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      Exome Sequencing Identified a Novel FBN2 Mutation in a Chinese Family with Congenital Contractural Arachnodactyly


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          Congenital contractural arachnodactyly (CCA) is an autosomal dominant disorder of connective tissue. CCA is characterized by arachnodactyly, camptodactyly, contrature of major joints, scoliosis, pectus deformities, and crumpled ears. The present study aimed to identify the genetic cause of a three-generation Chinese family with CCA. We successfully identified a novel missense mutation p.G1145D in the fibrillin-2 ( FBN2) gene as the pathogenic mutation by whole exome sequencing (WES). The p.G1145D mutation occurs in the 12th calcium-binding epidermal growth factor-like (cbEGF) domain. The p.G1145D mutation caused a hydrophobic to hydrophilic substitution, altering the amino acid property from neutral to acidic. Three-dimensional structural analysis showed that this mutation could alter the conformation of the residue side chain, thereby producing steric clashes with spatially adjacent residues, disrupting the formation of H bonds and causing folding destabilization. Therefore, this amino acid appears to play an important role in the structure and function of FBN2. Our results may also provide new insights into the cause and diagnosis of CCA and may have implications for genetic counseling and clinical management.

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          Most cited references13

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          SMART: recent updates, new developments and status in 2015

          SMART (Simple Modular Architecture Research Tool) is a web resource (http://smart.embl.de/) providing simple identification and extensive annotation of protein domains and the exploration of protein domain architectures. In the current version, SMART contains manually curated models for more than 1200 protein domains, with ∼200 new models since our last update article. The underlying protein databases were synchronized with UniProt, Ensembl and STRING, bringing the total number of annotated domains and other protein features above 100 million. SMART's ‘Genomic’ mode, which annotates proteins from completely sequenced genomes was greatly expanded and now includes 2031 species, compared to 1133 in the previous release. SMART analysis results pages have been completely redesigned and include links to several new information sources. A new, vector-based display engine has been developed for protein schematics in SMART, which can also be exported as high-resolution bitmap images for easy inclusion into other documents. Taxonomic tree displays in SMART have been significantly improved, and can be easily navigated using the integrated search engine.
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            Rapid automatic detection and alignment of repeats in protein sequences.

            Many large proteins have evolved by internal duplication and many internal sequence repeats correspond to functional and structural units. We have developed an automatic algorithm, RADAR, for segmenting a query sequence into repeats. The segmentation procedure has three steps: (i) repeat length is determined by the spacing between suboptimal self-alignment traces; (ii) repeat borders are optimized to yield a maximal integer number of repeats, and (iii) distant repeats are validated by iterative profile alignment. The method identifies short composition biased as well as gapped approximate repeats and complex repeat architectures involving many different types of repeats in the query sequence. No manual intervention and no prior assumptions on the number and length of repeats are required. Comparison to the Pfam-A database indicates good coverage, accurate alignments, and reasonable repeat borders. Screening the Swissprot database revealed 3,000 repeats not annotated in existing domain databases. A number of these repeats had been described in the literature but most were novel. This illustrates how in times when curated databases grapple with ever increasing backlogs, automatic (re)analysis of sequences provides an efficient way to capture this important information.
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              Linkage of Marfan syndrome and a phenotypically related disorder to two different fibrillin genes.

              Marfan syndrome (MFS), one of the most common genetic disorders of connective tissue, is characterized by skeletal, cardiovascular and ocular abnormalities. The incidence of the disease is about 1 in 20,000, with life expectancy severely reduced because of cardiovascular complications. As the underlying defect is unknown, MFS diagnosis is based solely on clinical criteria. Certain phenotypic features of MFS are also shared by other conditions, which may be genetically distinct entities although part of a clinical continuum. Immunohistochemical studies have implicated fibrillin, a major component of elastin-associated microfibrils, in MFS aetiology. Genetic linkage analysis with random probes has independently localized the MFS locus to chromosome 15. Here we report that these two experimental approaches converge with the cloning and mapping of the fibrillin gene to chromosome 15q15-21, and with the establishment of linkage to MFS. We also isolated a second fibrillin gene and mapped it to chromosome 5q23-31. We linked this novel gene to a condition, congenital contractural arachnodactyly, that shares some of the features of MFS. Thus, the cosegregation of two related genes with two related syndromes implies that fibrillin mutations are likely to be responsible for different MFS phenotypes.

                Author and article information

                Role: Academic Editor
                Int J Mol Sci
                Int J Mol Sci
                International Journal of Molecular Sciences
                05 April 2017
                April 2017
                : 18
                : 4
                : 626
                [1 ]Department of Laboratory Medicine, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China; youguoling@ 123456126.com (G.Y.); wangbao@ 123456scmc.com.cn (B.W.)
                [2 ]Department of Laboratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200127, China; zubailing@ 123456126.com
                [3 ]Department of Clinical Laboratory, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 200127, China
                [4 ]Department of Pediatric Orthopedics, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China; wangzhigang@ 123456scmc.com.cn
                Author notes
                [* ]Correspondence: xu.yunlan@ 123456hotmail.com (Y.X.); qihuafu@ 123456126.com (Q.F.); Tel.: +86-21-3862-5808 (Y.X.); +86-21-3862-5568 (Q.F.); Fax: +86-21-5875-6923 (Y.X. & Q.F.)

                These authors contributed equally to this work.

                © 2017 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                : 06 February 2017
                : 10 March 2017

                Molecular biology
                congenital contractural arachnodactyly,exome sequencing,fibrillin-2 (fbn2) gene


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