes are likely to affect the global function of the microfibrils, the term microfibrillopathy may be the most appropriate to designate the spectrum of disease associated with dysfunction of these molecules. The understanding of the global and the molecular functions of the fibrillin containing microfibrils is still incomplete and, correspondingly, no comprehensive theory of the pathogenesis of Marfan syndrome has emerged to date. Many, but not all, fibrillin-1 gene mutations are expected to exert a dominant negative effect, whereby mutant fibrillin monomers impair the global function of the microfibrils. In this paper we review the molecular physiology and pathophysiology of Marfan syndrome and related microfibrillopathies.
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novel exon skipping mutation in the fibrillin 1 gene two hot spots for the neonatal marfan syndrome
Clinical Genetics, 1999Co-Authors: Patrick Booms, Maurice Godfrey, Jason Cisler, Kurt R Mathews, Frank Tiecke, Ursula C Kaufmann, Ulrich Vetter, Christian Hagemeier, Peter N RobinsonAbstract:: The Marfan syndrome is an autosomal dominant heritable disorder of connective tissue that involves principally the skeletal, ocular, and cardiovascular systems. The most severe end of the phenotypic spectrum, the neonatal Marfan syndrome (nMFS), is characterized by pronounced atrioventricular valve dysfunction, and death often occurs within the first year of life due to congestive heart failure. Mutations in the gene coding for fibrillin-1, FBN1, are known to cause Marfan syndrome, and have been identified in almost all exons of FBN1. Here, we describe a novel mutation affecting the invariant + 1 position of the splice donor site in intron 31, associated with skipping of exon 31, in a patient with nMFS. Published reports of nMFS are reviewed and a strict definition for nMFS is suggested. If this definition is used, all nMFS mutations reported to date lie in one of two hot spots, comprising mainly missense mutations in FBN1 exons 24-27 and mutations causing skipping of exon 31 or 32.
Rachel De Basso - One of the best experts on this subject based on the ideXlab platform.
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higher blood pressure in elderly hypertensive females with increased arterial stiffness and blood pressure in females with the fibrillin 1 2 3 genotype
BMC Cardiovascular Disorders, 2020Co-Authors: Ida Astrom Malm, Urban Alehagen, Peter Blomstrand, Ulf Dahlstrom, Rachel De BassoAbstract:BACKGROUND: Elderly patients have a relatively high cardiovascular risk due to increased arterial stiffness, elevated blood pressure and decreased amounts of elastin in the arteries. The composition of the media layer in the arterial wall, comprising elastin, collagen, smooth muscle cells, proteoglycans, fibronectin and fibrillin-1, influences its mechanical properties. Mutations in the fibrillin-1 gene leads to increased aortic stiffness, elevated pulse pressure and aortic root dilatation. This study investigates whether there is a sex difference among hypertensive elderly patients regarding blood pressure, arterial stiffness and fibrillin-1 genotypes. METHODS: A total of 315 hypertensive subjects (systolic blood pressure > 140 mmHg) were included in this study (155 men and 160 women aged 71-88 years). Aortic pulse wave velocity and augmentation index were determined using SphygmoCor, and brachial blood pressure was measured using an oscillometric technique. Fibrillin-1 was genotyped by polymerase chain reaction and with a capillary electrophoresis system. RESULTS: Females showed a significantly higher peripheral mean arterial pressure (females; 107.20 mmHg, males 101.6 mmHg, p = 0.008), central mean arterial pressure (females; 107.2 mmHg, males 101.6 mmHg p = 0.008), central systolic blood pressure (females; 148.1 mmHg, males 139.2 mmHg, p < 0.001) and central pulse pressure (females; 68.9 mmHg, males 61.6 mmHg, p = 0.035) than males. Females with the Fibrillin-1 2/3 genotype showed a significantly higher augmentation index (FBN1 2/3; 39.9%, FBN1 2/2 35.0%, FBN1 2/4 35.8, p = 0.029) and systolic blood pressure (FBN1 2/3; 174.6 mmHg, FBN1 2/2168.9 mmHg, FBN1 2/4169.9 mmHg, p = 0.025) than females with the 2/2 and 2/4 genotypes. CONCLUSION: The findings of this study may indicate that hypertensive elderly females, especially elderly females with Fibrillin-1 2/3, have increased systolic blood pressure and arterial stiffness.
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increased carotid plaque burden in men with the fibrillin 1 2 3 genotype
Clinical and Experimental Pharmacology and Physiology, 2014Co-Authors: Rachel De Basso, Bo Hedblad, Joyce Carlson, Margaretha Persson, Gerd Ostling, Toste LanneAbstract:Fibrillin-1 (FBN1) is an important constituent of the vascular wall and earlier studies have indicated an effect of the FBN1 2/3 genotype on blood pressure as well as aortic stiffness in men. The aim of the present study was to determine whether the FBN1 2/3 genotype was associated with the presence of carotid plaque and incident cardiovascular morbidity and mortality in middle-aged subjects. The FBN1 genotype was characterized in 5765 subjects (2424 men, 3341 women; age 45-69years) recruited from the Malmo Diet and Cancer Study Cardiovascular Cohort, Sweden. Plaque occurrence and intima-media thickness (IMT) of the carotid artery were assessed by ultrasound. The incidence of first cardiovascular events (myocardial infarction and stroke) and cause-specific mortality were monitored over a mean follow-up period of 13.2years. The most common FBN1 genotypes were 2/2, 2/3 and 2/4, which accounted for 92.2% (n=5317) of subjects. There were no differences between the three genotypes regarding age, blood pressure, glucose, lipids, smoking habits, common carotid artery diameter and intima-media thickness in men and women. The presence of plaque in the carotid artery was higher in men with the 2/3 genotype compared with the 2/2 and 2/4 genotypes (55% vs 46% and 50%, respectively; P=0.007). No similar differences were observed in women. No significant relationship was observed between FBN1 genotypes and the incidence of cardiovascular disease or all-cause mortality. The increased prevalence of plaque in the carotid artery of middle-aged men with the FBN1 2/3 genotype indicates pathological arterial wall remodelling with a more pronounced atherosclerotic burden.
