Identification of FBN1 gene mutations in Ukrainian Marfan syndrome patients

SummaryMarfan syndrome is an autosomal dominant connective tissue disorder, predominantly affecting the ocular, skeletal and cardiovascular systems. Here, we present the results of the first genetic testing in 40 Ukrainian Marfan (-like) patients and 10 relatives. We applied a targeted next generation sequencing panel comprising FBN1 and 13 thoracic aortic aneurysm genes. We identified 27 causal mutations in FBN1, obtaining a mutation yield of 67·5%. A significant difference in age at aortic surgery between mutation positive and negative patients was observed. Thus, we conclude that genetic testing is important to identify patients at higher risk for developing life-threatening cardiovascular complications.

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A bioinformatics framework for genotype–phenotype correlation in humans with Marfan syndrome caused by FBN1 gene mutations

Journal of Biomedical Informatics ◽

10.1016/j.jbi.2005.06.001 ◽

2006 ◽

Vol 39 (2) ◽

pp. 171-183 ◽

Cited By ~ 8

Author(s):

Christian Baumgartner ◽

Gábor Mátyás ◽

Beat Steinmann ◽

Martin Eberle ◽

Jörg I. Stein ◽

...

Keyword(s):

Marfan Syndrome ◽

Gene Mutations ◽

Phenotype Correlation ◽

Fbn1 Gene ◽

Genotype Phenotype Correlation

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Marfan Syndrome Variability: Investigation of the Roles of Sarcolipin and Calcium as Potential Transregulator of FBN1 Expression

Genes ◽

10.3390/genes9090421 ◽

2018 ◽

Vol 9 (9) ◽

pp. 421 ◽

Cited By ~ 2

Author(s):

Louise Benarroch ◽

Mélodie Aubart ◽

Marie-Sylvie Gross ◽

Marie-Paule Jacob ◽

Pauline Arnaud ◽

...

Keyword(s):

Gene Expression ◽

Marfan Syndrome ◽

Messenger Rna ◽

Calcium Influx ◽

Surrogate Endpoint ◽

Connective Tissue Disorder ◽

Eqtl Analysis ◽

Chromosome 11 ◽

Fbn1 Gene ◽

The Impact

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder that displays a great clinical variability. Previous work in our laboratory showed that fibrillin-1 (FBN1) messenger RNA (mRNA) expression is a surrogate endpoint for MFS severity. Therefore, an expression quantitative trait loci (eQTL) analysis was performed to identify trans-acting regulators of FBN1 expression, and a significant signal reached genome-wide significant threshold on chromosome 11. This signal delineated a region comprising one expressed gene, SLN (encoding sarcolipin), and a single pseudogene, SNX7-ps1 (CTD-2651C21.3). We first investigated the region and then looked for association between the genes in the region and FBN1 expression. For the first time, we showed that the SLN gene is weakly expressed in skin fibroblasts. There is no direct correlation between SLN and FBN1 gene expression. We showed that calcium influx modulates FBN1 gene expression. Finally, SLN gene expression is highly correlated to that of the neighboring SNX7-ps1. We were able to confirm the impact of calcium influx on FBN1 gene expression but we could not conclude regarding the role of sarcolipin and/or the eQTL locus in this regulation.

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Endovascular Thoracoabdominal Replacement after Total Abdominal Aortic Debranching

Aorta ◽

10.1055/s-0038-1641607 ◽

2018 ◽

Vol 06 (01) ◽

pp. 043-045 ◽

Cited By ~ 1

Author(s):

Murat Ugurlucan ◽

Yilmaz Onal ◽

Omer Sayin ◽

Feza Ekiz ◽

Didem Oztas ◽

...

Keyword(s):

Marfan Syndrome ◽

Open Repair ◽

Connective Tissue Disorder ◽

Thoracoabdominal Aneurysm ◽

Stent Grafting ◽

Abdominal Aortic ◽

Cardiovascular Involvement ◽

Life Threatening ◽

History Of ◽

Aortic Pathologies

AbstractMarfan syndrome is an inherited connective tissue disorder affecting mainly eyes and skeletal and cardiovascular systems. Cardiovascular involvement may lead to life-threatening aortic pathologies including aneurysms and/or dissections. In this report, the authors present images of a patient with Marfan syndrome with a history of Bentall-De Bono procedure followed by aortic arch and infrarenal aortoiliac replacements who strongly refused conventional open repair and underwent abdominal debranching followed by thoracoabdominal endovascular stent grafting for the treatment of thoracoabdominal aneurysm.

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Abstract 11621: Fibrillin-1 Gene Mutations in Left Ventricular Non-Compaction Cardiomyopathy

Circulation ◽

10.1161/circ.130.suppl_2.11621 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

John J Parent ◽

Jeffrey A Towbin ◽

John L Jefferies

Keyword(s):

Extracellular Matrix ◽

Gene Mutation ◽

Marfan Syndrome ◽

Gene Mutations ◽

Left Ventricular ◽

Current Evidence ◽

Causative Gene ◽

Fbn1 Gene ◽

Gene Testing ◽

Fibrillin 1

Introduction: Left ventricular non-compaction cardiomyopathy (LVNC) is a rare and unique cardiomyopathy. Its presentation can range from a benign phenotype to overt heart failure and sudden cardiac death. The genetics of LVNC are not completely understood and current genetic testing has a yield of about 30% in identifying a causative gene mutation. We present a series of patients with LVNC and fibrillin-1 (FBN1) gene mutations. Hypothesis: We hypothesize that FBN1 gene mutations can lead to LVNC by way of its role in the myocardial extracellular matrix during cardiac development. Methods: A retrospective review of all patients with LVNC at our institution was performed for purposes of another investigation. The process unexpectedly identified patients with LVNC and FBN1 gene mutations, as well as LVNC and Marfan syndrome. Results: Approximately 150 patients are followed in our clinic with LVNC. We screened this population and found 51 patients on medical therapy for reduced function. We retrospectively reviewed gene testing in these 51 patients, when available, and identified 5 patients (10%) with an FBN1 gene mutation. All 5 patients had a dilated LVNC phenotype and previous or current evidence of left ventricular dysfunction. Syndrome breakdown as follows: 3 with Marfan, 1 with Shprintzen-Goldberg, and 1 with no identifiable syndrome. Dilated cardiomyopathy/LVNC gene testing was performed in 3 patients; 2 had disease causing myosin heavy chain 7 gene defects and 1 had no defects. Conclusions: The role of FBN1 in the human myocardium is not completely understood but it is expressed in the developing fetal heart and is a component of the myocardial extracellular matrix. Although causation has not been proven by our report, it certainly raises interest in a mechanistic relationship between LVNC and FBN1 given the increased prevalence of Marfan syndrome and probable increased prevalence of FBN1 gene mutations in this cohort of LVNC patients in light of FBN1.

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Rationale and design of a trial evaluating the effects of losartan vs. nebivolol vs. the association of both on the progression of aortic root dilation in Marfan syndrome with FBN1 gene mutations

Journal of Cardiovascular Medicine ◽

10.2459/jcm.0b013e3283232a45 ◽

2009 ◽

Vol 10 (4) ◽

pp. 354-362 ◽

Cited By ~ 48

Author(s):

Fabiana I Gambarin ◽

Valentina Favalli ◽

Alessandra Serio ◽

Mario Regazzi ◽

Michele Pasotti ◽

...

Keyword(s):

Marfan Syndrome ◽

Aortic Root ◽

Gene Mutations ◽

Fbn1 Gene

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A Novel Heterozygous Intronic Mutation in the FBN1 Gene Contributes to FBN1 RNA Missplicing Events in the Marfan Syndrome

BioMed Research International ◽

10.1155/2018/3536495 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 6

Author(s):

Mario Torrado ◽

Emilia Maneiro ◽

Juan Pablo Trujillo-Quintero ◽

Arturo Evangelista ◽

Alexander T. Mikhailov ◽

...

Keyword(s):

Connective Tissue ◽

Marfan Syndrome ◽

Premature Termination Codon ◽

Connective Tissue Disorder ◽

Aortic Dilatation ◽

Functional Protein ◽

Fbn1 Gene ◽

Intronic Mutation ◽

Aortic Pathology ◽

Fibrillin 1

Marfan syndrome (MFS) is an autosomal dominantly inherited connective tissue disorder, mostly caused by mutations in the fibrillin-1 (FBN1) gene. We, by using targeted next-generation sequence analysis, identified a novel intronic FBN1 mutation (the c.2678-15C>A variant) in a MFS patient with aortic dilatation. The computational predictions showed that the heterozygous c.2678-15C>A intronic variant might influence the splicing process by differentially affecting canonical versus cryptic splice site utilization within intron 22 of the FBN1 gene. RT-PCR and Western blot analyses, using FBN1 minigenes transfected into HeLa and COS-7 cells, revealed that the c.2678-15C>A variant disrupts normal splicing of intron 22 leading to aberrant 13-nt intron 22 inclusion, frameshift, and premature termination codon. Collectively, the results strongly suggest that the c.2678-15C>A variant could lead to haploinsufficiency of the FBN1 functional protein and structural connective tissue fragility in MFS complicated by aorta dilation, a finding that further expands on the genetic basis of aortic pathology.

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Reference Expression Profile of Three FBN1 Transcript Isoforms and Their Association with Clinical Variability in Marfan Syndrome

Genes ◽

10.3390/genes10020128 ◽

2019 ◽

Vol 10 (2) ◽

pp. 128

Author(s):

Louise Benarroch ◽

Mélodie Aubart ◽

Marie-Sylvie Gross ◽

Pauline Arnaud ◽

Nadine Hanna ◽

...

Keyword(s):

Marfan Syndrome ◽

Age Of Onset ◽

Expression Profiles ◽

Phenotypic Variability ◽

Surrogate Endpoint ◽

Connective Tissue Disorder ◽

Clinical Variability ◽

Fbn1 Gene ◽

Adventitial Fibroblasts ◽

Alternatively Spliced

Marfan syndrome (MFS) is a rare connective tissue disorder mainly due to mutations in the FBN1 gene. Great phenotypic variability is notable for age of onset, the presence and absence, and the number and the severity of the symptoms. Our team showed that FBN1 gene expression level was a good surrogate endpoint for severity of some MFS clinical features. Eight alternative transcripts are referenced for the FBN1 gene. We hypothesized that MFS clinical variability could be related to specific FBN1 isoforms. Isoform expression profiles were investigated in skin and adventitial fibroblasts from controls and MFS patients. The results of the study showed that, in skin and adventitial fibroblasts, only three isoforms were found: FBN1_001, FBN1_004, and FBN1_009. The main isoform was FBN1_001 and it was significantly reduced in skin and adventitial fibroblasts of MFS patients. The expressions of FBN1_004 and FBN1_009 isoforms were similar between controls and MFS patients. However, the expression of the three isoforms was correlated only in patients. Furthermore, their expression levels were associated with the presence of ectopia lentis in MFS patients. Therefore, our results highlight that the two minor alternatively spliced FBN1 isoforms play a possible role in the pathogenesis of the disease.

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Pathophysiology and Therapeutics of Thoracic Aortic Aneurysm in Marfan Syndrome

Biomolecules ◽

10.3390/biom12010128 ◽

2022 ◽

Vol 12 (1) ◽

pp. 128

Author(s):

Keiichi Asano ◽

Anna Cantalupo ◽

Lauriane Sedes ◽

Francesco Ramirez

Keyword(s):

Marfan Syndrome ◽

Single Gene ◽

Gene Mutations ◽

Aortic Disease ◽

Connective Tissue Disorder ◽

Tgfβ Signaling ◽

Thoracic Aortic Disease ◽

Molecular Determinants ◽

Fibrillin 1 ◽

Experimental Findings

About 20% of individuals afflicted with thoracic aortic disease have single-gene mutations that predispose the vessel to aneurysm formation and/or acute aortic dissection often without associated syndromic features. One widely studied exception is Marfan syndrome (MFS) in which mutations in the extracellular protein fibrillin-1 cause additional abnormalities in the heart, eyes, and skeleton. Mouse models of MFS have been instrumental in delineating major cellular and molecular determinants of thoracic aortic disease. In spite of research efforts, translating experimental findings from MFS mice into effective drug therapies for MFS patients remains an unfulfilled promise. Here, we describe a series of studies that have implicated endothelial dysfunction and improper angiotensin II and TGFβ signaling in driving thoracic aortic disease in MFS mice. We also discuss how these investigations have influenced the way we conceptualized possible new therapies to slow down or even halt aneurysm progression in this relatively common connective tissue disorder.

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Overview of Marfan Syndrome: knowns and unknowns

Journal of Controversies in Biomedical Research ◽

10.15586/jcbmr.2015.10 ◽

2015 ◽

Vol 1 (1) ◽

pp. 51-66

Author(s):

Pratiek N Matkar ◽

Hao H Chen ◽

Howard Leong-Poi ◽

Krishna Kumar Singh

Keyword(s):

Marfan Syndrome ◽

Drug Targets ◽

Transforming Growth Factor ◽

Surgical Techniques ◽

Clinical Manifestations ◽

Gene Mutations ◽

Transforming Growth Factor Β ◽

The Body ◽

Fbn1 Gene ◽

Fibrillin 1

Marfan syndrome (MFS) is a relatively rare disease of the connective tissue that affects several organs of the body. Cardiovascular abnormalities such as aortic root dilatation and mitral valve prolapse are the two main life-threatening complications associated with MFS. The complete pathogenesis of MFS is yet unclear. However, fibrillin-1 (FBN1) gene mutations and mutations in the transforming growth factor-β (TGFβ) signaling pathway are the leading causes of this lethal disease. Detailed assessment based on several major and minor clinical manifestations has led to the evolution of different nosologies for MFS diagnoses with reliable accuracies. Nevertheless, heterogeneous disease advancement and overlapping clinical outcomes make MFS diagnosis challenging. Rapid strides in research and surgical avenues over the last two decades have improved the life expectancy and the quality of life of MFS patients remarkably. More specific diagnostic criteria have been established, novel therapeutic targets for pharmacotherapy have been identified and validated, and newer surgical techniques have been tested. Current research efforts are focusing on the identification of prognostic biomarkers, gene modifiers, drug targets, and surgical procedures. This review aims to provide a brief overview of these aspects associated with MFS.

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