Journal articles: 'FBN1'

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Bastian, Nicole A., Rosemary A. Bayne, Katja Hummitzsch, Nicholas Hatzirodos, Wendy M. Bonner, Monica D. Hartanti, Helen F. Irving-Rodgers, Richard A. Anderson, and Raymond J. Rodgers. "Regulation of fibrillins and modulators of TGFβ in fetal bovine and human ovaries." Reproduction 152, no. 2 (August 2016): 127–37. http://dx.doi.org/10.1530/rep-16-0172.

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Fibrillins 1–3 are stromal extracellular matrix proteins that play important roles in regulating TGFβ activity, which stimulates fibroblasts to proliferate and synthesize collagen. In the developing ovary, the action of stroma is initially necessary for the formation of ovigerous cords and subsequently for the formation of follicles and the surface epithelium of the ovary. FBN3 is highly expressed only in early ovarian development and then it declines. In contrast, FBN1 and 2 are upregulated in later ovarian development. We examined the expression of FBN1–3 in bovine and human fetal ovaries. We used cell dispersion and monolayer culture, cell passaging and tissue culture. Cells were treated with growth factors, hormones or inhibitors to assess the regulation of expression of FBN1–3. When bovine fetal ovarian tissue was cultured, FBN3 expression declined significantly. Treatment with TGFβ-1 increased FBN1 and FBN2 expression in bovine fibroblasts, but did not affect FBN3 expression. Additionally, in cultures of human fetal ovarian fibroblasts (9–17weeks gestational age), the expression of FBN1 and FBN2 increased with passage, whereas FBN3 dramatically decreased. Treatment with activin A and a TGFβ family signaling inhibitor, SB431542, differentially regulated the expression of a range of modulators of TGFβ signaling and of other growth factors in cultured human fetal ovarian fibroblasts suggesting that TGFβ signaling is differentially involved in the regulation of ovarian fibroblasts. Additionally, since the changes in FBN1–3 expression that occur in vitro are those that occur with increasing gestational age in vivo, we suggest that the fetal ovarian fibroblasts mature in vitro.

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Nishimura, Akira, Haruya Sakai, Shiro Ikegawa, Hiroshi Kitoh, Nobuyuki Haga, Satoshi Ishikiriyama, Toshiro Nagai, et al. "FBN2,FBN1,TGFBR1, andTGFBR2 analyses in congenital contractural arachnodactyly." American Journal of Medical Genetics Part A 143A, no. 7 (2007): 694–98. http://dx.doi.org/10.1002/ajmg.a.31639.

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Wang, Zanxin, Xianmian Zhuang, Bailang Chen, Junmin Wen, Fang Peng, Xiling Liu, and Minxin Wei. "99-Case Study of Sporadic Aortic Dissection by Whole Exome Sequencing Indicated Novel Disease-Associated Genes and Variants in Chinese Population." BioMed Research International 2020 (October 2, 2020): 1–12. http://dx.doi.org/10.1155/2020/7857043.

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Background. In this study, the whole exome sequencing in human aortic dissection, a highly lethal cardiovascular disease, was investigated to explore the aortic dissection-associated genes and variants in Chinese population. Methods. Whole exome sequencing was performed in 99 cases of aortic dissection. All single nucleotide polymorphisms (SNPs), insertions/deletions (InDels), and copy number variations (CNVs) were filtered to exclude the benign variants. Enrichment analysis and disease-gene correlation analysis were performed. Results. 3425873 SNPs, 685245 InDels, and 1177 CNVs were identified, and aortic dissection-associated SNPs, InDels, and CNVs were collected. After the disease correlation analysis, 20 candidate genes were identified. Part of these genes such as MYH11, FBN1, and ACTA2 were consistent with previous studies, while MLX, DAB2IP, EP300, ZFYVE9, PML, and PRKCD were newly identified as candidate aortic dissection-associated genes. Conclusion. The pathogenic and likely pathogenic variants in most of AD-associated genes (FBN1, MYH11, EFEMP2, TGFBR2, FBN2, COL3A1, and MYLK) were identified in our cohort study, and pathogenic CNVs involved in MYH11, COL family, and FBN were also identified which are not detectable by other NGS analysis. The correlation between MLX, DAB2IP, EP300, ZFYVE9, PML, PRKCD, and aortic dissection was identified, and EP300 may play a key role in AD.

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Zhang, H., SD Apfelroth, W. Hu, EC Davis, C. Sanguineti, J. Bonadio, RP Mecham, and F. Ramirez. "Structure and expression of fibrillin-2, a novel microfibrillar component preferentially located in elastic matrices." Journal of Cell Biology 124, no. 5 (March 1, 1994): 855–63. http://dx.doi.org/10.1083/jcb.124.5.855.

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During the previous cloning of the fibrillin gene (FBN1), we isolated a partial cDNA coding for a fibrillin-like peptide and mapped the corresponding gene (FBN2) to human chromosome 5. (Lee, B., M. Godfrey, E. Vitale, H. Hori, M. G. Mattei, M. Sarfarazi, P. Tsipouras, F. Ramirez, and D. W. Hollister. 1991. Nature [Lond.]. 352:330-334). The study left, however, unresolved whether or not the FBN2 gene product is an extracellular component structurally related to fibrillin. Work presented in this report clarifies this important point. Determination of the entire primary structure of the FBN2 gene product demonstrated that this polypeptide is highly homologous to fibrillin. Immunoelectron microscopy localized both fibrillin proteins to elastin-associated extracellular microfibrils. Finally, immunohistochemistry revealed that the fibrillins co-distribute in elastic and non-elastic connective tissues of the developing embryo, with preferential accumulation of the FBN2 gene product in elastic fiber-rich matrices. These results support the original hypothesis that the fibrillins may have distinct but related functions in the formation and maintenance of extracellular microfibrils. Accordingly, we propose to classify the FBN1 and FBN2 gene products as a new family of extracellular proteins and to name its members fibrillin-1 and fibrillin-2, respectively.

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Chen, Chider, Kentaro Akiyama, Dandan Wang, Xingtian Xu, Bei Li, Alireza Moshaverinia, Frank Brombacher, Lingyun Sun, and Songtao Shi. "mTOR inhibition rescues osteopenia in mice with systemic sclerosis." Journal of Experimental Medicine 212, no. 1 (December 22, 2014): 73–91. http://dx.doi.org/10.1084/jem.20140643.

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Fibrillin-1 (FBN1) deficiency-induced systemic sclerosis is attributed to elevation of interleukin-4 (IL4) and TGF-β, but the mechanism underlying FBN1 deficiency–associated osteopenia is not fully understood. We show that bone marrow mesenchymal stem cells (BMMSCs) from FBN1-deficient (Fbn1+/−) mice exhibit decreased osteogenic differentiation and increased adipogenic differentiation. Mechanistically, this lineage alteration is regulated by IL4/IL4Rα-mediated activation of mTOR signaling to down-regulate RUNX2 and up-regulate PPARγ2, respectively, via P70 ribosomal S6 protein kinase (P70S6K). Additionally, we reveal that activation of TGF-β/SMAD3/SP1 signaling results in enhancement of SP1 binding to the IL4Rα promoter to synergistically activate mTOR pathway in Fbn1+/− BMMSCs. Blockage of mTOR signaling by osteoblastic-specific knockout or rapamycin treatment rescues osteopenia phenotype in Fbn1+/− mice by improving osteogenic differentiation of BMMSCs. Collectively, this study identifies a previously unrecognized role of the FBN1/TGF-β/IL4Rα/mTOR cascade in BMMSC lineage selection and provides experimental evidence that rapamycin treatment may provide an anabolic therapy for osteopenia in Fbn1+/− mice.

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Maylem, Excel Rio, Leon Spicer, Isadora Batalha, and Luis Schutz. "PSIV-5 Developmental and hormonal regulation of gene expression of fibrillin-1 (FBN1) and the asprosin receptor, olfactory receptor family 4 subfamily M member 1 (OR4M1), in bovine ovarian cells." Journal of Animal Science 98, Supplement_4 (November 3, 2020): 283–84. http://dx.doi.org/10.1093/jas/skaa278.510.

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Abstract Asprosin is a novel fasting-induced protein associated with insulin resistance and polycystic ovaries in humans. It is encoded by FBN1 gene and produced when FBN1 is cleaved by the enzyme furin. In cattle, the role of asprosin is unknown. To characterize mRNA abundance of FBN1, furin, and the asprosin receptor, OR4M1, in granulosa (GC) and theca cells (TC), and identify hormones regulating FBN1 mRNA expression, GC and TC from small (< 6 mm; SM) and large (>5 mm; LG) follicles were collected from heifers at an abattoir and used for real-time gene expression analysis or in vitro evaluation of hormone regulation. SMTC had 151-fold greater (P < 0.05) FBN1 mRNA abundance than SMGC, and LGTC had 50-fold greater (P < 0.05) FBN1 mRNA than LGGC. In contrast, OR4M1 mRNA abundance was significantly greater (by 81-fold) in SMGC than LGGC and did not differ from SMTC, but LGTC had 9-fold greater (P < 0.05) OR4M1 mRNA abundance than LGGC. Furin mRNA was significantly greater (by 2.6-fold) in SMGC than SMTC but did not differ between LGTC and LGGC. In SMGC, leptin, insulin, GH, FSH, EGF, and steroids had no effect (P >0.10) on FBN1 mRNA abundance. In contrast, TGFB1, WNT3A and FGF9 increased (P < 0.05) and IGF1 significantly decreased SMGC FBN1 mRNA abundance. In LGTC, leptin, insulin, LH, IGF1 and steroids did not significantly affect FBN1 mRNA, but TGFB1, WNT3A, EGF, FGF2 and FGF9 increased (P< 0.05) FBN1 mRNA abundance. Altogether, FBN1 mRNA was more highly expressed in TC than GC and was stimulated by TGFB1, WNT3A and FGF9 in both cell types. Developmental and hormonal regulation of FBN1, furin and OR4M1 along with a greater expression of OR4M1 mRNA in GC than TC suggests that asprosin may be acting as a paracrine regulator of ovarian follicular function in cattle.

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Maylem, Excel Rio S., Leon J. Spicer, Isadora Batalha, and Luis F. Schutz. "Discovery of a possible role of asprosin in ovarian follicular function." Journal of Molecular Endocrinology 66, no. 1 (January 2021): 35–44. http://dx.doi.org/10.1530/jme-20-0218.

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Asprosin is a novel fasting-induced protein encoded by fibrillin-1 (FBN1) gene, produced when FBN1 is cleaved by the enzyme furin, and is associated with insulin resistance and polycystic ovarian syndrome in humans. To characterize mRNA abundance of FBN1, FURIN, and the presumed asprosin receptor, olfactory receptor family 4 subfamily M member 1 (OR4M1) in granulosa (GC) and theca cells (TC), and identify hormones regulating FBN1 mRNA expression, GC and TC from small (1–5 mm; SM) and large (>8 mm; LG) follicles were collected from ovaries of heifers obtained at an abattoir and used for real-time PCR gene expression analysis or in vitro evaluation of hormone regulation and asprosin effects. SMTC had 151-fold greater (P < 0.05) FBN1 mRNA abundance than SMGC, and LGTC had 50-fold greater FBN1 mRNA than LGGC. In contrast, OR4M1 mRNA was 81-fold greater in SMGC than LGGC and did not differ from SMTC, but LGTC had 9-fold greater OR4M1 mRNA than LGGC. FURIN mRNA was 2.6-fold greater in SMTC than SMGC, but did not differ among follicular sizes. In cultured TC, leptin, insulin, LH, IGF1 and steroids did not affect FBN1 mRNA, but TGFB1 increased (P < 0.05) FBN1 mRNA by 2.2-fold; EGF and FGFs increased FBN1 mRNA by 1.3- to 1.5-fold. Asprosin enhanced LH-induced TC androstenedione production, reduced IGF1-induced TC proliferation, and had no effect on progesterone production. Developmental regulation of FBN1, FURIN and OR4M1 along with direct effects of asprosin on TC suggests that asprosin may be a novel regulator of ovarian follicular function.

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Benarroch, Louise, Mélodie Aubart, Marie-Sylvie Gross, Marie-Paule Jacob, Pauline Arnaud, Nadine Hanna, Guillaume Jondeau, and Catherine Boileau. "Marfan Syndrome Variability: Investigation of the Roles of Sarcolipin and Calcium as Potential Transregulator of FBN1 Expression." Genes 9, no. 9 (August 21, 2018): 421. http://dx.doi.org/10.3390/genes9090421.

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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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Lin, Mao, Sen Zhao, Gang Liu, Yingzhao Huang, Chenxi Yu, Yanxue Zhao, Lianlei Wang, et al. "Identification of novel FBN1 variations implicated in congenital scoliosis." Journal of Human Genetics 65, no. 3 (December 11, 2019): 221–30. http://dx.doi.org/10.1038/s10038-019-0698-x.

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AbstractCongenital scoliosis (CS) is a form of scoliosis caused by congenital vertebral malformations. Genetic predisposition has been demonstrated in CS. We previously reported that TBX6 loss-of-function causes CS in a compound heterozygous model; however, this model can explain only 10% of CS. Many monogenic and polygenic CS genes remain to be elucidated. In this study, we analyzed exome sequencing (ES) data of 615 Chinese CS from the Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) project. Cosegregation studies for 103 familial CS identified a novel heterozygous nonsense variant, c.2649G>A (p.Trp883Ter) in FBN1. The association between FBN1 and CS was then analyzed by extracting FBN1 variants from ES data of 574 sporadic CS and 828 controls; 30 novel variants were identified and prioritized for further analyses. A mutational burden test showed that the deleterious FBN1 variants were significantly enriched in CS subjects (OR = 3.9, P = 0.03 by Fisher’s exact test). One missense variant, c.2613A>C (p.Leu871Phe) was recurrent in two unrelated CS subjects, and in vitro functional experiments for the variant suggest that FBN1 may contribute to CS by upregulating the transforming growth factor beta (TGF-β) signaling. Our study expanded the phenotypic spectrum of FBN1, and provided nove insights into the genetic etiology of CS.

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Jensen, Sacha A., Ondine Atwa, and Penny A. Handford. "Assembly assay identifies a critical region of human fibrillin-1 required for 10–12 nm diameter microfibril biogenesis." PLOS ONE 16, no. 3 (March 18, 2021): e0248532. http://dx.doi.org/10.1371/journal.pone.0248532.

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The human FBN1 gene encodes fibrillin-1 (FBN1); the main component of the 10–12 nm diameter extracellular matrix microfibrils. Marfan syndrome (MFS) is a common inherited connective tissue disorder, caused by FBN1 mutations. It features a wide spectrum of disease severity, from mild cases to the lethal neonatal form (nMFS), that is yet to be explained at the molecular level. Mutations associated with nMFS generally affect a region of FBN1 between domains TB3-cbEGF18—the "neonatal region". To gain insight into the process of fibril assembly and increase our understanding of the mechanisms determining disease severity in MFS, we compared the secretion and assembly properties of FBN1 variants containing nMFS-associated substitutions with variants associated with milder, classical MFS (cMFS). In the majority of cases, both nMFS- and cMFS-associated neonatal region variants were secreted at levels comparable to wild type. Microfibril incorporation by the nMFS variants was greatly reduced or absent compared to the cMFS forms, however, suggesting that nMFS substitutions disrupt a previously undefined site of microfibril assembly. Additional analysis of a domain deletion variant caused by exon skipping also indicates that register in the neonatal region is likely to be critical for assembly. These data demonstrate for the first time new requirements for microfibril biogenesis and identify at least two distinct molecular mechanisms associated with disease substitutions in the TB3-cbEGF18 region; incorporation of mutant FBN1 into microfibrils changing their integral properties (cMFS) or the blocking of wild type FBN1 assembly by mutant molecules that prevents late-stage lateral assembly (nMFS).

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Torrado, Mario, Emilia Maneiro, Juan Pablo Trujillo-Quintero, Arturo Evangelista, Alexander T. Mikhailov, and Lorenzo Monserrat. "A Novel Heterozygous Intronic Mutation in the FBN1 Gene Contributes to FBN1 RNA Missplicing Events in the Marfan Syndrome." BioMed Research International 2018 (May 29, 2018): 1–10. http://dx.doi.org/10.1155/2018/3536495.

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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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Benarroch, Louise, Mélodie Aubart, Marie-Sylvie Gross, Pauline Arnaud, Nadine Hanna, Guillaume Jondeau, and Catherine Boileau. "Reference Expression Profile of Three FBN1 Transcript Isoforms and Their Association with Clinical Variability in Marfan Syndrome." Genes 10, no. 2 (February 11, 2019): 128. http://dx.doi.org/10.3390/genes10020128.

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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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Fusco, Carmela, Silvia Morlino, Lucia Micale, Alessandro Ferraris, Paola Grammatico, and Marco Castori. "Characterization of Two Novel Intronic Variants Affecting Splicing in FBN1-Related Disorders." Genes 10, no. 6 (June 10, 2019): 442. http://dx.doi.org/10.3390/genes10060442.

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FBN1 encodes fibrillin 1, a key structural component of the extracellular matrix, and its variants are associated with a wide range of hereditary connective tissues disorders, such as Marfan syndrome (MFS) and mitral valve–aorta–skeleton–skin (MASS) syndrome. Interpretations of the genomic data and possible genotype–phenotype correlations in FBN1 are complicated by the high rate of intronic variants of unknown significance. Here, we report two unrelated individuals with the FBN1 deep intronic variants c.6872-24T>A and c.7571-12T>A, clinically associated with MFS and MASS syndrome, respectively. The individual carrying the c.6872-24T>A variant is positive for aortic disease. Both individuals lacked ectopia lentis. In silico analysis and subsequent mRNA study by RT-PCR demonstrated the effect of the identified variant on the splicing process in both cases. The c.6872-24T>A and c.7571-12T>A variants generate the retention of intronic nucleotides and lead to the introduction of a premature stop codon. This study enlarges the mutation spectrum of FBN1 and points out the importance of intronic sequence analysis and the need for integrative functional studies in FBN1 diagnostics.

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Li, Wen-han, Hao Zhang, Qi Guo, Xuan-di Wu, Zi-sen Xu, Cheng-xue Dang, Peng Xia, and Yong-chun Song. "Detection of SNCA and FBN1 Methylation in the Stool as a Biomarker for Colorectal Cancer." Disease Markers 2015 (2015): 1–6. http://dx.doi.org/10.1155/2015/657570.

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Aim.We examined the methylation status of SNCA and FBN1 genes in patients’ paired tissue and stool samples for detection of colorectal cancer (CRC).Patients and Methods. 89 DNA tissue samples (normal/cancer) and corresponding stool samples were analyzed in our study. In addition, 30 stool samples were collected as healthy controls.Results. The methylation level of those samples was measured by methylation-specific polymerase chain reaction (MSP). The result shows that compared with the paired controls, both SNCA and FBN1 were significantly hypermethylated in CRC patients in tissue samples (P<0.001). In the stool samples, hypermethylated SNCA and FBN1 were detected to be significantly higher than that in normal stool samples (P<0.001). The combined sensitivity of at least one positive among the two markers in stool samples was 84.3%, with a specificity of 93.3%. In addition, our experiment suggested that the positive rates of SNCA and FBN1 in Dukes A stage were significantly higher than that of FOBT (P=0.039;P=0.006, resp.).Conclusion. We concluded that methylation testing of SNCA and FBN1 genes in stool sample may offer a good alternative in a simple, promising, and noninvasive detection of colorectal cancer.

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Buchan, Jillian G., David M. Alvarado, Gabe E. Haller, Carlos Cruchaga, Matthew B. Harms, Tianxiao Zhang, Marcia C. Willing, et al. "Rare variants in FBN1 and FBN2 are associated with severe adolescent idiopathic scoliosis." Human Molecular Genetics 23, no. 19 (May 15, 2014): 5271–82. http://dx.doi.org/10.1093/hmg/ddu224.

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Yalcintepe, Sinem, Selma Demir, Emine Ikbal Atli, Murat Deveci, Engin Atli, and Hakan Gurkan. "Two Novel Pathogenic FBN1 Variations and Their Phenotypic Relationship of Marfan Syndrome." Global Medical Genetics 07, no. 02 (August 2020): 068–71. http://dx.doi.org/10.1055/s-0040-1714092.

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AbstractMarfan syndrome is an autosomal dominant disease affecting connective tissue involving the ocular, skeletal systems with a prevalence of 1/5,000 to 1/10,000 cases. Especially cardiovascular system disorders (aortic root dilatation and enlargement of the pulmonary artery) may be life-threatening. We report here the genetic analysis results of three unrelated cases clinically diagnosed as Marfan syndrome. Deoxyribonucleic acid (DNA) was isolated from EDTA (ethylenediaminetetraacetic acid)-blood samples of the patients. A next-generation sequencing panel containing 15 genes including FBN1 was used to determine the underlying pathogenic variants of Marfan syndrome. Three different variations, NM_000138.4(FBN1):c.229G > A(p.Gly77Arg), NM_000138.4(FBN1):c.165–2A > G (novel), NM_000138.4(FBN1):c.399delC (p.Cys134ValfsTer8) (novel) were determined in our three cases referred with a prediagnosis of Marfan syndrome. Our study has confirmed the utility of molecular testing in Marfan syndrome to support clinical diagnosis. With an accurate diagnosis and genetic counseling for prognosis of patients and family testing, the prenatal diagnosis will be possible.

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Mohammad, Ahmed, and Paldeep Atwal. "A 2-Year-Old Child with Bilateral Ectopis Lentis and a Novel FBN1 Gene Variant Cys129Ser." Journal of Pediatric Genetics 07, no. 02 (December 8, 2017): 083–85. http://dx.doi.org/10.1055/s-0037-1612592.

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AbstractMarfan syndrome and dominant ectopia lentis are part of type 1 fibrillinopathies that are caused by FBN1 pathogenic variants. Making a diagnosis could be challenging due to the clinical overlap between these disorders. The revised Ghent criteria used for Marfan syndrome diagnosis helped in resolving some of the confusion, especially in younger children. We report on a case of bilateral ectopia lentis in a 2-year-old child with a normal echocardiogram. FBN1 sequencing revealed a novel likely pathogenic variant described as c.385T > A (p.Cys129Ser). The patient's father also has a history of bilateral ectopia lentis and his genetic analysis detected the same FBN1 variant as the proband.

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Cale, Jessica M., Kane Greer, Sue Fletcher, and Steve D. Wilton. "Proof-of-Concept: Antisense Oligonucleotide Mediated Skipping of Fibrillin-1 Exon 52." International Journal of Molecular Sciences 22, no. 7 (March 27, 2021): 3479. http://dx.doi.org/10.3390/ijms22073479.

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Marfan syndrome is one of the most common dominantly inherited connective tissue disorders, affecting 2–3 in 10,000 individuals, and is caused by one of over 2800 unique FBN1 mutations. Mutations in FBN1 result in reduced fibrillin-1 expression, or the production of two different fibrillin-1 monomers unable to interact to form functional microfibrils. Here, we describe in vitro evaluation of antisense oligonucleotides designed to mediate exclusion of FBN1 exon 52 during pre-mRNA splicing to restore monomer homology. Antisense oligonucleotide sequences were screened in healthy control fibroblasts. The most effective sequence was synthesised as a phosphorodiamidate morpholino oligomer, a chemistry shown to be safe and effective clinically. We show that exon 52 can be excluded in up to 100% of FBN1 transcripts in healthy control fibroblasts transfected with PMO52. Immunofluorescent staining revealed the loss of fibrillin 1 fibres with ~50% skipping and the subsequent re-appearance of fibres with >80% skipping. However, the effect of exon skipping on the function of the induced fibrillin-1 isoform remains to be explored. Therefore, these findings demonstrate proof-of-concept that exclusion of an exon from FBN1 pre-mRNA can result in internally truncated but identical monomers capable of forming fibres and lay a foundation for further investigation to determine the effect of exon skipping on fibrillin-1 function.

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Oller, Jorge, Enrique Gabandé-Rodríguez, María Jesús Ruiz-Rodríguez, Gabriela Desdín-Micó, Juan Francisco Aranda, Raquel Rodrigues-Diez, Constanza Ballesteros-Martínez, et al. "Extracellular Tuning of Mitochondrial Respiration Leads to Aortic Aneurysm." Circulation 143, no. 21 (May 25, 2021): 2091–109. http://dx.doi.org/10.1161/circulationaha.120.051171.

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Background: Marfan syndrome (MFS) is an autosomal dominant disorder of the connective tissue caused by mutations in the FBN1 (fibrillin-1) gene encoding a large glycoprotein in the extracellular matrix called fibrillin-1. The major complication of this connective disorder is the risk to develop thoracic aortic aneurysm. To date, no effective pharmacologic therapies have been identified for the management of thoracic aortic disease and the only options capable of preventing aneurysm rupture are endovascular repair or open surgery. Here, we have studied the role of mitochondrial dysfunction in the progression of thoracic aortic aneurysm and mitochondrial boosting strategies as a potential treatment to managing aortic aneurysms. Methods: Combining transcriptomics and metabolic analysis of aortas from an MFS mouse model ( Fbn1 c1039g/+ ) and MFS patients, we have identified mitochondrial dysfunction alongside with mtDNA depletion as a new hallmark of aortic aneurysm disease in MFS. To demonstrate the importance of mitochondrial decline in the development of aneurysms, we generated a conditional mouse model with mitochondrial dysfunction specifically in vascular smooth muscle cells (VSMC) by conditional depleting Tfam (mitochondrial transcription factor A; Myh11-Cre ERT2 Tfam flox/flox mice). We used a mouse model of MFS to test for drugs that can revert aortic disease by enhancing Tfam levels and mitochondrial respiration. Results: The main canonical pathways highlighted in the transcriptomic analysis in aortas from Fbn1 c1039g/+ mice were those related to metabolic function, such as mitochondrial dysfunction. Mitochondrial complexes, whose transcription depends on Tfam and mitochondrial DNA content, were reduced in aortas from young Fbn1 c1039g/+ mice. In vitro experiments in Fbn1 -silenced VSMCs presented increased lactate production and decreased oxygen consumption. Similar results were found in MFS patients. VSMCs seeded in matrices produced by Fbn1-deficient VSMCs undergo mitochondrial dysfunction. Conditional Tfam-deficient VSMC mice lose their contractile capacity, showed aortic aneurysms, and died prematurely. Restoring mitochondrial metabolism with the NAD precursor nicotinamide riboside rapidly reverses aortic aneurysm in Fbn1 c1039g/+ mice. Conclusions: Mitochondrial function of VSMCs is controlled by the extracellular matrix and drives the development of aortic aneurysm in Marfan syndrome. Targeting vascular metabolism is a new available therapeutic strategy for managing aortic aneurysms associated with genetic disorders.

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Biddinger, A. L., J. T. Hecht, and D. M. Milewicz. "Repeat polymorphisms in human fibrillin genes on chromosome 15 (FBN1) and chromosome 5 (FBN2)." Human Molecular Genetics 2, no. 8 (1993): 1323. http://dx.doi.org/10.1093/hmg/2.8.1323.

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Goldstein, Craig, Phillip Liaw, Sergio A. Jimenez, Arthur M. Buchberg, and Linda D. Siracusa. "Genetic linkage analyses of the fibrillin genes, Fbn1 and Fbn2, in the mouse genome." Matrix Biology 14, no. 5 (September 1994): 368. http://dx.doi.org/10.1016/0945-053x(94)90068-x.

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Gusina, A. A., N. S. Stalybko, K. A. Krinitskaya, V. F. Ivanova, N. V. Rumiantseva, V. D. Kulak, T. V. Zubova, and N. B. Gusina. "FBN1 gene mutations in patients with congenital ectopia lentis caused by Marfan syndrome." Proceedings of the National Academy of Sciences of Belarus, Medical series 17, no. 1 (March 18, 2020): 87–100. http://dx.doi.org/10.29235/1814-6023-2020-17-1-87-100.

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The prevalence of congenital ectopia lentis is 7–10 cases per 100 000 people. The most common causes of congenital lens displacement are the FBN1 gene mutations that have been found in 25–85 % of patients with this pathology. The aim of the study is to establish the FBN1 gene mutations in patients with congenital lens displacement and in their families. The study group included three families with children and adults suffered from the congenital lens dislocation. The nucleotide sequence of the FBN1 gene was analyzed by direct sequencing. The pathogenicity of the identified mutations was assessed using the Ghent criteria revised in 2010. The mutation c.1884C> G (p.Cys628Trp) in the heterozygous state in the 16th exon of the FBN1 gene was detected in proband 1 and her brother. Proband 2 was found to be a heterozygous career of the mutation c.2461T> A (p.Cys821Ser) in the 21st exon; this mutation was absent in parents and a healthy brother. The mutation c.7851delС (p.Cys2617Trpfs*65) in the heterozygous state in the 64th exon was identified in proband 3 and her mother. In accordance with the revised Ghent classification and the clinical manifestations and molecular genetic studies, Marfan’s syndrome (MS) was diagnosed in all probands and their affected relatives. We detected three pathogenic mutations not previously described in the literature in the 16th, 21st, and 64th exons of the FBN1 gene in patients with congenital ectopia lentis caused by MS. We established the spectrum of clinical manifestations of MS characteristic for the identified mutations.

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Mohamed, Salah A., Hans H. Sievers, Thorsten Hanke, Doreen Richardt, Claudia Schmidtke, Efstratios I. Charitos, Gazanfer Belge, and Joern Bullerdiek. "Pathway Analysis of Differentially Expressed Genes in Patients with Acute Aortic Dissection." Biomarker Insights 4 (January 2009): BMI.S2530. http://dx.doi.org/10.4137/bmi.s2530.

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Background Acute aortic dissection (AAD) is a life-threatening condition with high mortality and a relatively unclarified pathophysiological mechanism. Although differentially expressed genes in AAD have been recognized, interactions between these genes remain poorly defined. This study was conducted to gain a better understanding of the molecular mechanisms underlying AAD and to support the future development of a clinical test for monitoring patients at high risk. Materials and Methods Aortic tissue was collected from 19 patients with AAD (mean age 61.7 ± 13.1 years), and from eight other patients (mean age 32.9 ± 12.2 years) who carried the mutated gene for Marfan syndrome (MS). Six patients (mean age 56.7 ± 12.3 years) served as the control group. The PIQOR™ Immunology microarray with 1076 probes in quadruplicates was utilized; the differentially expressed genes were analysed in a MedScan search using PathwayAssist software. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and protein analysis were performed. Results Interactions of MS fibrillin-1 (FBN1) in the MedScan pathway analysis showed four genes, fibulin-1 (FBLN1), fibulin-2 (FBLN2), decorin (DCN) and microfibrillar associated protein 5 (MFAP5), which were differentially expressed in all tissue from AAD. The validation of these genes by qRT-PCR revealed a minimum of three-fold downregulation of FBLN1 (0.5 ± 0.4 vs. 6.1 ± 2.3 fold, p = 0.003) and of DCN (2.5 ± 1.0 vs. 8.5 ± 4.7 fold, p = 0.04) in AAD compared to MS and control samples. Conclusions Downregulation of fibrillin-1 (FBN1) may weaken extracellular components in the aorta and/or interfer with the transmission of cellular signals and eventually cause AAD. Additional research on these four identified genes can be a starting point to develop a diagnostic tool.

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Cardy, Caroline M., Nick A. Maskell, Penny A. Handford, Anthony G. Arnold, Robert J. O. Davies, Patrick J. Morrison, and Peter E. Thornley. "Familial Spontaneous Pneumothorax and FBN1 Mutations." American Journal of Respiratory and Critical Care Medicine 169, no. 11 (June 2004): 1260–62. http://dx.doi.org/10.1164/ajrccm.169.11.967.

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Hayward, Caroline, Marion Keston, David J. H. Brock, and Harry C. Dietz. "Fabrillin (FBN1) mutations in Marfan syndrome." Human Mutation 1, no. 1 (1992): 79. http://dx.doi.org/10.1002/humu.1380010115.

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Gaikwad, Anil B., Jeena Gupta, and Kulbhushan Tikoo. "Epigenetic changes and alteration of Fbn1 and Col3A1 gene expression under hyperglycaemic and hyperinsulinaemic conditions." Biochemical Journal 432, no. 2 (November 12, 2010): 333–41. http://dx.doi.org/10.1042/bj20100414.

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Little is known regarding the role of hyperglycaemia on histone H3 modifications and, in turn, altering the expression of genes during the development of diabetes-associated complications. In the present study, we have investigated the hyperinsulinaemia/hyperglycaemia-induced epigenetic changes and alteration of Fbn1 (fibrillin 1) and Col3A1 (collagen type III α1) gene expression. Insulin resistance and Type 2 diabetes in male Sprague–Dawley rats was developed by feeding rats an HFD (high-fat diet) and administering a low dose of STZ (streptozotocin). Hyperglycaemia induced deacetylation and dephosphorylation of histone H3 in the heart and kidneys of diabetic rats. Furthermore, mRNA expression of Fbn1 and Col3A1 increased in the kidneys and decreased in the heart under hyperglycaemic/hyperinsulinaemic conditions. Similar to mRNA expression, chromatin immunoprecipitation also showed an increase in the level of histone H3 acetylation of the Fbn1 gene, but not of the Col3A1 gene. Our present findings suggests that the change in expression of the Fbn1 gene is epigenetically regulated, but the expression of the Col3A1 gene may either be independent of epigenetic regulation or may involve other histone modifications. We provide the first evidence regarding the role of hyperglycaemia/hyperinsulinaemia in altering histone H3 modifications, which may result in the alteration of extracellular matrix gene expression.

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Stephenson, Kirk A. J., Adrian Dockery, Michael O’Keefe, Andrew Green, G. Jane Farrar, and David J. Keegan. "A FBN1 variant manifesting as non-syndromic ectopia lentis with retinal detachment: clinical and genetic characteristics." Eye 34, no. 4 (September 16, 2019): 690–94. http://dx.doi.org/10.1038/s41433-019-0580-2.

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Abstract Background/objectives Fibrillin-1 (FBN1) mutations cause connective tissue dysgenesis the main ocular manifestation being ectopia lentis (EL), which may be syndromic or non-syndromic. We describe a pedigree with a FBN1 mutation causing non-syndromic EL with retinal detachment (RRD) and their management. Subjects/methods Patients with familial EL with RRD were invited to participate (vitreoretinopathy branch of Target 5000, the Irish inherited retinal degeneration study). All patients signed full informed consent. The study was approved by the Institutional Review Board of the Mater Hospital, Dublin and abided by the Declaration of Helsinki. Results Seven adults were affected with bilateral EL. All subjects had RRD with bilateral non-synchronous RRD in 57%. Conclusions The FBN1 variant described herein confers an increased risk of both EL and RRD and can now be upgraded to ‘pathogenic’ ACMG status.

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Pedroza, Albert J., Yasushi Tashima, Rohan Shad, Paul Cheng, Robert Wirka, Samantha Churovich, Ken Nakamura, et al. "Single-Cell Transcriptomic Profiling of Vascular Smooth Muscle Cell Phenotype Modulation in Marfan Syndrome Aortic Aneurysm." Arteriosclerosis, Thrombosis, and Vascular Biology 40, no. 9 (September 2020): 2195–211. http://dx.doi.org/10.1161/atvbaha.120.314670.

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Objective: To delineate temporal and spatial dynamics of vascular smooth muscle cell (SMC) transcriptomic changes during aortic aneurysm development in Marfan syndrome (MFS). Approach and Results: We performed single-cell RNA sequencing to study aortic root/ascending aneurysm tissue from Fbn1 C1041G/ + (MFS) mice and healthy controls, identifying all aortic cell types. A distinct cluster of transcriptomically modulated SMCs (modSMCs) was identified in adult Fbn1 C1041G/ + mouse aortic aneurysm tissue only. Comparison with atherosclerotic aortic data (ApoE −/− mice) revealed similar patterns of SMC modulation but identified an MFS-specific gene signature, including plasminogen activator inhibitor-1 ( Serpine1 ) and Kruppel-like factor 4 ( Klf4 ). We identified 481 differentially expressed genes between modSMC and SMC subsets; functional annotation highlighted extracellular matrix modulation, collagen synthesis, adhesion, and proliferation. Pseudotime trajectory analysis of Fbn1 C1041G/ + SMC/modSMC transcriptomes identified genes activated differentially throughout the course of phenotype modulation. While modSMCs were not present in young Fbn1 C1041G/ + mouse aortas despite small aortic aneurysm, multiple early modSMCs marker genes were enriched, suggesting activation of phenotype modulation. modSMCs were not found in nondilated adult Fbn1 C1041G/ + descending thoracic aortas. Single-cell RNA sequencing from human MFS aortic root aneurysm tissue confirmed analogous SMC modulation in clinical disease. Enhanced expression of TGF-β (transforming growth factor beta)-responsive genes correlated with SMC modulation in mouse and human data sets. Conclusions: Dynamic SMC phenotype modulation promotes extracellular matrix substrate modulation and aortic aneurysm progression in MFS. We characterize the disease-specific signature of modSMCs and provide temporal, transcriptomic context to the current understanding of the role TGF-β plays in MFS aortopathy. Collectively, single-cell RNA sequencing implicates TGF-β signaling and Klf4 overexpression as potential upstream drivers of SMC modulation.

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Aggarwal, Shagun, Aneek Das Bhowmik, Ashwani Tandon, and Ashwin Dalal. "Exome sequencing reveals blended phenotype of double heterozygous FBN1 and FBN2 variants in a fetus." European Journal of Medical Genetics 61, no. 7 (July 2018): 399–402. http://dx.doi.org/10.1016/j.ejmg.2018.02.009.

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Sheppard, Mary Burchett, Jeff Zheying Chen, Debra L. Rateri, Jessica J. Moorleghen, Mackenzie Weiland, and Alan Daugherty. "3204 Renin-Angiotensin System Inhibitors Do Not Improve Survival in Fibrillin-1 Hypomorphic Mice with Established Aortic Aneurysm." Journal of Clinical and Translational Science 3, s1 (March 2019): 112–13. http://dx.doi.org/10.1017/cts.2019.258.

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OBJECTIVES/SPECIFIC AIMS: Drugs to attenuate aortic growth are usually not initiated in patients with Marfan syndrome until aortic dilation is already present. Therefore, we measured the impact of drugs (the renin-angiotensin system inhibitors losartan and enalapril) on survival and thoracic aortic growth in a mouse model of Marfan syndrome when extensive aortic dilation was already present. METHODS/STUDY POPULATION: Male and female fibrillin-1 hypomorphic (FBN1 mgR/mgR) mice (n=10-12/group) were stratified into treatment groups by aortic diameter at 6 weeks of age to ensure an equivalent average aortic diameter in each group at the start of the study. Osmotic mini pumps filled with PBS (vehicle), enalapril (2 mg/kg/d), or losartan (20 mg/kg/d) were implanted subcutaneously into mice after stratification. Mini pumps infusing drug or vehicle were replaced every 4 weeks for a total duration of 12 weeks. Wild type littermates (n=10) were infused with PBS as a negative control to the Marfan mouse model. Ascending aortic diameters from male and female FBN1 mgR/mgR mice and their wild type littermates were assessed by ultrasound every 4 weeks from 6 to 18 weeks of age. Aortic diameters were measured luminal edge to luminal edge during diastole. RESULTS/ANTICIPATED RESULTS: 6 week old FBN1 mgR/mgR mice exhibited significantly dilated ascending thoracic aortas at study initiation compared to their wild type sex-matched littermates (in males: FBN1 mgR/mgR = 1.87 +/− 0.07mm, wild type = 1.23 +/− 0.07mm; p <0.001) (in females: FBN1 mgR/mgR = 1.56 +/− 0.07mm, wild type = 1.18 +/− 0.07mm; p <0.001). Baseline mortality of FBN1 mgR/mgR mice infused with PBS was 36% in male and 22% in female mice at the time of study termination. Within sex-matched mgR littermates, there was no significant difference in survival between groups treated with PBS, enalapril, or losartan after 12 weeks (p=0.224 for males, p=0.094 in females). In the same groups, no significant difference in maximum ascending aortic diameter was detected after treatment for 12 weeks (in males: PBS=2.69 +/− 0.19 mm, enalapril=2.04 +/− 0.27 mm, losartan=2.42 +/− 0.28 mm; p=0.24) (in females: PBS = 1.92 +/− 0.13, enalapril=1.89 +/− 0.31, losartan=1.98 +/− 0.17; p=0.86). Furthermore, aortic diameters in the FBN1 mgR/mgR mice were found to demonstrate sexual dimorphism. DISCUSSION/SIGNIFICANCE OF IMPACT: This research shows that losartan is not effective when administered after significant thoracic aortic dilation has already occurred in FBN1 mgR/mgR mice. This has important translational implications because losartan is usually not started in patients with Marfan syndrome until significant aortic dilation is already present. Therefore, more research needs to be done to determine the critical time period within which this medicine will be effective if given to patients. In addition, this research demonstrates that male FBN1mgR/mgR mice have a significantly larger aortic diameter than female FBN1mgR/mgR mice. This sexual dimorphism has recently been observed in patients with Marfan syndrome as well. Additional studies for understanding the mechanism underlying this sexual dimorphism have the potential to elucidate new therapeutic approaches for aortic disease.

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Mohammad, Ahmed, Haytham Helmi, and Paldeep S. Atwal. "Patient with Marfan Syndrome and a Novel Variant in FBN1 Presenting with Bilateral Popliteal Artery Aneurysm." Case Reports in Genetics 2018 (2018): 1–4. http://dx.doi.org/10.1155/2018/6780494.

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We present a 43-year-old man with aortic root dilation, mitral valve prolapse, and marfanoid appearance, who presented with acute onset left leg pain. He underwent a Doppler ultrasound that revealed left popliteal artery aneurysm with thrombus. CT angiogram showed bilateral popliteal artery aneurysms. After repairing of his left popliteal artery aneurysm, he was sent for genetic evaluation. He was diagnosed with Marfan syndrome (MFS) based on the revised Ghent criteria and then underwent FBN1 sequencing and deletion/duplication analysis, which detected a novel pathogenic variant in gene FBN1, denoted by c.5872 T>A (p.Cys1958Ser). MFS is a connective tissue disorder with an autosomal dominant inheritance due to pathogenic variants in FBN1 that encodes Fibrillin-1, a major element of the extracellular matrix, and connective tissue throughout the body. MFS involves multiple systems, most commonly the cardiovascular, musculoskeletal, and visual systems. In our case we present a rare finding of bilateral popliteal artery aneurysms in a male patient with MFS.

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Maylem, E. R., L. Spicer, E. Atabay, E. Atabay, I. Batalha, and L. Schutz. "2 Intrafollicular injection of asprosin in water buffaloes and the potential role of FBN1 mRNA and asprosin in follicular function." Reproduction, Fertility and Development 33, no. 2 (2021): 108. http://dx.doi.org/10.1071/rdv33n2ab2.

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Fibrillin-1 (FBN1) functions as a structural protein in the ovary, whereas the role of its protein product asprosin remains unknown. Both proteins are encoded by the FBN1 gene; when it is cleaved at the C-terminal end, asprosin is produced. Asprosin acts as an orexigenic hormone and is associated with various metabolic parameters and sex related hormones in women. One goal of this research was to quantify FBN1 and the presumed asprosin receptor, olfactory receptor family 4 subfamily M member 1 (OR4M1) mRNA in water buffalo granulosa cells (GC) and correlate them to aromatase (CYP19A1) gene expression. A second goal was to determine the effect of asprosin on follicular growth invivo. In Experiment 1, ovaries were collected from a local slaughterhouse, GC from small (<6mm) and large (6–13mm) follicles were aspirated, RNA was extracted, and gene expression analysis conducted. In Experiment 2, an intrafollicular injection of asprosin (6μL of asprosin in 194μL of phosphate-buffered saline; to achieve 20ng mL−1) or vehicle (200μL of phosphate-buffered saline; Controls) was given via the ovarian stroma below the dominant follicle of synchronized cows (n=5/group) 1 day after injection of prostaglandin F2α, and follicle sizes were measured daily via transrectal ultrasonography until the day of ovulation. Means were compared using t-test for gene expression analysis, and Pearson correlation coefficients calculated among FBN1, OR4M1, and CYP19A1 gene expression. A repeated-measures ANOVA was used to determine the effect of asprosin on follicle size and growth rate of follicles. In Experiment 1, FBN1 mRNA abundance was 7.51-fold greater in GC of small than large follicles (P<0.05). There was no significant difference in the OR4M1 (57.83±39.89 vs. 38.98±4.86) or CYP19A1 (11.46±3.72 vs. 8.27±4.81) mRNA abundance between the 2 sizes of follicles (P>0.10). Abundance of CYP19A1 mRNA was positively correlated with FBN1 (r=0.55, P<0.05) and OR4M1 mRNA (r=0.50, P<0.05). In Experiment 2, there was a treatment×day interaction (P<0.10) for follicle size and growth rate of follicles. Cows treated with asprosin had a higher growth rate from Day 1 to 2 (1.09±0.39 to 2.37±0.32 mm/day) than placebo cows (1.74±0.55 to 1.05±0.61 mm/day) after injection. Most of the follicles from both treatment groups ovulated 3 days post injection. These findings suggest that FBN1 (and thus asprosin) are present in buffalo GC and may be developmentally expressed. Also, asprosin may induce follicular growth when given invivo. Whether these proteins directly regulate aromatase expression, and therefore oestradiol production, during follicle development will require further study.

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Maylem, E. R., L. Spicer, E. Atabay, E. Atabay, I. Batalha, and L. Schutz. "2 Intrafollicular injection of asprosin in water buffaloes and the potential role of FBN1 mRNA and asprosin in follicular function." Reproduction, Fertility and Development 33, no. 2 (2021): 108. http://dx.doi.org/10.1071/rdv33n2ab2.

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Fibrillin-1 (FBN1) functions as a structural protein in the ovary, whereas the role of its protein product asprosin remains unknown. Both proteins are encoded by the FBN1 gene; when it is cleaved at the C-terminal end, asprosin is produced. Asprosin acts as an orexigenic hormone and is associated with various metabolic parameters and sex related hormones in women. One goal of this research was to quantify FBN1 and the presumed asprosin receptor, olfactory receptor family 4 subfamily M member 1 (OR4M1) mRNA in water buffalo granulosa cells (GC) and correlate them to aromatase (CYP19A1) gene expression. A second goal was to determine the effect of asprosin on follicular growth invivo. In Experiment 1, ovaries were collected from a local slaughterhouse, GC from small (<6mm) and large (6–13mm) follicles were aspirated, RNA was extracted, and gene expression analysis conducted. In Experiment 2, an intrafollicular injection of asprosin (6μL of asprosin in 194μL of phosphate-buffered saline; to achieve 20ng mL−1) or vehicle (200μL of phosphate-buffered saline; Controls) was given via the ovarian stroma below the dominant follicle of synchronized cows (n=5/group) 1 day after injection of prostaglandin F2α, and follicle sizes were measured daily via transrectal ultrasonography until the day of ovulation. Means were compared using t-test for gene expression analysis, and Pearson correlation coefficients calculated among FBN1, OR4M1, and CYP19A1 gene expression. A repeated-measures ANOVA was used to determine the effect of asprosin on follicle size and growth rate of follicles. In Experiment 1, FBN1 mRNA abundance was 7.51-fold greater in GC of small than large follicles (P<0.05). There was no significant difference in the OR4M1 (57.83±39.89 vs. 38.98±4.86) or CYP19A1 (11.46±3.72 vs. 8.27±4.81) mRNA abundance between the 2 sizes of follicles (P>0.10). Abundance of CYP19A1 mRNA was positively correlated with FBN1 (r=0.55, P<0.05) and OR4M1 mRNA (r=0.50, P<0.05). In Experiment 2, there was a treatment×day interaction (P<0.10) for follicle size and growth rate of follicles. Cows treated with asprosin had a higher growth rate from Day 1 to 2 (1.09±0.39 to 2.37±0.32 mm/day) than placebo cows (1.74±0.55 to 1.05±0.61 mm/day) after injection. Most of the follicles from both treatment groups ovulated 3 days post injection. These findings suggest that FBN1 (and thus asprosin) are present in buffalo GC and may be developmentally expressed. Also, asprosin may induce follicular growth when given invivo. Whether these proteins directly regulate aromatase expression, and therefore oestradiol production, during follicle development will require further study.

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Attanasio, M., I. Lapini, L. Evangelisti, L. Lucarini, B. Giusti, MC Porciani, R. Fattori, et al. "FBN1 mutation screening of patients with Marfan syndrome and related disorders: detection of 46 novel FBN1 mutations." Clinical Genetics 74, no. 1 (April 23, 2008): 39–46. http://dx.doi.org/10.1111/j.1399-0004.2008.01007.x.

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Lim, Gregory B. "FBN1 mutation affects survival in Marfan syndrome." Nature Reviews Cardiology 13, no. 3 (February 4, 2016): 123. http://dx.doi.org/10.1038/nrcardio.2016.16.

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Halliday, D., S. Hutchinson, S. Kettle, P. A. Handford, H. Firth, and P. Wordsworth. "Molecular analysis of eight mutations in FBN1." Human Genetics 105, no. 6 (December 14, 1999): 587–97. http://dx.doi.org/10.1007/s004390051150.

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Halliday, D., S. Hutchinson, S. Kettle, H. Firth, P. Wordsworth, and P. A. Handford. "Molecular analysis of eight mutations in FBN1." Human Genetics 105, no. 6 (November 17, 1999): 587–97. http://dx.doi.org/10.1007/s004399900190.

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Ashvetiya, Tamara, Sherry X. Fan, Yi-Ju Chen, Charles H. Williams, Jeffery R. O’Connell, James A. Perry, and Charles C. Hong. "Identification of novel genetic susceptibility loci for thoracic and abdominal aortic aneurysms via genome-wide association study using the UK Biobank Cohort." PLOS ONE 16, no. 9 (September 1, 2021): e0247287. http://dx.doi.org/10.1371/journal.pone.0247287.

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Background Thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA) are known to have a strong genetic component. Methods and results In a genome-wide association study (GWAS) using the UK Biobank, we analyzed the genomes of 1,363 individuals with AAA compared to 27,260 age, ancestry, and sex-matched controls (1:20 case:control study design). A similar analysis was repeated for 435 individuals with TAA compared to 8,700 controls. Polymorphism with minor allele frequency (MAF) >0.5% were evaluated. We identified novel loci near LINC01021, ATOH8 and JAK2 genes that achieved genome-wide significance for AAA (p-value <5x10-8), in addition to three known loci. For TAA, three novel loci in CTNNA3, FRMD6 and MBP achieved genome-wide significance. There was no overlap in the genes associated with AAAs and TAAs. Additionally, we identified a linkage group of high-frequency variants (MAFs ~10%) encompassing FBN1, the causal gene for Marfan syndrome, which was associated with TAA. In FinnGen PheWeb, this FBN1 haplotype was associated with aortic dissection. Finally, we found that baseline bradycardia was associated with TAA, but not AAA. Conclusions Our GWAS found that AAA and TAA were associated with distinct sets of genes, suggesting distinct underlying genetic architecture. We also found association between baseline bradycardia and TAA. These findings, including JAK2 association, offer plausible mechanistic and therapeutic insights. We also found a common FBN1 linkage group that is associated with TAA and aortic dissection in patients who do not have Marfan syndrome. These FBN1 variants suggest shared pathophysiology between Marfan disease and sporadic TAA.

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Baudhuin, Linnea M., Katrina E. Kotzer, and Susan A. Lagerstedt. "Decreased frequency of FBN1 missense variants in Ghent criteria-positive Marfan syndrome and characterization of novel FBN1 variants." Journal of Human Genetics 60, no. 5 (February 5, 2015): 241–52. http://dx.doi.org/10.1038/jhg.2015.10.

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Phokaew, Chureerat, Rekwan Sittiwangkul, Kanya Suphapeetiporn, and Vorasuk Shotelersuk. "Double heterozygous variants in FBN1 and FBN2 in a Thai woman with Marfan and Beals syndromes." European Journal of Medical Genetics 63, no. 9 (September 2020): 103982. http://dx.doi.org/10.1016/j.ejmg.2020.103982.

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Biswas, Tonmoy. "Mutation in Genes FBN1, AKT1, and LMNA: Marfan Syndrome, Proteus Syndrome, and Progeria Share Common Systemic Involvement." International Journal of Medical Students 3, no. 2 (March 19, 2015): 92–101. http://dx.doi.org/10.5195/ijms.2015.124.

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Genetic mutations are becoming more deleterious day by day. Mutations of Genes named FBN1, AKT1, LMNA result specific protein malfunction that in turn commonly cause Marfan syndrome, Proteus syndrome, and Progeria, respectively. Articles about these conditions have been reviewed in PubMed and Google scholar with a view to finding relevant clinical features. Precise keywords have been used in search for systemic involvement of FBN1, AKT1, and LMNA gene mutations. It has been found that Marfan syndrome, Proteus syndrome, and Progeria commonly affected musculo-skeletal system, cardiovascular system, eye, and nervous system. Not only all of them shared identical systemic involvement, but also caused several very specific anomalies in various parts of the body. In spite of having some individual signs and symptoms, the mutual manifestations were worth mentioning. Moreover, all the features of the mutations of all three responsible genes had been co-related and systemically mentioned in this review. There can be some mutual properties of the genes FBN1, AKT1, and LMNA or in their corresponding proteins that result in the same presentations. This study may progress vision of knowledge regarding risk factors, patho-physiology, and management of these conditions, and relation to other mutations.

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Wang, Yueli, Xiaoyan Li, Rongjuan Li, Ya Yang, and Jie Du. "Identification of Novel Causal FBN1 Mutations in Pedigrees of Marfan Syndrome." International Journal of Genomics 2018 (2018): 1–8. http://dx.doi.org/10.1155/2018/1246516.

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Marfan syndrome (MFS) is an autosomal dominant genetic disorder of the connective tissue, typically characteristic of cardiovascular manifestations, valve prolapse, left ventricle enlargement, and cardiac failure. Fibrillin-1 (FBN1) is the causative gene in the pathogenesis of MFS. Patients with different FBN1 mutations often present more considerable phenotypic variation. In the present study, three affected MFS pedigrees were collected for genetic analysis. Using next-generation sequencing (NGS) technologies, 3 novel frameshift pathogenic mutations which are cosegregated with affected subjects in 3 pedigrees were identified. These novel mutations provide important diagnostic and therapeutic insights for precision medicine in MFS, especially regarding the lethal cardiovascular events.

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Nistala, Harikiran, Sui Lee-Arteaga, Silvia Smaldone, Gabriella Siciliano, Luca Carta, Robert N. Ono, Gerhard Sengle, et al. "Fibrillin-1 and -2 differentially modulate endogenous TGF-β and BMP bioavailability during bone formation." Journal of Cell Biology 190, no. 6 (September 20, 2010): 1107–21. http://dx.doi.org/10.1083/jcb.201003089.

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Extracellular regulation of signaling by transforming growth factor (TGF)–β family members is emerging as a key aspect of organ formation and tissue remodeling. In this study, we demonstrate that fibrillin-1 and -2, the structural components of extracellular microfibrils, differentially regulate TGF-β and bone morphogenetic protein (BMP) bioavailability in bone. Fibrillin-2–null (Fbn2−/−) mice display a low bone mass phenotype that is associated with reduced bone formation in vivo and impaired osteoblast maturation in vitro. This Fbn2−/− phenotype is accounted for by improper activation of latent TGF-β that selectively blunts expression of osterix, the transcriptional regulator of osteoblast maturation, and collagen I, the structural template for bone mineralization. Cultured osteoblasts from Fbn1−/− mice exhibit improper latent TGF-β activation as well, but mature faster because of increased availability of otherwise matrix-bound BMPs. Additional in vitro evidence excludes a direct role of microfibrils in supporting mineral deposition. Together, these findings identify the extracellular microfibrils as critical regulators of bone formation through the modulation of endogenous TGF-β and BMP signaling.

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van Dijk, Christian G. M., Laura Louzao-Martinez, Elise van Mulligen, Bart Boermans, Jeroen A. A. Demmers, Thierry P. P. van den Bosch, Marie-José Goumans, Dirk J. Duncker, Marianne C. Verhaar, and Caroline Cheng. "Extracellular Matrix Analysis of Human Renal Arteries in Both Quiescent and Active Vascular State." International Journal of Molecular Sciences 21, no. 11 (May 30, 2020): 3905. http://dx.doi.org/10.3390/ijms21113905.

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In vascular tissue engineering strategies, the addition of vascular-specific extracellular matrix (ECM) components may better mimic the in vivo microenvironment and potentially enhance cell–matrix interactions and subsequent tissue growth. For this purpose, the exact composition of the human vascular ECM first needs to be fully characterized. Most research has focused on characterizing ECM components in mature vascular tissue; however, the developing fetal ECM matches the active environment required in vascular tissue engineering more closely. Consequently, we characterized the ECM protein composition of active (fetal) and quiescent (mature) renal arteries using a proteome analysis of decellularized tissue. The obtained human fetal renal artery ECM proteome dataset contains higher levels of 15 ECM proteins versus the mature renal artery ECM proteome, whereas 16 ECM proteins showed higher levels in the mature tissue compared to fetal. Elastic ECM proteins EMILIN1 and FBN1 are significantly enriched in fetal renal arteries and are mainly produced by cells of mesenchymal origin. We functionally tested the role of EMILIN1 and FBN1 by anchoring the ECM secreted by vascular smooth muscle cells (SMCs) to glass coverslips. This ECM layer was depleted from either EMILIN1 or FBN1 by using siRNA targeting of the SMCs. Cultured endothelial cells (ECs) on this modified ECM layer showed alterations on the transcriptome level of multiple pathways, especially the Rho GTPase controlled pathways. However, no significant alterations in adhesion, migration or proliferation were observed when ECs were cultured on EMILIN1- or FNB1-deficient ECM. To conclude, the proteome analysis identified unique ECM proteins involved in the embryonic development of renal arteries. Alterations in transcriptome levels of ECs cultured on EMILIN1- or FBN1-deficient ECM showed that these candidate proteins could affect the endothelial (regenerative) response.

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Yagi, Hiroki, Masaru Hatano, Norifumi Takeda, Saori Harada, Yukari Suzuki, Yuki Taniguchi, Yukako Shintani, et al. "Congenital Contractural Arachnodactyly without FBN1 or FBN2 Gene Mutations Complicated by Dilated Cardiomyopathy." Internal Medicine 54, no. 10 (2015): 1237–41. http://dx.doi.org/10.2169/internalmedicine.54.4280.

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Shin, Seung Jae, and Hiromi Yanagisawa. "Recent updates on the molecular network of elastic fiber formation." Essays in Biochemistry 63, no. 3 (August 8, 2019): 365–76. http://dx.doi.org/10.1042/ebc20180052.

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Abstract Elastic fibers confer elasticity and recoiling to tissues and organs and play an essential role in induction of biochemical responses in a cell against mechanical forces derived from the microenvironment. The core component of elastic fibers is elastin (ELN), which is secreted as the monomer tropoelastin from elastogenic cells, and undergoes self-aggregation, cross-linking and deposition on to microfibrils, and assemble into insoluble ELN polymers. For elastic fibers to form, a microfibril scaffold (primarily formed by fibrillin-1 (FBN1)) is required. Numerous elastic fiber-associated proteins are involved in each step of elastogenesis and they instruct and/or facilitate the elastogenesis processes. In this review, we designated five proteins as key molecules in elastic fiber formation, including ELN, FBN1, fibulin-4 (FBLN4), fibulin-5 (FBLN5), and latent TGFβ-binding protein-4 (LTBP4). ELN and FBN1 serve as building blocks for elastic fibers. FBLN5, FBLN4 and LTBP4 have been demonstrated to play crucial roles in elastogenesis through knockout studies in mice. Using these molecules as a platform and expanding the elastic fiber network through the generation of an interactome map, we provide a concise review of elastogenesis with a recent update as well as discuss various biological functions of elastic fiber-associated proteins beyond elastogenesis in vivo.

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Arnaud, Pauline, Hélène Morel, Olivier Milleron, Laurent Gouya, Christine Francannet, Antoine Da Costa, Carine Le Goff, Guillaume Jondeau, Catherine Boileau, and Nadine Hanna. "Unsuspected somatic mosaicism for FBN1 gene contributes to Marfan syndrome." Genetics in Medicine 23, no. 5 (January 25, 2021): 865–71. http://dx.doi.org/10.1038/s41436-020-01078-6.

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Abstract Purpose Individuals with mosaic pathogenic variants in the FBN1 gene are mainly described in the course of familial screening. In the literature, almost all these mosaic individuals are asymptomatic. In this study, we report the experience of our team on more than 5,000 Marfan syndrome (MFS) probands. Methods Next-generation sequencing (NGS) capture technology allowed us to identify five cases of MFS probands who harbored a mosaic pathogenic variant in the FBN1 gene. Results These five sporadic mosaic probands displayed classical features usually seen in Marfan syndrome. Combined with the results of the literature, these rare findings concerned both single-nucleotide variants and copy-number variations. Conclusion This underestimated finding should not be overlooked in the molecular diagnosis of MFS patients and warrants an adaptation of the parameters used in bioinformatics analyses. The five present cases of symptomatic MFS probands harboring a mosaic FBN1 pathogenic variant reinforce the fact that apparently asymptomatic mosaic parents should have a complete clinical examination and a regular cardiovascular follow-up. We advise that individuals with a typical MFS for whom no single-nucleotide pathogenic variant or exon deletion/duplication was identified should be tested by NGS capture panel with an adapted variant calling analysis.

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Hilhorst-Hofstee, Yvonne, Ben CJ Hamel, Joke BGM Verheij, Marry EB Rijlaarsdam, Grazia MS Mancini, Jan M. Cobben, Cindy Giroth, et al. "The clinical spectrum of complete FBN1 allele deletions." European Journal of Human Genetics 19, no. 3 (November 10, 2010): 247–52. http://dx.doi.org/10.1038/ejhg.2010.174.

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Thue, T. D., and F. C. Buchanan. "Linkage mapping of FBN1 to bovine chromosome 10." Animal Genetics 34, no. 2 (March 21, 2003): 150. http://dx.doi.org/10.1046/j.1365-2052.2003.00965_4.x.

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Buoni, S., R. Zannolli, F. Macucci, S. Ansaldi, M. Grasso, E. Arbustini, and A. Fois. "The FBN1 (R2726W) mutation is not fully penetrant." Annals of Human Genetics 68, no. 6 (December 8, 2004): 633–38. http://dx.doi.org/10.1046/j.1529-8817.2004.00113.x.

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Journal articles on the topic 'FBN1'

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