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Heritable thoracic aortic aneurysms and dissections (hTAAD) are life-threatening complications of well-known syndromic diseases or underdiagnosed nonsyndromic heritable forms (nshTAAD). Both have an autosomal dominant transmission and are genetically heterogeneous. Our objective was to describe the relevance of molecular diagnosis in these patients and the contribution of each gene in nshTAAD. Two hundred twenty-six consecutive nshTAAD probands, either young (<45 years) sporadic or familial cases were included. A next-generation sequencing capture panel comprising 23 known disease-causing genes was performed. Class 4 or 5 variants were identified in 18% of the nshTAAD probands, while class 3 variants were found in 10% of them. The yield in familial cases was greater than in sporadic cases. SMAD3 and FBN1 genes were the major disease-causing genes. Unexpectedly, no premature termination codon variant was identified in the FBN1 gene. Furthermore, we report for the first time that aortic dissection or surgery occurred significantly more often and earlier in probands with a class 4 or 5 pathogenic variant. This study indicates that genetic screening using NGS is efficient in young and familial nshTAAD. The presence of a pathogenic variant has a possible predictive value, which needs to be further investigated because it may influence care.

Marfan syndrome (MFS) is a connective tissue disorder in which several systems are affected with great phenotypic variability. Although known to be associated with pathogenic variants in the FBN1 gene, few genotype–phenotype correlations have been found in proband studies only. In 1,575 consecutive MFS probands and relatives from the most comprehensive database worldwide, we established survival curves and sought genotype–phenotype correlations. A risk chart could be established with clinical and genetic data. Premature termination codon variants were not only associated with a shorter life expectancy and a high lifelong risk of aortic event, but also with the highest risk of severe scoliosis and a lower risk for ectopia lentis (EL) surgery. In-frame variants could be subdivided according to their impact on the cysteine content of fibrillin-1 with a global higher severity for cysteine loss variants and the highest frequency of EL surgery for cysteine addition variants. This study shows that FBN1 genotype–phenotype correlations exist for both aortic and extra-aortic features. It can be used for optimal risk stratification of patients with a great importance for genetic counseling and personalized medicine. This also provides additional data for the overall understanding of the role of fibrillin-1 in various organs.

Background Chemotherapy resistance is a primary reason of ovarian cancer therapy failure; hence it is important to investigate the underlying mechanisms of chemotherapy resistance and develop novel potential therapeutic targets. Methods RNA sequencing of cisplatin‐resistant and ‐sensitive (chemoresistant and chemosensitive, respectively) ovarian cancer organoids was performed, followed by detection of the expression level of fibrillin‐1 (FBN1) in organoids and clinical specimens of ovarian cancer. Subsequently, glucose metabolism, angiogenesis, and chemosensitivity were analyzed in structural glycoprotein FBN1‐knockout cisplatin‐resistant ovarian cancer organoids and cell lines. To gain insights into the specific functions and mechanisms of action of FBN1 in ovarian cancer, immunoprecipitation, silver nitrate staining, mass spectrometry, immunofluorescence, Western blotting, and Fӧrster resonance energy transfer‐fluorescence lifetime imaging analyses were performed, followed by in vivo assays using vertebrate model systems of nude mice and zebrafish. Results FBN1 expression was significantly enhanced in cisplatin‐resistant ovarian cancer organoids and tissues, indicating that FBN1 might be a key factor in chemoresistance of ovarian cancer. We also discovered that FBN1 sustained the energy stress and induced angiogenesis in vitro and in vivo, which promoted the cisplatin‐resistance of ovarian cancer. Knockout of FBN1 combined with treatment of the antiangiogenic drug apatinib improved the cisplatin‐sensitivity of ovarian cancer cells. Mechanistically, FBN1 mediated the phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2) at the Tyr1054 residue, which activated its downstream focal adhesion kinase (FAK)/protein kinase B (PKB or AKT) pathway, induced the phosphorylation of signal transducer and activator of transcription 2 (STAT2) at the tyrosine residue 690 (Tyr690), promoted the nuclear translocation of STAT2, and ultimately altered the expression of genes associated with STAT2‐mediated angiogenesis and glycolysis. Conclusions The FBN1/VEGFR2/STAT2 signaling axis may induce chemoresistance of ovarian cancer cells by participating in the process of glycolysis and angiogenesis. The present study suggested a novel FBN1‐targeted therapy and/or combination of FBN1 inhibition and antiangiogenic drug for treating ovarian cancer.

Osteosarcoma is an uncommon tumor occurring in bone, accompanied by elevated incidence and reduced rate of healing. Epithelial‐to‐mesenchymal transition (EMT) serves as a conceptual paradigm to explain the invasion and metastasis of osteosarcoma and other cancers. Hence, developing effective therapeutic strategy to treat the EMT of osteosarcoma is essential. Here, we identified the molecular mechanism of long noncoding RNA (lncRNA) PGM5‐AS1 in EMT and progression of osteosarcoma. Microarray‐based analysis was employed to screen the osteosarcoma‐related differentially expressed lncRNAs. The levels of PGM5‐AS1 as well as microRNA‐140‐5p (miR‐140‐5p) and fibrillin‐1 (FBN1) in osteosarcoma tissues and cells were determined. Dual‐luciferase reporter gene assay, RNA pull‐down assay, and RNA immunoprecipitation assay were conducted to validate the relationship among PGM5‐AS1, miR‐140‐5p, and FBN1. Expression of PGM5‐AS1, miR‐140‐5p, and FBN1 was altered by overexpression, shRNA, mimic, or inhibitors in order to investigate how they regulated migration, invasion, and EMT of osteosarcoma cells in vitro. Loss‐ and gain‐of‐function approaches were employed in nude mice to detect their roles in tumorigenesis in vivo. Osteosarcoma tissues and cells exhibited low expression of miR‐140‐5p, but high expression of PGM5‐AS1 and FBN1. PGM5‐AS1 competitively bound to miR‐140‐5p to upregulate FBN1. Furthermore, hindering PGM5‐AS1 and FBN1 or overexpressing miR‐140‐5p dampened migration, invasion, and EMT of osteosarcoma cells in vitro. Furthermore, silencing PGM5‐AS1 or FBN1, or overexpressing miR‐140‐5p markedly inhibited tumorigenesis in nude mice in vivo. Taken together, PGM5‐AS1 depletion causes FBN1 reduction to retard osteosarcoma processes by negatively modulating miR‐140‐5p. In this study, we analyzed the modulatory role of PGM5‐AS1 in the progression and EMT of osteosarcoma. In osteosarcoma tissues and cells, PGM5‐AS1 and FBN1 are highly expressed, while miR‐140‐5p exhibits low expression. We reveal that PGM5‐AS1 specifically binds to miR‐140‐5p to silence the expression of FBN1, and thereby attenuate EMT, invasion, and migration of osteosarcoma in vitro as well as tumorigenesis in vivo. In this study, we analyzed the modulatory role of PGM5‐AS1 in the progression and EMT of osteosarcoma. In osteosarcoma tissues and cells, PGM5‐AS1 and FBN1 are highly expressed, while miR‐140‐5p exhibits low expression. We reveal that PGM5‐AS1 specifically binds to miR‐140‐5p to silence the expression of FBN1, and thereby attenuate EMT, invasion, and migration of osteosarcoma in vitro as well as tumorigenesis in vivo.

Thoracic aortic aneurysms (TAA) in Marfan syndrome, caused by fibrillin-1 mutations, are characterized by elevated cytokines and fragmentated elastic laminae in the aortic wall. This study explored whether and how specific fibrillin-1-regulated miRNAs mediate inflammatory cytokine expression and elastic laminae degradation in TAA. miRNA expression profiling at early and late TAA stages using a severe Marfan mouse model ( Fbn1 mgR/mgR ) revealed a spectrum of differentially regulated miRNAs. Bioinformatic analyses predicted the involvement of these miRNAs in inflammatory and extracellular matrix-related pathways. We demonstrate that upregulation of pro-inflammatory cytokines and matrix metalloproteinases is a common characteristic of mouse and human TAA tissues. miR-122, the most downregulated miRNA in the aortae of 10-week-old Fbn1 mgR/mgR mice, post-transcriptionally upregulated CCL2, IL-1β and MMP12. Similar data were obtained at 70 weeks of age using Fbn1 C1041G/ + mice. Deficient fibrillin-1–smooth muscle cell interaction suppressed miR-122 levels. The marker for tissue hypoxia HIF-1α was upregulated in the aortic wall of Fbn1 mgR/mgR mice, and miR-122 was reduced under hypoxic conditions in cell and organ cultures. Reduced miR-122 was partially rescued by HIF-1α inhibitors, digoxin and 2-methoxyestradiol in aortic smooth muscle cells. Digoxin-treated Fbn1 mgR/mgR mice demonstrated elevated miR-122 and suppressed CCL2 and MMP12 levels in the ascending aortae, with reduced elastin fragmentation and aortic dilation. In summary, this study demonstrates that miR-122 in the aortic wall inhibits inflammatory responses and matrix remodeling, which is suppressed by deficient fibrillin-1–cell interaction and hypoxia in TAA.

Background Marfan syndrome (MFS) is an inherited autosomal dominant disorder that affects connective tissue with an incidence of about 1 in 5,000 to 10,000 people. 90% of MFS is caused by mutations in the fibrillin-1 ( FBN1 ) gene. We recruited a family with MFS phenotype in South China and identified a novel variant. This study investigated whether this genetic variant is pathogenic and the potential pathway related to lipid metabolism in MFS. Methods A three-generation consanguineous family was recruited for this study. Whole exome sequencing (WES) was utilized on family members. The 3D structure of the protein was predicted using AlphaFold. CRISPR/Cas9 was applied to generate a similar fbn1 nonsense mutation ( fbn1 +/− ) in zebrafish. RNA-seq analysis on zebrafish was performed to identify potential pathways related to MFS pathogenesis. Results Our study identified a novel variant [NM_000138.5; c.7764 C > G: p.(Y2588*)] in FBN1 gene from the family and identified the same site mutation among the proband along with her son and daughter. Structural modeling showed the p.Y2588* mutation resulted from a truncated protein. Compared to wild-type zebrafish, the F2 generation fbn1 +/− zebrafish exhibited MFS phenotype. RNA-seq analysis indicated that many genes related to leptin are up-regulating, which could affect bone development and adipose homeostasis. Conclusion A novel variant was identified in FBN1 gene. In a zebrafish model, we found functional evidence supporting the pathogenicity of the detected nonsense mutation. Our research proposes a possible mechanism underlying the relationship between lipid metabolism and MFS. These findings can help improve the clinical diagnosis and treatment of MFS.

Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1 , ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus ( r  = −0.62, P  = 5.30 × 10 −5 ) but not between CCT and primary open-angle glaucoma ( r  = −0.17, P  = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation. Reduced central corneal thickness (CCT) is observed in common eye diseases as well as in rare Mendelian disorders. Here, in a cross-ancestry GWAS, the authors identify 19 novel genetic loci associated with CCT, a subset of which is involved in rare corneal or connective tissue disorders.

Marfan syndrome (MFS) is an autosomal dominant, age-related but highly penetrant condition with substantial intrafamilial and interfamilial variability. MFS is caused by pathogenetic variants in FBN1 , which encodes fibrillin-1, a major structural component of the extracellular matrix that provides support to connective tissues, particularly in arteries, the pericondrium and structures in the eye. Up to 25% of individuals with MFS have de novo variants. The most prominent manifestations of MFS are asymptomatic aortic root aneurysms, aortic dissections, dislocation of the ocular lens (ectopia lentis) and skeletal abnormalities that are characterized by overgrowth of the long bones. MFS is diagnosed based on the Ghent II nosology; genetic testing confirming the presence of a FBN1 pathogenetic variant is not always required for diagnosis but can help distinguish MFS from other heritable thoracic aortic disease syndromes that can present with skeletal features similar to those in MFS. Untreated aortic root aneurysms can progress to life-threatening acute aortic dissections. Management of MFS requires medical therapy to slow the rate of growth of aneurysms and decrease the risk of dissection. Routine surveillance with imaging techniques such as transthoracic echocardiography, CT or MRI is necessary to monitor aneurysm growth and determine when to perform prophylactic repair surgery to prevent an acute aortic dissection. Marfan syndrome (MFS) is a genetic disorder affecting the connective tissue, caused by mutations in FBN1 (which encodes fibrillin-1, a structural component of the extracellular matrix); individuals with MFS usually present with cardiovascular (aortic aneurysms and dissections), skeletal and ocular manifestations.

Mitral valve prolapse is often benign, but progression to mitral regurgitation may require invasive intervention and there is no specific medical therapy. An association of mitral valve prolapse with Marfan syndrome resulting from pathogenic FBN1 variants supports the use of hypomorphic fibrillin-1 mgR mice to investigate mechanisms and therapy for mitral valve disease. mgR mice developed severe myxomatous mitral valve degeneration with mitral regurgitation by 12 weeks of age. Persistent activation of TGF-β and mTOR signaling along with macrophage recruitment preceded histological changes at 4 weeks of age. Short-term mTOR inhibition with rapamycin from 4 to 5 weeks of age prevented TGF-β overactivity and leukocytic infiltrates, while long-term inhibition of mTOR or TGF-β signaling from 4 to 12 weeks of age rescued mitral valve leaflet degeneration. Transcriptomic analysis identified integrins as key receptors in signaling interactions, and serologic neutralization of integrin signaling or a chimeric integrin receptor altering signaling prevented mTOR activation. We confirmed increased mTOR signaling and a conserved transcriptome signature in human specimens of sporadic mitral valve prolapse. Thus, mTOR activation from abnormal integrin-dependent cell-matrix interactions drives TGF-β overactivity and myxomatous mitral valve degeneration, and mTOR inhibition may prevent disease progression of mitral valve prolapse.

Microfibril-associated glycoprotein 4 (MFAP4) is a 36-kDa extracellular matrix glycoprotein with critical roles in organ fibrosis, chronic obstructive pulmonary disease, and cardiovascular disorders, including aortic aneurysms. MFAP4 multimerises and interacts with elastogenic proteins, including fibrillin-1 and tropoelastin, and with cells via integrins. Structural details of MFAP4 and its potential interfaces for these interactions are unknown. Here, we present a cryo-electron microscopy structure of human MFAP4. In the presence of calcium, MFAP4 assembles as an octamer, where two sets of homodimers constitute the top and bottom halves of each octamer. Each homodimer is linked together by an intermolecular disulphide bond. A C34S missense mutation prevents disulphide-bond formation between monomers but does not prevent octamer assembly. The atomic model, built into the 3.55 Å cryo-EM map, suggests that salt-bridge interactions mediate homodimer assembly, while non-polar residues form the interface between octamer halves. In the absence of calcium, an MFAP4 octamer dissociates into two tetramers. Binding studies with fibrillin-1, tropoelastin, LTBP4, and small fibulins show that MFAP4 has multiple surfaces for protein-protein interactions, most of which depend upon MFAP4 octamer assembly. The C34S mutation does not affect these protein interactions or cell interactions. MFAP4 assemblies with fibrillin-1 abrogate MFAP4 interactions with cells. Microfibrillar-associated protein 4 (MFAP4) is involved in fibrotic and cardiovascular diseases. Wozny et al. reveal structural aspects mediating MFAP4 octamer formation critical for its interaction with elastogenic proteins and cells.