Fibrillin-1 Research Articles

Zonule-Associated Gene Variants in Isolated Ectopia Lentis and Glaucoma.

We report 3 novel variants in fibrillin-1 (FBN1) and latent transforming growth factor-β-binding protein 2 (LTBP2) in 3 families with isolated ectopia lentis (EL), which shed new light on the diagnosis and genetic counseling of EL and secondary glaucoma in clinical settings. To explore the genetic mechanism in 3 families with isolated EL and secondary angle closure glaucoma. Three Han Chinese families with EL and glaucoma were recruited. All of the participants underwent complete ocular and general physical examinations and DNA samples were extracted from peripheral venous blood and screened for disease-causing variants using whole exome and Sanger sequencing. In silico analyses were performed to predict the structural and functional changes in gene variants and abnormal proteins. All 3 probands presented with EL and pupillary-blocking glaucoma. Genetic testing showed that all the patients have zonule-related gene mutations, with the proband (II:1), as well as his mother (I:2) and daughters (III:1 and III:2) from family 1 carrying a heterozygous mutation in FBN1 gene (c.6493G>T:p.(V2165L)); the proband (II:1) from family 2 carrying a heterozygous mutation in FBN1 gene (c.2543C>A:p.(T848N)), and the proband (II:1) from family 3 carrying a pair of compound heterozygous mutations in LTBP2 gene (c.4825T>A:p.(C1609S) / c.529T>C:p.(W177R)). No other genetic variants were found to be associated with the phenotypes of patients and other family members in this study. All variants are predicted to affect the structure and function of proteins as risk factors for EL based on bioinformatics analysis. Four novel mutations were identified in 3 families with EL, suggesting an intimate link between specific mutations in FBN1 and LTBP2 and isolated EL and angle closure glaucoma. Our results expanded the variant spectrum of zonule-related genes and helped explore the underlying molecular pathology of these disorders.

Molecular cloning, characterization and 3D modelling of spotted snakehead fbn1 C-terminal region encoding asprosin and expression analysis of fbn1

The FBN1 gene encodes profibrillin protein that is cleaved by the enzyme furin to release fibrillin-1 and a glucogenic hormone, asprosin. Asprosin is implicated in diverse metabolic functions as well as pathological conditions in mammals. However, till date, there are no studies on asprosin in any non-mammalian vertebrate. In this study, we have retrieved the spotted snakehead Channa punctata fbn1 gene (ss fbn1) from the testicular transcriptome data and validated it. The transcript is predicted to encode 2817 amino acid long putative profibrillin protein. Amino acid sequence alignment of deduced ss profibrillin with human profibrillin revealed that the furin cleavage site in profibrillin is well conserved in C. punctata. Further, differential expression of ss fbn1 was observed in various tissues with the highest expression in gonads. Prominent expression of furin was also observed in the gonads suggesting the possibility of proteolytic cleavage of profibrillin protein and secretion of asprosin in C. punctata. In addition, the C-terminal of the fbn1 gene of C. punctata that codes for asprosin protein has been cloned. Using in silico approach, physicochemical properties of the putative ss asprosin were characterized and post-translational changes were predicted. The putative ss asprosin protein sequence is predicted to consist of 142 amino acid residues, with conserved glycosylation sites. Further, the 3D model of ss asprosin was predicted followed by MD (molecular dynamics) simulation for energy minimization. Thus, the current study, for the first time in non-mammalian vertebrates, predicts and characterizes the novel protein asprosin using in silico approach.

Marfan syndrome in a paediatric cohort: the importance of family history.

Abstract Marfan syndrome is a rare connective tissue disorder secondary to mutations in the FBN1 gene, characterised by skeletal, ocular, and cardiovascular manifestations. We present an extensive cohort of paediatric patients with Marfan syndrome highlighting the vital importance of promptly referring paediatric first-degree relatives of Marfan syndrome paediatric patients to a tertiary hospital as our results confirm that they are at higher risk of aortic dilatation.

IL11 (Interleukin-11) Causes Emphysematous Lung Disease in a Mouse Model of Marfan Syndrome.

Marfan Syndrome (MFS) is an inherited connective tissue disorder caused by mutations in the FBN1 (fibrillin-1) gene. Lung abnormalities are common in MFS, but their pathogenesis is poorly understood. IL11 (interleukin-11) causes aortic disease in a mouse model of MFS and was studied here in the lung. We examined histological and molecular phenotypes in the lungs of Fbn1C1041G/+ mice (mouse model of Marfan Syndrome [mMFS]), an established mouse model of MFS. To identify IL11-expressing cells, we used immunohistochemistry on lungs of 4- and 16-week-old Fbn1C1041G/+:Il11EGFP/+ reporter mice. We studied the effects of IL11 inhibition by RT-qPCR, immunoblots and histopathology in lungs from genetic or pharmacologic models: (1) 16-week-old IL11 receptor (IL11RA) knockout mMFS mice (Fbn1C1041G/+:Il11ra1-/- mice) and (2) in mMFS mice administered IgG control or interleukin-11 receptor antibodies twice weekly from 4 to 24 weeks of age. mMFS lungs showed progressive loss and enlargement of distal airspaces associated with increased proinflammatory and profibrotic gene expression as well as matrix metalloproteinases 2, 9, and 12. IL11 was increased in mMFS lungs and localized to smooth muscle and endothelial cells in young mMFS mice in the Fbn1C1041G/+:Il11EGFP/+ reporter strain and in fibroblasts, in older mice. In mMFS mice, genetic (Fbn1C1041G/+:Il11ra1-/-) or pharmacologic (anti-interleukin-11 receptor) inhibition of IL11 signaling reduced lung emphysema, fibrosis, and inflammation. This protective effect was associated with reduced pathogenic ERK1/2 signaling and lower metalloproteinase 2, 9, and 12 expression. IL11 causes lung disease in mMFS. This reveals a shared IL11-driven disease mechanism in lung and aorta in MFS and suggests inhibition of IL11 signaling as a holistic approach for treating multiorgan morbidity in MFS.

Deneysel Hipertansiyon Oluşturulan Sıçanlarda Rosuvastatinin Böbrek Üzerine Koruyucu Etkileri

Hypertension is responsible for approximately 30% of patients who reach end-stage renal disease. Caspase-3 is an important protein in the apoptosis of renal tubular epithelial cells. The presence of fibrillin-1(FBN1) microfibrils in the structure of the kidney glomerulus causes changes in FBN1 levels in the hypertensive kidney. Statin therapy is known to reduce the risk of developing kidney disease. In this study, the changes in caspase-3 and FBN1 in the kidney tissue of rats with hypertension using N-Nitro-L-Arginine Methyl Ester (L-NAME) were investigated along with how rosuvastatin affected the changes caused by hypertension on these proteins.
 To induce hypertension, rats were given L-NAME for 7 weeks. After the second week, rosuvastatin was given by oral gavage for 5 weeks. Blood pressure values were evaluated on days 0, 14, 28, 42. At the end of the experiment, all rats were sacrificed and caspase-3 and FBN1 levels were evaluated.
 Blood pressures were found to be higher in the hypertension group on the 14th, 28th, and 42nd days (p

Long non-coding RNA H19 regulates matrisome signature and impacts cell behavior on MSC-engineered extracellular matrices

BackgroundThe vast and promising class of long non-coding RNAs (lncRNAs) has been under investigation for distinct therapeutic applications. Nevertheless, their role as molecular drivers of bone regeneration remains poorly studied. The lncRNA H19 mediates osteogenic differentiation of Mesenchymal Stem/Stromal Cells (MSCs) through the control of intracellular pathways. However, the effect of H19 on the extracellular matrix (ECM) components is still largely unknown. This research study was designed to decode the H19-mediated ECM regulatory network, and to reveal how the decellularized siH19-engineered matrices influence MSC proliferation and fate. This is particularly relevant for diseases in which the ECM regulation and remodeling processes are disrupted, such as osteoporosis.MethodsMass spectrometry-based quantitative proteomics analysis was used to identify ECM components, after oligonucleotides delivery to osteoporosis-derived hMSCs. Moreover, qRT-PCR, immunofluorescence and proliferation, differentiation and apoptosis assays were performed. Engineered matrices were decellularized, characterized by atomic force microscopy and repopulated with hMSC and pre-adipocytes. Clinical bone samples were characterized by histomorphometry analysis.ResultsOur study provides an in-depth proteome-wide and matrisome-specific analysis of the ECM proteins controlled by the lncRNA H19. Using bone marrow-isolated MSC from patients with osteoporosis, we identified fibrillin-1 (FBN1), vitronectin (VTN) and collagen triple helix repeat containing 1 (CTHRC1), among others, as having different pattern levels following H19 silencing. Decellularized siH19-engineered matrices are less dense and have a decreased collagen content compared with control matrices. Repopulation with naïve MSCs promotes a shift towards the adipogenic lineage in detriment of the osteogenic lineage and inhibits proliferation. In pre-adipocytes, these siH19-matrices enhance lipid droplets formation. Mechanistically, H19 is targeted by miR-29c, whose expression is decreased in osteoporotic bone clinical samples. Accordingly, miR-29c impacts MSC proliferation and collagen production, but does not influence ALP staining or mineralization, revealing that H19 silencing and miR-29c mimics have complementary but not overlapping functions.ConclusionOur data suggest H19 as a therapeutic target to engineer the bone ECM and to control cell behavior.

Lack of evidence that fibrillin1 regulates bone morphogenetic protein 4 activity in kidney or lung.

The Bone morphogenetic protein 4 (BMP4) precursor protein is cleaved at two sites to generate an active ligand and inactive prodomain. The ligand and prodomain form a noncovalent complex following the first cleavage, but dissociate after the second cleavage. Transient formation of this complex is essential to generate a stable ligand. Fibrillins (FBNs) bind to the prodomains of BMPs, and can regulate the activity of some ligands. Whether FBNs regulate BMP4 activity is unknown. Mice heterozygous for a null allele of Bmp4 showed incompletely penetrant kidney defects and females showed increased mortality between postnatal day 6 and 8. Removal of one copy of Fbn1 did not rescue or enhance kidney defects or lethality. The lungs of Fbn1+/- females had enlarged airspaces that were unchanged in Bmp4+/- ;Fbn1+/- mice. Additionally, removal of one or both alleles of Fbn1 had no effect on steady state levels of BMP4 ligand or on BMP activity in postnatal lungs. These findings do not support the hypothesis that FBN1 plays a role in promoting BMP4 ligand stability or signaling, nor do they support the alternative hypothesis that FBN1 sequesters BMP4 in a latent form, as is the case for other BMP family members.

Generation of an induced pluripotent stem cell (iPSC) line of a Marfan syndrome patient with a pathogenic FBN1 c.5372G > A (p.Cys1791Tyr) variant

Marfan syndrome (MFS) is a connective tissue disorder with pleiotropic manifestations in the ocular, skeletal and cardiovascular system. Ruptured aortic aneurysms in MFS patients are associated with high mortality rates. MFS is typically caused by pathogenic variants in the fibrillin-1 (FBN1) gene. Here, we report a generated induced pluripotent cell (iPSC) line of a MFS patient with a FBN1 c.5372G > A (p.Cys1791Tyr) variant. For that, skin fibroblasts of a MFS patient carrying a FBN1 c.5372G > A (p.Cys1791Tyr) variant were successfully reprogrammed into iPSCs using the CytoTune™-iPS 2.0 Sendai Kit (Invitrogen). The iPSCs showed a normal karyotype, expressed pluripotency markers, were able to differentiate into three germ layers and carried the original genotype.

Differentially expressed glycoproteins in pre- and post-digital rectal examination urine samples for detecting aggressive prostate cancer.

Urinary glycoproteins associated with aggressive prostate cancer (AG-PCa) were previously reported using post-digital rectal examination (DRE) urine specimens. To explore the potential of using pre-DRE urine specimens for detecting AG-PCa, we compared glycoproteins between pre- and post-DRE urine specimens, verified the previously identified post-DRE AG-PCa-associated urinary glycoproteins in pre-DRE urine specimens, and explored potential new glycoproteins for AG-PCa detection in pre-DRE urine specimens. Quantitative glycoproteomic data were acquired for 154 pre-DRE urine specimens from 41 patients with no cancer at biopsy, 48 patients with non-AG-PCa (Gleason score=6), and 65 patients with AG-PCa (Gleason score 7 or above). Compared to glycopeptides from the post-DRE urine data, humoral immunity-related proteins were enriched in pre-DRE urine samples, whereas cell mediated immune response proteins were enriched in post-DRE urine samples. Analyses of AG-PCa-associated glycoproteins from pre-DRE urine revealed that the three urinary glycoproteins, prostate-specific antigen (PSA), prostatic acid phosphatase (ACPP), and CD97 antigen (CD97) that were previously identified in post-DRE urine samples, were also observed as AG-PCa associated glycoproteins in pre-DRE urine. In addition, we identified three new glycoproteins, fibrillin 1 (FBN1), vitronectin (VTN), and hemicentin 2 (HMCN2), to be potentially associated with AG-PCa in pre-DRE urine specimens. In summary, glycoprotein profiles differ between pre- and post-DRE urine specimens. The identified AG-PCa-associated glycoproteins may be further evaluated in large cohort of pre-DRE urine specimens for detecting clinically significant PCa.

Generation of human induced pluripotent stem cell line UGENTi001-A from a patient with Marfan syndrome carrying a heterozygous c.7754 T > C variant in FBN1 and the isogenic control UGENT001-A-1 using CRISPR/Cas9 editing

Marfan syndrome is an autosomal dominant genetic disorder resulting from pathogenic variants in FBN1 gene. FBN1 encodes for fibrillin-1, an important extracellular matrix protein. Impaired fibrillin-1 affects multiple organ systems, including the cardiovascular system. We generated an iPSC line carrying a heterozygous variant c.7754 T > C (p.Ile2585Thr, missense) in FBN1 from a patient with Marfan syndrome. Also, an isogenic control is generated, where the pathogenic variant is repaired using CRISPR-Cas9. This isogenic pair provides a valuable resource for in vitro disease modelling.

Bioinformatics Identification of Therapeutic Gene Targets for Gastric Cancer.

The global prevalence of gastric cancer (GC) is increasing, and novel chemotherapeutic targets are needed. We searched for potential biomarkers for GC in three microarray datasets within the Gene Expression Omnibus (GEO) database. FunRich (v3.1.3) was used to perform Gene Ontology (GO) analyses and STRUN and Cytoscape (v3.6.0) were employed to construct a protein-protein interaction (PPI) network. To explore hub gene expression and survival, we used Gene Expression Profiling Interactive Analysis (GEPIA) and Kaplan-Meier (KM) plotter. Drugs that were closely related to key genes were screened by the Gene Set Cancer Analysis (GSCA), and relevant correlations were verified experimentally. We validated that the sensitivity of a GC cell line to these drugs was correlated with fibrillin1 (FBN1) mRNA expression levels. We identified 83 upregulated and 133 downregulated differentially expressed genes (DEGs) and these were enriched with regards to their cellular component (extracellular and exosomes), molecular function (extracellular matrix structural constituent and catalytic activity), and biological process (cell growth and/or maintenance and metabolism). The biological pathways most prominently involved were epithelial-to-mesenchymal transition (EMT) and β3integrin cell surface interactions. For the PPI network, we selected 10 hub genes, and 70% of these were significantly connected to poor overall survival (OS) in patients with GC. We found a significant link between the expression of FBN1 and two small molecule drugs (PAC-1 and PHA-793887). Overall, we suggest that these hub genes can be used as biomarkers and novel targets for GC. FBN1 may be associated with drug resistance in gastric cancer.

A generated induced pluripotent stem cell (iPSC) line (CMGANTi005-A) of a Marfan syndrome patient with an FBN1 c.7754T > C (p.Ile2585Thr) variation

Marfan syndrome (MFS) is a connective tissue disorder with pleiotropic manifestations in the ocular, skeletal and cardiovascular system; and is typically cause by pathogenic variants in the fibrillin-1 (FBN1) gene. We report a generated induced pluripotent cell (iPSC) line of a MFS patient with an FBN1 c.7754T > C (p.Ile2585Thr) variant. The cell line was generated from peripheral blood mononuclear cells (PBMCs) and after reprogramming the line showed a no relevant copy number alterations, expression of pluripotency markers and was able to differentiate into three germ layers while carrying the original genotype.

Clinical and genetic findings in Chinese families with congenital ectopia lentis.

Congenital ectopia lentis (EL) refers to the congenital dysplasia or weakness of the lens suspensory ligament, resulting in an abnormal position of the crystalline lens, which can appear as isolated EL or as an ocular manifestation of a syndrome, such as the Marfan syndrome. The fibrillin-1 protein encoded by the FBN1 gene is an essential component of the lens zonules. Mutations in FBN1 are the leading causes of congenital EL and Marfan syndrome. Owing to the complexity and individual heterogeneity of FBN1 gene mutations, the correlation between FBN1 mutation characteristics and various clinical phenotypes remains unclear. This study describes the clinical characteristics and identifies possible causative genes in eight families with Marfan syndrome or isolated EL using Sanger and whole-exome sequencing. Eight FBN1 mutations were identified in these families, of which three (c.5065G > C, c.1600 T > A, and c.2210G > C) are reported for the first time. Based on in silico analyses, we hypothesized that these mutations may be pathogenic by affecting the fibrillin-1 protein structure and function. These findings expand the number of known mutations involved in EL and provide a reference for the research on their genotype and phenotype associations.

No differences in FBN1 genotype between men with and without abdominal aortic aneurysm

BackgroundAbdominal aortic aneurysm (AAA) is an aortic enlargement in which the transverse diameter reaches at least 30 mm. Certain risk factors, such as age, male gender, and smoking, are well known; however, less is known about the genetic factors involved. Fibrillin-1 (FBN1) is a protein that coordinates the deposition of elastin fibres in the extracellular matrix and is therefore likely to affect the elastic properties in the aortic wall. Previously studies have found associations between the FBN1-2/3 genotype and arterial stiffness, but how different FBN1 genotypes, AAA, and arterial stiffness are related has been less frequently investigated.AimThis study aimed to investigate whether there is a difference in FBN1 genotype between men with and without AAA. A further aim was to study whether the FBN1 genotype affects arterial wall stiffness differently in men with and without AAA.MethodsPulse wave velocity and FBN1 genotyping were performed in 229 men (159 with AAA, 70 without AAA). Participants were recruited from ultrasound AAA surveillance programs or ongoing ultrasound screening programs from 2011 to 2016.ResultsThe distribution of the FBN1 genotype in the AAA and control groups were as follows: FBN1-2/2: 62% vs. 64%; FBN1-2/3: 8% vs. 14%; and FBN1-2/4: 30% vs. 21%, respectively. Men with AAA and FBN1-2/2 had increased central pulse wave velocity (p < 0.005) compared to the control group (those without AAA) with the FBN1-2/2 genotype.ConclusionNo differences were found with respect to FBN1 genotypes between men with and without AAA. The development of AAA in men does not appear to be linked to a specific FBN1 genotype. Nevertheless, men with FBN1-2/2 and AAA have increased central arterial stiffness compared to men with the same FBN1 genotype but without AAA.

High frequency of heterozygous rare variants of the SLC34A1 and SLC9A3R1 genes in patients with atypical femur fracture

Atypical femur fractures (AFFs) are rare fragility fractures originating at the lateral cortex of the femur, affecting the subtrochanteric or diaphyseal area of thebone with a transverse morphology. Occurrence of AFF is specifically associated with a small number of rare monogenic congenital metabolic bone disorders, such as hypophosphatasia, and with long-term treatment with antiresorptiondrugs. The exact pathogenesis of these fractures remains poorly understood and, except for cases of diagnosed HPP or other AFF-causing bone diseases, it is not possible to assess which patients are at higher riskof developing AFFs as a consequence of anti-resorption therapy. We genetically screened 25 unrelated patients who had developed at least one AFF. Genetic screening was performed through a nextgeneration sequencing analysis with a customized panel containing 76 human genes involved in the regulation of the mineralization processWe genetically screened 25 unrelated patients who had developed at least one AFF. We found a relatively high frequency (32.0%) of heterozygous rare variants inthe SLC34A1 and SLC9A3R1 genes, two genes whose heterozygous inactivating mutations have been respectively associated with autosomal dominant hypophosphatemic nephrolithiasis/osteoporosis types 1 and 2 (NPHLOP1and NPHLOP2). Other heterozygous rare variants were found in the BMPR1B, CYP27B1, FBN1, MEPE, PIGO, and PHOSPHO1 genes, each in a single AFF case (4.0%). Our findings suggest that rarevariants of SLC34A1 and SLC9A3R1 could represent a possible genetic risk factor for the occurrence of AFFs. On the other hand, AFFs could represent an unsuspected clinical manifestation and/or an anti-resorption therapycorrelatedadverse event in patients with NPHLOP disorders.

Rare variants in the FBN1 gene are associated with sporadic dilated cardiomyopathy in a Chinese Han population

Introduction: Dilated cardiomyopathy (DCM) represents a diverse set of myocardial diseases characterized by notable genetic heterogeneity. Although over 50 genes have been associated with DCM, these collectively explain 35% of idiopathic DCM cases. Variants in the FBN1 gene encoding fibrillin-1 are primarily linked to connective tissue disorders. Considering the potential of these disorders to impact myocardial tissue, this study probes into the possible association between FBN1 variants and DCM. Aim: The objective of this study was to investigate the association between FBN1 variants and DCM in a Chinese Han population. Methods and Results: We performed whole-exome sequencing (WES) to identify rare FBN1 variants among 1,059 DCM cases and 514 controls. Utilizing a case-control strategy and the optimal sequence kernel association test (SKAT-O), we found a significant enrichment of rare deleterious FBN1 variants in DCM patients (19 of 1,059 vs. 0 of 514, PSKAT-O = 7.49E-04). Clinical characteristics analysis indicated a higher occurrence of atrial fibrillation and a higher rate of implantable cardioverter-defibrillator (ICD) implantation among DCM patients carrying FBN1 variants (FBN1+) compared to non-carriers (FBN1-). However, these FBN1 variants did not significantly affect primary endpoints, defined as cardiac mortality or heart transplantation, yet appeared to increase the risk of secondary endpoints, including all-cause mortality or heart failure recurrence. Conclusion: The findings suggest an association between rare deleterious variants in the FBN1 gene and DCM in a Chinese Han population. Our findings underline the importance of further research to validate these results and elucidate the role of FBN1 in DCM. Potential Impact of the findings: This research provides fresh insights into the potential role of FBN1 rare variants in DCM, pointing to new directions for future genetic studies and potential therapeutic strategies in DCM management.

A Novel Missense Mutation in the TGF-β-binding Protein-Like Domain 3 of FBN1 Causes Weill-Marchesani Syndrome with Intellectual Disability.

Weill-Marchesani syndrome (WMS) is a rare connective tissue disorder characterized by locus heterogeneity and variable expressivity. Patients suffering from WMS are described by short stature, brachydactyly, joint stiffness, congenital heart defects, and eye abnormalities. This disorder is inherited in two different modes; the autosomal dominant form of the disease occurs due to a mutation in FBN1, and the recessive form results from mutations in ADAMTS10, ADAMTS17, or LTP2 genes. The family recruited in this study was a consanguineous Iranian family with an intellectually disabled girl referred to the Sadra Genetics laboratory, Shahrekord, Iran. The clinical history of family members was investigated. Whole-Exome Sequencing (WES) for the proband was performed. Sanger sequencing was used to assess the segregation of candidate variants in the other family members. Whole-exome sequencing analysis revealed a novel heterozygote mutation in the proband located at the third TGF-β-binding protein-like (TB) domain of the FBN1 gene (NM000138: c.2066A>G: (p. Glu689Gly), NP_000129.3, in exon 17 of the gene). Co-segregation analysis with Sanger sequencing confirmed this mutation in the affected members of the pedigree. Our findings represent an autosomal dominant form of specific WMS resulting from a substitution mutation in the FBN1 gene. In addition to the typical manifestations of the disorder, mild intellectual disability (ID) was identified in the 8-year-old proband. Given the fact that ID is primarily reported in ADAMTS10 mutated cases, this family was clinically and genetically a novel case.

Orthodontic Perspective on Marfan Syndrome: A Unique Case Report

Marfan syndrome is considered a relatively rare genetic disorder that affects the connective tissues in the body. It is caused by a specific mutation in the Fibrillin 1 (FBN1) gene, which is a critical component of microfibrils. The elastic fibres in various connective tissues, composed of microfibrils, are affected in Marfan syndrome. This syndrome is associated with a vast array of clinical features involving the cardiovascular, ocular, musculoskeletal, respiratory, and nervous systems. Skeletal malocclusion is an early and characteristic manifestation of Marfan syndrome. Other cardinal features of the syndrome include tall stature, arachnodactyly, ectopic lentis, and thoracic aortic aneurysm and dissection. Most clinicians fail to correlate the systemic features with the oral features, leading to misdiagnosis or under-reported. Marfan Syndrome requires thorough understanding of the genetic components that directly result in systemic manifestations, eventually leading to skeletal malocclusion, is crucial in managing the syndrome. A multidisciplinary approach is required to assess the condition before planning and implementing appropriate treatment protocols. In the present case report, authors presented a diagnosed case of Marfan syndrome. An 18-year-old female visited the Outpatient Department (OPD) of Oral Medicine and Radiology at a Tertiary Care Centre in Siliguri, West Bengal, India, seeking management for her skeletal malocclusion. After a thorough intraoral and extraoral examination, as well as smile assessment, orthognathic surgery was performed for preliminary tooth alignment using fixed appliances. The patient’s healing process was uneventful, and she is currently being followed-up without any evidence of relapse. Early diagnosis, intervention, and judicious treatment planning with a multidisciplinary approach are key to achieving long-term stable results in correcting skeletal malocclusions associated with Marfan syndrome.

Fibrillin-1 and asprosin, novel players in metabolic syndrome.

Fibrillin-1 is a major component of the extracellular microfibrils, where it interacts with other extracellular matrix proteins to provide elasticity to connective tissues, and regulates the bioavailability of TGFβ family members. A peptide consisting of the C-terminal 140 amino acids of fibrillin-1 has recently been identified as a glucogenic hormone, secreted from adipose tissue during fasting and targeting the liver to release glucose. This fragment, called asprosin, also signals in the hypothalamus to stimulate appetite. Asprosin levels are correlated with many of the pathologies indicative of metabolic syndrome, including insulin resistance and obesity. Previous studies and reviews have addressed the therapeutic potential of asprosin as a target in obesity, diabetes and related conditions without considering mechanisms underlying the relationship between generation of asprosin and expression of the much larger fibrillin-1 protein. Profibrillin-1 undergoes obligatory cleavage at the cell surface as part of its assembly into microfibrils, producing the asprosin peptide as well as mature fibrillin-1. Patterns of FBN1 mRNA expression are inconsistent with the necessity for regulated release of asprosin. The asprosin peptide may be protected from degradation in adipose tissue. We present evidence for an alternative possibility, that asprosin mRNA is generated independently from an internal promoter within the 3' end of the FBN1 gene, which would allow for regulation independent of fibrillin-synthesis and is more economical of cellular resources. The discovery of asprosin opened exciting possibilities for treatment of metabolic syndrome related conditions, but there is much to be understood before such therapies could be introduced into the clinic.

Endothelial dysfunction in Marfan syndrome mice is restored by resveratrol

Patients with Marfan syndrome (MFS) develop thoracic aortic aneurysms as the aorta presents excessive elastin breaks, fibrosis, and vascular smooth muscle cell (vSMC) death due to mutations in the FBN1 gene. Despite elaborate vSMC to aortic endothelial cell (EC) signaling, the contribution of ECs to the development of aortic pathology remains largely unresolved. The aim of this study is to investigate the EC properties in Fbn1C1041G/+ MFS mice. Using en face immunofluorescence confocal microscopy, we showed that EC alignment with blood flow was reduced, EC roundness was increased, individual EC surface area was larger, and EC junctional linearity was decreased in aortae of Fbn1C1041G/+ MFS mice. This modified EC phenotype was most prominent in the ascending aorta and occurred before aortic dilatation. To reverse EC morphology, we performed treatment with resveratrol. This restored EC blood flow alignment, junctional linearity, phospho-eNOS expression, and improved the structural integrity of the internal elastic lamina of Fbn1C1041G/+ mice. In conclusion, these experiments identify the involvement of ECs and underlying internal elastic lamina in MFS aortic pathology, which could act as potential target for future MFS pharmacotherapies.