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International Journal of Molecular... Oct 2023Marfan syndrome (MFS) is a connective tissue disorder caused by gene mutations leading to TGF-β signaling hyperactivation, vascular wall weakness, and thoracic aortic...
Marfan syndrome (MFS) is a connective tissue disorder caused by gene mutations leading to TGF-β signaling hyperactivation, vascular wall weakness, and thoracic aortic aneurysms (TAAs). The pathogenetic mechanisms are not completely understood and patients undergo early vascular surgery to prevent TAA ruptures. We previously reported miR-632 upregulation in MFS TAA tissues compared with non-genetic TAA tissues. DNAJB6 is a gene target of miR-632 in cancer and plays a critical role in blocking epithelial-to-mesenchymal transition by inhibiting the Wnt/β catenin pathway. TGF-β signaling also activates Wnt/β catenin signaling and induces endothelial-to-mesenchymal transition (End-Mt) and fibrosis. We documented that miR-632 upregulation correlated with DNAJB6 expression in both the endothelium and the tunica media of MFS TAA ( < 0.01). Wnt/β catenin signaling, End-Mt, and fibrosis markers were also upregulated in MFS TAA tissues ( < 0.05, < 0.01 and < 0.001). Moreover, miR-632 overexpression inhibited , inducing Wnt/β catenin signaling, as well as End-Mt and fibrosis exacerbation ( < 0.05 and < 0.01). TGF-β1 treatment also determined miR-632 upregulation ( < 0.01 and < 0.001), with the consequent activation of the aforementioned processes. Our study provides new insights about the pathogenetic mechanisms in MFS aortopathy. Moreover, the high disease specificity of miR-632 and DNAJB6 suggests new potential prognostic factors and/or therapeutic targets in the progression of MFS aortopathy.
Topics: Humans; Marfan Syndrome; beta Catenin; Fibrosis; Transforming Growth Factor beta; MicroRNAs; Nerve Tissue Proteins; Molecular Chaperones; HSP40 Heat-Shock Proteins
PubMed: 37894814
DOI: 10.3390/ijms242015133 -
American Journal of Medical Genetics.... Feb 2023To optimize care for children with Marfan syndrome (MFS) in the Netherlands, Dutch MFS growth charts were constructed. Additionally, we aimed to investigate the effect...
To optimize care for children with Marfan syndrome (MFS) in the Netherlands, Dutch MFS growth charts were constructed. Additionally, we aimed to investigate the effect of FBN1 variant type (haploinsufficiency [HI]/dominant negative [DN]) on growth, and compare MFS-related height increase across populations. Height and weight data of individuals with MFS aged 0-21 years were retrospectively collected. Generalized Additive Models for Location, Scale and Shape (GAMLSS) was used for growth chart modeling. To investigate genotype-phenotype relationships, FBN1 variant type was included as an independent variable in height-for-age and BMI-for-age models. MFS-related height increase was compared with that of previous MFS growth studies from the United States, Korea, and France. Height and weight data of 389 individuals with MFS were included (210 males). Height-for-age, BMI-for-age, and weight-for-height charts reflected the tall and slender MFS habitus throughout childhood. Mean increase in height of individuals with MFS compared with the general Dutch population was significantly lower than in the other three MFS populations compared to their reference populations. FBN1-HI variants were associated with taller height in both sexes, and decreased BMI in females (p-values <0.05). This Dutch MFS growth study broadens the notion that genetic background and MFS variant type (HI/DN) influence tall and slender stature in MFS.
Topics: Male; Female; Humans; Marfan Syndrome; Growth Charts; Retrospective Studies; Netherlands; Mutation; Genotype; Phenotype; Fibrillin-1
PubMed: 36380655
DOI: 10.1002/ajmg.a.63047 -
International Journal of Molecular... Feb 2022Fibrillin-1 is the major structural component of the 10 nm-diameter microfibrils that confer key physical and mechanical properties to virtually every tissue, alone and... (Review)
Review
Fibrillin-1 is the major structural component of the 10 nm-diameter microfibrils that confer key physical and mechanical properties to virtually every tissue, alone and together with elastin in the elastic fibers. Mutations in fibrillin-1 cause pleiotropic manifestations in Marfan syndrome (MFS), including dissecting thoracic aortic aneurysms, myocardial dysfunction, progressive bone loss, disproportionate skeletal growth, and the dislocation of the crystalline lens. The characterization of these MFS manifestations in mice, that replicate the human phenotype, have revealed that the underlying mechanisms are distinct and organ-specific. This brief review summarizes relevant findings supporting this conclusion.
Topics: Animals; Disease Models, Animal; Fibrillin-1; Humans; Marfan Syndrome; Mice; Mutation; Organ Specificity
PubMed: 35163812
DOI: 10.3390/ijms23031892 -
American Journal of Medical Genetics.... Jan 2021Marfan syndrome (MFS) is a multisystemic, autosomal dominant connective tissue disorder that occurs de novo in 25%. In many families, parent and child(ren) are affected,...
Marfan syndrome (MFS) is a multisystemic, autosomal dominant connective tissue disorder that occurs de novo in 25%. In many families, parent and child(ren) are affected, which may increase distress in parents. To assess distress, 42 mothers (29% MFS) and 25 fathers (60% MFS) of 43 affected children, completed the validated screening-questionnaire Distress thermometer for parents of a chronically ill child, including questions on overall distress (score 0-10; ≥4 denoting "clinical distress") and everyday problems (score 0-36). Data were compared to 1,134 control-group-parents of healthy children. Mothers reported significantly less overall distress (2, 1-4 vs. 3, 1-6; p = .049; r = -.07) and total everyday problems (3, 0-6 vs. 4, 1-8; p = .03; r = -.08) compared to control-group-mothers. Mothers without MFS reported significantly less overall distress compared to mothers with MFS, both of a child with MFS (1, 0-4 vs. 3.5, 2-5; p = .039; r = -.17). No significant differences were found between the father-groups, nor between the group of healthy parents of an affected child living together with an affected partner compared to control-group-parents. No differences in percentages of clinical distress were reported between mothers and control-group-mothers (33 vs. 42%); fathers and control-group-fathers (28 vs. 32%); nor between the other groups. Distress was not associated with the children's MFS characteristics. Concluding, parents of a child with MFS did not show more clinical distress compared to parents of healthy children. However, clinical distress was reported in approximately one-third and may increase in case of acute medical complications. We advise monitoring distress in parents of a child with MFS to provide targeted support.
Topics: Adult; Anxiety; Child; Child, Preschool; Chronic Disease; Depression; Fathers; Female; Humans; Male; Marfan Syndrome; Mothers; Parenting; Parents; Quality of Life; Stress, Psychological; Surveys and Questionnaires
PubMed: 33034422
DOI: 10.1002/ajmg.a.61906 -
The Journal of Thoracic and... Jan 2018
Topics: Aorta; Humans; Marfan Syndrome; Replantation
PubMed: 28969850
DOI: 10.1016/j.jtcvs.2017.08.085 -
Acta Ophthalmologica May 2022The aim of the present study was to investigate photophobia and disability glare in adult patients with Marfan syndrome (MFS).
PURPOSE
The aim of the present study was to investigate photophobia and disability glare in adult patients with Marfan syndrome (MFS).
METHODS
In this case-control study, 44 patients with MFS (87 eyes) were compared to 44 controls (88 eyes), who were matched for age and sex. The subjects were asked to grade their photophobia and glare using 10-cm visual analogue scales (VAS), which were marked with 'never' at zero and 'always' at 10 -cm. In addition, disability glare was measured with C-Quant straylight meter.
RESULTS
The patients with MFS had significantly higher VAS scores than the controls in four out of seven statements related to photophobia and glare. When including cataract, spherical equivalent, iris colour, axial length and corneal curvature, three of the seven statements were still significantly different between the two groups. The mean straylight values were 1.29 ± 0.03 log(s) in the MFS group and 1.01 ± 0.03 log(s) in the control group (p < 0.001, mixed model). These differences remained significant after adjusting for cataract, spherical equivalent, iris colour, axial length and corneal curvature.
CONCLUSION
Patients with MFS reported more photophobia and had a higher straylight value than the control group. Awareness of these findings of more photophobia and glare in the MFS patients is important when counselling and treating these patients.
Topics: Adult; Case-Control Studies; Cataract; Glare; Humans; Light; Marfan Syndrome; Photophobia; Scattering, Radiation; Visual Acuity
PubMed: 34173343
DOI: 10.1111/aos.14935 -
Acta Ophthalmologica Sep 2022The main objective of this study was to examine the pupillary response in patients with Marfan syndrome (MFS) and secondarily to determine whether changes in the...
PURPOSE
The main objective of this study was to examine the pupillary response in patients with Marfan syndrome (MFS) and secondarily to determine whether changes in the pupillary response are associated with the increased disability glare previously shown in the same patient population.
METHODS
This study included 60 eyes of 34 patients with MFS diagnosed in accordance with the Ghent-2 criteria and 81 eyes of 44 controls. Pupillary response was measured with a pupillograph and disability glare with a straylight meter.
RESULTS
The patients with MFS had a significantly smaller maximum pupil size than the control group, 4.87 (4.50-5.23) mm versus 5.58 (5.25-5.90) mm (p = 0.01). In addition, they exhibited slower contraction velocities (p = 0.03) and longer re-dilation times (p = 0.01) compared with the control group. The mean straylight value was higher in patients with MFS than controls, even when including pupillary parameters together with lens surgery, cataract, iris colour, axial length and corneal curvature as possible explanatory variables in the analysis. However, when including data from both groups, a significant negative correlation was seen between maximum pupillary diameter and straylight value (p = 0.01). The other pupillary parameters did not correlate with straylight.
CONCLUSION
Patients with MFS had a smaller maximum pupil diameter, slower pupillary contraction and longer re-dilation time than the controls. Despite the correlation between pupil size and straylight value, the pupillary response demonstrated in MFS eyes could not explain the increased straylight in these patients.
Topics: Adult; Glare; Humans; Light; Marfan Syndrome; Pupil; Scattering, Radiation
PubMed: 34890490
DOI: 10.1111/aos.15079 -
Matrix Biology : Journal of the... Oct 2018Mutations in fibrillin-1 cause Marfan syndrome (MFS), the most common heritable disorder of connective tissue. Fibrillin-1 assemblies (microfibrils and elastic fibers)... (Review)
Review
Mutations in fibrillin-1 cause Marfan syndrome (MFS), the most common heritable disorder of connective tissue. Fibrillin-1 assemblies (microfibrils and elastic fibers) represent a unique dual-function component of the architectural matrix. The first role is structural for they endow tissues with tensile strength and elasticity, transmit forces across them and demarcate functionally discrete areas within them. The second role is instructive in that these macroaggregates modulate a large variety of sub-cellular processes by interacting with mechanosensors, and integrin and syndecan receptors, and by modulating the bioavailability of local TGFβ signals. The multifunctional, tissue-specific nature of fibrillin-1 assemblies is reflected in the variety of clinical manifestations and disease mechanisms associated with the MFS phenotype. Characterization of mice with ubiquitous or cell type-restricted fibrillin-1 deficiency has unraveled some pathophysiological mechanisms associated with the MFS phenotype, such as altered mechanotransduction in the heart, dysregulated TGFβ signaling in the ascending aorta and perturbed stem cell fate in the bone marrow. In each case, potential druggable targets have also been identified. However, the finding that distinct disease mechanisms underlie different organ abnormalities strongly argues for developing multi-drug strategies to mitigate or even prevent both life-threatening and morbid manifestations in pediatric and adult MFS patients.
Topics: Animals; Disease Models, Animal; Fibrillin-1; Humans; Marfan Syndrome; Mechanotransduction, Cellular; Mutation; Myocardium; Signal Transduction; Stem Cells; Transforming Growth Factor beta
PubMed: 28782645
DOI: 10.1016/j.matbio.2017.07.004 -
JCI Insight May 2023To improve our limited understanding of the pathogenesis of thoracic aortic aneurysm (TAA) that leads to acute aortic dissection, single-cell RNA sequencing (scRNA-seq)...
To improve our limited understanding of the pathogenesis of thoracic aortic aneurysm (TAA) that leads to acute aortic dissection, single-cell RNA sequencing (scRNA-seq) was employed to profile disease-relevant transcriptomic changes of aortic cell populations in a well-characterized mouse model of the most commonly diagnosed form of Marfan syndrome (MFS). As result, 2 discrete subpopulations of aortic cells (SMC3 and EC4) were identified only in the aorta of Fbn1mgR/mgR mice. SMC3 cells highly express genes related to extracellular matrix formation and nitric oxide signaling, whereas the EC4 transcriptional profile is enriched in smooth muscle cell (SMC), fibroblast, and immune cell-related genes. Trajectory analysis predicted close phenotypic modulation between SMC3 and EC4, which were therefore analyzed together as a discrete MFS-modulated (MFSmod) subpopulation. In situ hybridization of diagnostic transcripts located MFSmod cells at the intima of Fbn1mgR/mgR aortas. Reference-based data set integration revealed transcriptomic similarity between MFSmod- and SMC-derived cell clusters modulated in human TAA. Consistent with the angiotensin II type I receptor (At1r) contribution to TAA development, MFSmod cells were absent in the aorta of Fbn1mgR/mgR mice treated with the At1r antagonist losartan. Altogether, our findings indicate that a discrete dynamic alteration of aortic cell identity is associated with dissecting TAA in MFS mice and increased risk of aortic dissection in MFS patients.
Topics: Humans; Mice; Animals; Transcriptome; Losartan; Marfan Syndrome; Aortic Aneurysm; Aortic Aneurysm, Thoracic; Aorta; Aortic Dissection
PubMed: 37022786
DOI: 10.1172/jci.insight.168793 -
Genes Sep 2021Marfan syndrome (MFS) and Loeys-Dietz syndrome type 4 (LDS4) are two hereditary connective tissue disorders. MFS displays ectopia lentis as a distinguishing,...
Marfan syndrome (MFS) and Loeys-Dietz syndrome type 4 (LDS4) are two hereditary connective tissue disorders. MFS displays ectopia lentis as a distinguishing, characterising feature, and thoracic aortic ectasia, aneurysm, dissection, and systemic features as manifestations overlapping with LDS4. LDS4 is characterised by the presence of hypertelorism, cleft palate and/or bifid uvula, with possible ectasia or aneurysms in other arteries. The variable age of onset of clinical manifestations makes clinical diagnosis more difficult. In this study, we report the case of a patient with Marfan syndrome diagnosed at our centre at the age of 33 on the basis of typical clinical manifestations of this syndrome. At the age of 38, the appearance of ectasia of the left common iliac artery and tortuosity of the iliac arteries suggested the presence of LDS4. Next Generation Sequencing (NGS) analysis, followed by Array-CGH, allowed the detection of a novel chromosomal deletion including the entire TGFB2 gene, confirming not only the clinical suspicion of LDS4, but also the clinical phenotype associated with the haploinsufficiency mechanism, which is, in turn, associated with the deletion of the entire gene. The same mutation was detected in the two young sons. This emblematic case confirms that we must be very careful in the differential diagnosis of these two pathologies, especially before the age of 40, and that, in young subjects suspected to be affected by MFS in particular, we must verify the diagnosis, extending genetic analysis, when necessary, to the search for chromosomal alterations. Recently, ectopia lentis has been reported in a patient with LDS4, confirming the tight overlap between the two syndromes. An accurate revision of the clinical parameters both characterising and overlapping the two pathologies is highly desirable.
Topics: Chromosome Deletion; Diagnosis, Differential; Female; Humans; Loeys-Dietz Syndrome; Male; Marfan Syndrome; Pedigree; Transforming Growth Factor beta2
PubMed: 34680857
DOI: 10.3390/genes12101462