[Clinical phenotype and genetic analysis of six Chinese patients affected with Acromicric dysplasia due to variants of FBN1 gene].

OBJECTIVE: To retrospectively analyze the clinical and genetic characteristics of six patients with Acromicric dysplasia due to variants of the FBN1 gene. METHODS: Six patients who had visited the Affiliated Hospital of Qingdao University between February 2018 and October 2020 were selected as the study subjects. Clinical data of the patients were collected. High-throughput sequencing was carried out. And candidate variants were verified by Sanger sequencing. RESULTS: All of the six patients had presented with severe short stature (< 3s), brachydactyly, short and broad hands and feet. Other manifestations included joint stiffness, facial dysmorphism, delayed bone age, liver enlargement, coracoid femoral head, and lumbar lordosis. Genetic testing revealed that all had harbored heterozygous variants of the FBN1 gene. Patient 1 had harbored a c.5183C>T (p.A1728V) missense variant in exon 42, which had derived from his father (patient 2). Patient 3 had harbored a c.5284G>A (p.G1762S) missense variant in exon 43, which had derived from her mother (patient 4). Patient 5 had harbored a c.5156G>T (p.C1719F) missense variant in exon 42, which was de novo in origin. Patient 6 had harbored a c.5272G>T (p.D1758Y) missense variant in exon 43, which was also de novo in origin. The variants carried by patients 1, 3 and 6 were known to be pathogenic. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the FBN1: c.5156G>T was rated as a pathogenic variant (PS2+PM1+PM2_Supporting +PM5+PP3). CONCLUSION: All of the six patients had severe short stature and a variety of other clinical manifestations, which may be attributed to the variants of the FBN1 gene.

[Retracted] Inhibition airway remodeling and transforming growth factor­ß1/Smad signaling pathway by astragalus extract in asthmatic mice.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that the P­smad2 western blotting data shown in Fig. 7 were strikingly similar to data appearing in different form (namely, the bands appeared in the reverse orientation) in Fig. 4A in another article [Lv Z­D, Na D, Liu F­N, Du Z­M, Sun Z, Li Z, Ma X­Y, Wang Z­N and Xu H­M: Induction of gastric cancer cell adhesion through transforming growth factor­beta1­mediated peritoneal fibrosis. J Exp Clin Cancer Res 29: 139, 2010], which was written by mostly different authors at different research institutes (the author Zheng­Hai Qu did appear as an author on both papers). Owing to the fact that the contentious data in the above article had already been published prior to its submission to International Journal of Molecular Medicine, and due to a lack of overall confidence in the presented data, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they accepted the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Molecular Medicine 29: 564­568, 2012; DOI: 10.3892/ijmm.2011.868].

A Review of Three Chinese Cases of Acromicric/Geleophysic Dysplasia with FBN1 Mutations.

OBJECTIVE: This study aims to explore the clinical features and molecular diagnosis of FBN1-related acromelic dysplasia in Chinese patients. METHODS: The clinical and genetic features of three FBN1-related acromicric dysplasia (AD)/geleophysic dysplasia (GD) Chinese patients from two families were reviewed, and comprehensive medical evaluations were performed. Targeted next-generation sequencing was used to detect genetic mutations associated with short statures, including FBN1. Sanger sequencing was used to determine the de novo mutation origin. RESULTS: Patient 1 presented with short stature, short and stubby hands and feet, mild facial dysmorphism, hepatomegaly, delayed bone age and beak-like femoral heads. Patient 2 and this patient's father merely presented with short stature, wide and short hands, and beak-like femoral heads. One novel mutation, c.5272G>T(p.D1758Y), and one known mutation, c.5183C>T(p.A1728V), were identified in these patients. CONCLUSION: The clinical features varied among these patients. The variant c.5272G>T(p.D1758Y) is a novel mutation.

MiR-448-5p inhibits TGF-ß1-induced epithelial-mesenchymal transition and pulmonary fibrosis by targeting Six1 in asthma.

MicroRNAs (miRNAs) are small yet versatile gene tuners that regulate a variety of cellular processes, including cell growth and proliferation. The aim of this study was to explore how miR-448-5p affects airway remodeling and transforming growth factor-ß1 (TGF-ß1)-stimulated epithelial-mesenchymal transition (EMT) by targeting Sine oculis homeobox homolog 1 (Six1) in asthma. Asthmatic mice models with airway remodeling were induced with ovalbumin solution. MiRNA expression was evaluated using quantitative real-time polymerase chain reaction. Transfection studies of bronchial epithelial cells were performed to determine the target genes. A luciferase reporter assay system was applied to identify whether Six1 is a target gene of miR-448-5p. In the current study, we found that miR-448-5p was dramatically decreased in lung tissues of asthmatic mice and TGF-ß1-stimulated bronchial epithelial cells. In addition, the decreased level of miR-448-5p was closely associated with the increased expression of Six1. Overexpression of miR-448-5p decreased Six1 expression and, in turn, suppressed TGF-ß1-mediated EMT and fibrosis. Next, we predicted that Six1 was a potential target gene of miR-448-5p and demonstrated that miR-448-5p could directly target Six1. An SiRNA targeting Six1 was sufficient to suppress TGF-ß1-induced EMT and fibrosis in 16HBE cells. Furthermore, the overexpression of Six1 partially reversed the protective effect of miR-448-5p on TGF-ß1-mediated EMT and fibrosis in bronchial epithelial cells. Taken together, the miR-448-5p/TGF-ß1/Six1 link may play roles in the progression of EMT and pulmonary fibrosis in asthma.

Transforming growth factor-ß1 induces bronchial epithelial cells to mesenchymal transition by activating the Snail pathway and promotes airway remodeling in asthma.

Airway remodeling is characterized by airway wall thickening, subepithelial fibrosis, increased smooth muscle mass, angiogenesis and an increase in mucous glands, which may lead to a chronic and obstinate asthma with pulmonary function depression. In the present study, we observed substantially thickened lung tissue with extensive fibrosis in ovalbumin-sensitized mice, which was interrelated with transforming growth factor-ß1 (TGF-ß1) expression in bronchoalveolar lavage fluid. In vitro experiments further demonstrated that TGF-ß1 resulted in epithelial-mesenchymal transition (EMT) in bronchial epithelial cells, which was characterized by the expected decrease in E-cadherin expression and the increase in vimentin and α-smooth muscle actin expression, as well as the associated increase in Snail expression at mRNA and protein levels. Furthermore, the downregulation of Snail by small interfering RNA (siRNA) attenuated the TGF-ß1­induced EMT-like phenotype. Of note, a significantly increased synthesis of fibronectin was observed following TGF-ß1 treatment, which further supported the hypothesis that EMT is a pivotal factor in peribronchial fibrosis. In combination, the results indicated that myofibroblasts deriving from bronchial epithelial cells via EMT may contribute to peribronchial fibrosis and that Snail may be an important factor in this phenomenon.

Inhibition airway remodeling and transforming growth factor-ß1/Smad signaling pathway by astragalus extract in asthmatic mice.

Airway remodeling is characterized by airway wall thickening, subepithelial fibrosis, increased smooth muscle mass, angiogenesis and increased mucous glands, which can lead to a chronic and obstinate asthma with pulmonary function depression. In the present study, we investigated whether the astragalus extract inhibits airway remodeling in a mouse asthma model and observed the effects of astragalus extract on the transforming growth factor-ß1 (TGF-ß1)/Smad signaling pathway in ovalbumin-sensitized mice. Mice were sensitized and challenged by ovalbumin to establish a model of asthma. Treatments included the astragalus extract and budesonide. Lung tissues were obtained for hematoxylin and eosin staining and Periodic acid-Schiff staining after the final ovalbumin challenge. Levels of TGF-ß1 were assessed by immunohistology and ELISA, levels of TGF-ß1 mRNA were measured by RT-PCR, and levels of P-Smad2/3 and T-Smad2/3 were assessed by western blotting. Astragalus extract and budesonide reduced allergen-induced increases in the thickness of bronchial airway and mucous gland hypertrophy, goblet cell hyperplasia and collagen deposition. Levels of lung TGF-ß1, TGF-ß1 mRNA and P-Smad2/3 were significantly reduced in mice treated with astragalus extract and budesonide. Astragalus extract improved asthma airway remodeling by inhibiting the expression of the TGF-ß1/Smad signaling pathway, and may be a potential drug for the treatment of patients with a severe asthma airway.