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Linxin Jiang, Dingding Zhang, Ying Xiao, Qi Wang, Bo Gong, Xiaoxin Guo, Maomin Huang, Zhenglin Yang
OBJECTIVE: To detect potential mutations of fibrillin-1 (FBN1) gene in a child with Marfan syndrome (MFS) and explore its molecular pathogenesis. METHODS: The 66 exons of the FBN1 gene were analyzed by direct sequencing. SIFT and PolyPhen-2 were used to predict the structural and functional changes at the protein level. RESULTS: A novel heterozygous mutation c.3998 G>A (p.Cys1333Tyr) was found in exon 32 in the child. The same mutation was not found among his unaffected family members and 683 healthy controls...
June 10, 2018: Zhonghua Yi Xue Yi Chuan Xue za Zhi, Zhonghua Yixue Yichuanxue Zazhi, Chinese Journal of Medical Genetics
Rebecca Bell, N Remi Gendron, Matthew Anderson, Evan L Flatow, Nelly Andarawis-Puri
Tendons are ineffective at repairing sub-rupture fatigue injuries. Accordingly, we evaluated whether an exercise protocol that we have previously found to decrease structural damage kinks in fatigue damaged tendons, leads to improvement in mechanical properties. We hypothesized that exercise that promotes repair of fatigue damage will decrease apoptosis and increase the population of myofibroblasts. Rat patellar tendons underwent in vivo fatigue loading for 500 or 7200 cycles. Animals resumed cage activity for 2-weeks, then either remained cage active or began treadmill running until sacrifice at 4- or 10-weeks post-fatigue loading...
June 12, 2018: Scientific Reports
Christopher Yu, Richmond W Jeremy
Marfan syndrome is consequent upon mutations in FBN1 , which encodes the extracellular matrix microfibrillar protein fibrillin-1. The phenotype is characterised by development of thoracic aortic aneurysm. Current understanding of the pathogenesis of aneurysms in Marfan syndrome focuses upon abnormal vascular smooth muscle cell signalling through the transforming growth factor beta (TGFβ) pathway. Angiotensin II (Ang II) can directly induce aortic dilatation and also influence TGFβ synthesis and signalling...
March 2018: IJC Heart & Vasculature
Laura Muiño-Mosquera, Felke Steijns, Tjorven Audenaert, Ilse Meerschaut, Anne De Paepe, Wouter Steyaert, Sofie Symoens, Paul Coucke, Bert Callewaert, Marjolijn Renard, Julie De Backer
BACKGROUND: The introduction of next-generation sequencing techniques has substantially increased the identification of new genetic variants and hence the necessity of accurate variant interpretation. In 2015, the American College of Medical Genetics and Genomics and the Association for Molecular Pathology proposed new variant interpretation guidelines. Gene-specific characteristics were, however, not considered, sometimes leading to inconsistent variant interpretation. METHODS: To allow a more uniform interpretation of variants in the FBN1 (fibrillin-1) gene, causing Marfan syndrome, we tailored these guidelines to this gene and disease...
June 2018: Circulation. Genomic and precision medicine
Yueli Wang, Xiaoyan Li, Rongjuan Li, Ya Yang, Jie Du
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...
2018: International Journal of Genomics
Miao Zhang, Yaqi Zhou, Yang Peng, Lijun Jin
The present report aimed to evaluate the results of screen mutations of the fibrillin (FBN) 1 gene and analyze the symptoms in one Chinese patient clinically diagnosed with Marfan syndrome (MFS). Clinical data were collected and FBN1 gene sequencing was performed. Genomic DNA was extracted from the blood sample of the patient. All 65 exons were screened using a polymerase chain reaction assay. The diagnosis of MFS was confirmed via identification of symptoms presenting in the skeletal system (arachnodactyly, walker wrist and thumb signs) and the ocular system (ectopia lentis), in addition to a positive family history...
May 22, 2018: Molecular Medicine Reports
Ahmed Mohammad, Haytham Helmi, Paldeep S Atwal
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...
2018: Case Reports in Genetics
Youn Hee Jee, Jeffrey Baron, Ola Nilsson
PURPOSE OF REVIEW: Genome-wide approaches including genome-wide association studies as well as exome and genome sequencing represent powerful new approaches that have improved our ability to identify genetic causes of human disorders. The purpose of this review is to describe recent advances in the genetic causes of short stature. RECENT FINDINGS: In addition to SHOX deficiency which is one of the most common causes of isolated short stature, PAPPA2, aggrecan, C-natriuretic peptide, C-type natriuretic peptide (CNP), NPR2 (CNP receptor), protein tyrosine phosphatase, non-receptor type 11(PTPN11) (and other rasopathies), Fibrillin 1 (FBN1), IHH and BMP2 have been identified in isolated growth disorders with or without other mild skeletal findings...
May 18, 2018: Current Opinion in Pediatrics
Thomas Ratschiller, Hannes Müller, Thomas Schachner, Franz Fellner, Gregor Sulzbacher, Andreas Zierer
Degenerative femoral artery aneurysms are uncommon and often associated with aneurysm in other distributions. We report a case of a 68-year-old man with multianeurysmal disease involving the aorta, iliac, femoral, and popliteal arteries managed interdisciplinary by stent-graft placement and open surgical repair. Genetic testing revealed a variant in the FBN2 gene encoding fibrillin-2, an important component of microfibrils. We detail arterial reconstruction of the femoral artery and discuss incidence, diagnosis, and therapy of femoral artery aneurysms...
January 1, 2018: Vascular and Endovascular Surgery
Paola Zigrino, Gerhard Sengle
Supramolecular networks composed of multi-domain ECM proteins represent intricate cellular microenvironments which are required to balance tissue homeostasis and direct remodeling. Structural deficiency in ECM proteins results in imbalances in ECM-cell communication resulting often times in fibrotic reactions. To understand how individual components of the ECM integrate communication with the cell surface by presenting growth factors or providing fine-tuned biomechanical properties is mandatory for gaining a better understanding of disease mechanisms in the quest for new therapeutic approaches...
April 27, 2018: Advanced Drug Delivery Reviews
Bruna Romana-Souza, Welker Silva-Xavier, Andréa Monte-Alto-Costa
Stress-induced oxidative damage and the inflammatory response lead to degradation of collagen and elastic fibers and wrinkle formation. Topical retinol (or vitamin A) can be a strategy to attenuate the effects of stress in skin since it promotes collagen and elastic fiber production and reduces protease synthesis. This study investigated the effect of topical retinol in stressed human skin using in vivo and ex vivo models. Human skin explants were treated with high levels of epinephrine (as observed in stressed patients) and topically with retinol for 13 days...
April 28, 2018: Experimental Dermatology
Nisamanee Charoenchon, Lesley E Rhodes, Suzanne M Pilkington, Mark D Farrar, Rachel E B Watson
Long-term exposure of human skin to ultraviolet radiation (UVR) in sunlight negatively impacts its appearance and function with photoaged skin having a characteristic leathery, rough appearance, with deep wrinkles. These clinical features of photodamage are thought to result from UVR-induced remodelling of the dermal extracellular matrix, particularly the elastic fibre system. There are few in vivo human data on the impact of acute UVR exposure on this fibre system and particularly solar-simulated radiation (SSR)-mediated effects...
April 26, 2018: Photochemical & Photobiological Sciences
Caasy Thomas-Porch, Jie Li, Fabiana Zanata, Elizabeth C Martin, Nicholas Pashos, Kaylynn Genemaras, J Nicholas Poche, Nicholas P Totaro, Melyssa R Bratton, Dina Gaupp, Trivia Frazier, Xiying Wu, Lydia Masako Ferreira, Weidong Tian, Guangdi Wang, Bruce A Bunnell, Lauren Flynn, Daniel Hayes, Jeffrey M Gimble
Decellularized human adipose tissue has potential clinical utility as a processed biological scaffold for soft tissue cosmesis, grafting and reconstruction. Adipose tissue decellularization has been accomplished using enzymatic-, detergent-, and/or solvent-based methods. To examine the hypothesis that distinct decellularization processes may yield scaffolds with differing compositions, the current study employed mass spectrometry to compare the proteomes of human adipose-derived matrices generated through three independent methods combining enzymatic-, detergent-, and/or solvent-based steps...
April 25, 2018: Journal of Biomedical Materials Research. Part A
Taisuke Masuda, Mitsuhiro Ukiki, Yuka Yamagishi, Michiya Matsusaki, Mitsuru Akashi, Utako Yokoyama, Fumihito Arai
Although there is a great need for suitable vascular replacements in clinical practice, much progress needs to be made toward the development of a fully functional tissue-engineered construct. We propose a fabrication method of engineered tubular tissue for small blood vessels via a layer-by-layer cellular assembly technique using mouse smooth muscle cells, the construction of a poly-(l-lactide-co-ε-caprolactone) (PLCL) scaffold, and integration in a microfluidic perfusion culture system. The cylindrical PLCL scaffold is incised, expanded, and its surface is laminated with the cell layers...
June 20, 2018: Journal of Biotechnology
Rahel Schnellmann, Ragna Sack, Daniel Hess, Douglas S Annis, Deane F Mosher, Suneel S Apte, Ruth Chiquet-Ehrismann
Secreted and cell-surface proteases are major mediators of extracellular matrix (ECM) turnover, but their mechanisms and regulatory impact are poorly understood. We developed a mass spectrometry approach using a cell-free ECM produced in vitro to identify fibronectin (FN) as a novel substrate of the secreted metalloprotease ADAMTS16. ADAMTS16 cleaves FN between its (I)5 and (I)6 modules, releasing the N-terminal 30 kDa heparin-binding domain essential for FN self-assembly. ADAMTS16 impairs FN fibrillogenesis as well as fibrillin-1 and tenascin-C assembly, thus inhibiting formation of a mature ECM by cultured fibroblasts...
April 18, 2018: Molecular & Cellular Proteomics: MCP
Mao Chen, Bing Yao, Qiangbing Yang, Jichao Deng, Yuning Song, Tingting Sui, Lina Zhou, HaoBing Yao, Yuanyuan Xu, Hongsheng Ouyang, Daxin Pang, Zhanjun Li, Liangxue Lai
Various clinical differences have been observed between patients with the FBN1 gene mutation and those with the classical Marfan phenotype. Although FBN1 knockout (KO) or dominant-negative mutant mice are widely used as an animal model for Marfan syndrome (MFS), these mice cannot recapitulate the genotype/phenotype relationship of Marfanoid-progeroid-lipodystrophy (MPL) syndrome, which is caused by a mutation in the C-terminus of fibrillin-1, the penultimate exon of the FBN1 gene. Here, we describe the generation of a rabbit MPL model with C-terminal truncation of fibrillin-1 using a CRISPR/Cas9 system...
April 9, 2018: Disease Models & Mechanisms
Lara Cristóbal, Miguel A Ortega, Ángel Asúnsolo, Beatriz Romero, Melchor Álvarez-Mon, Julia Buján, Andrés A Maldonado, Natalio García-Honduvilla
Despite advances in regenerative medicine and tissue engineering, human skin substitutes remain a clear goal to achieve. Autografts remain the principal clinical option. The long-term changes in dermis, as well as its response after injuries, are not well known. Research in this field has been hindered by a lack of experimental animal models. This study analyzes the architectural dermal scaffold (collagen and elastin fibers plus fibrillin-microfibrils) changes in a model of human skin pressure ulcers in mice...
April 17, 2018: Histology and Histopathology
Neena Philips, Jovinna Chalensouk-Khaosaat, Salvador Gonzalez
Skin aging/photoaging is associated with altered the structure of collagen and elastin fibers, and increased activity of matrix metalloproteinases (MMP) and elastase. Nicotinamide and its derivatives, 2,6-dihydroxynicotinamide, 2,4,5,6-tetrahydroxynicotinamide, and 3-hydroxypicolinamide (collectively niacin derivatives) stimulate fibrillar collagen and heat shock proteins in dermal fibroblasts. The goal of this research was to extend the understanding of the anti-skin aging mechanism of these niacin derivatives through the stimulation of elastin (at the protein and promoter levels), fibrillin (1 and 2) in nonirradiated or ultraviolet (UVA) radiated dermal fibroblasts, and through the direct inhibition of MMP (1, 3, and 9) and elastase activities...
January 2018: Journal of Cosmetic Science
Jun Wang, Wen-Jia Liang, Guang-Tao Min, Hong-Peng Wang, Wei Chen, Nan Yao
Latent transforming growth factor-β-binding protein (LTBP)2 is a member of the fibrillin/LTBP superfamily of extracellular matrix proteins, and has been demonstrated to exhibit tumor-promoting and tumor-suppressive functions in different types of cancer. However, the function of LTBP2 in gastric cancer (GC) remains unknown. The aim of the present study was to investigate the expression and molecular function of LTBP2 in GC, and to evaluate its prognostic value for patients with GC. The results revealed that the expression of LTBP2 was upregulated in GC tissues and cell lines...
June 2018: International Journal of Oncology
Keisuke Handa, Syouta Abe, V Venkata Suresh, Yoshiyasu Fujieda, Masaki Ishikawa, Ai Orimoto, Yoko Kobayashi, Satoru Yamada, Satoko Yamaba, Shinya Murakami, Masahiro Saito
OBJECTIVE: Marfan syndrome (MFS) is a systemic connective tissue disorder caused by insufficient fibrillin-1 (FBN-1), a major component of microfibrils that controls the elasticity and integrity of connective tissues. FBN-1 insufficiency in MFS leads to structural weakness, which causes various tissue disorders, including cardiovascular and periodontal disease. However, the role of FBN-1 insufficiency in the destruction and regeneration of connective tissue has not yet been clarified...
June 2018: Archives of Oral Biology
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