{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T01:50:53Z","timestamp":1768528253342,"version":"3.49.0"},"reference-count":28,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2017,4,5]],"date-time":"2017-04-05T00:00:00Z","timestamp":1491350400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ijms18040626","type":"journal-article","created":{"date-parts":[[2017,4,5]],"date-time":"2017-04-05T10:33:01Z","timestamp":1491388381000},"page":"626","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Exome Sequencing Identified a Novel FBN2 Mutation in a Chinese Family with Congenital Contractural Arachnodactyly"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6051-6303","authenticated-orcid":false,"given":"Guoling","family":"You","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine, Shanghai Children\u2019s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bailing","family":"Zu","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200127, China"},{"name":"Department of Clinical Laboratory, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 200127, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Shanghai Children\u2019s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhigang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pediatric Orthopedics, Shanghai Children\u2019s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunlan","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Pediatric Orthopedics, Shanghai Children\u2019s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qihua","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Shanghai Children\u2019s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2017,4,5]]},"reference":[{"key":"ref_1","unstructured":"Pagon, R.A., Adam, M.P., Ardinger, H.H., Wallace, S.E., Amemiya, A., Bean, L.J.H., Bird, T.D., Ledbetter, N., Mefford, H.C., and Smith, R.J.H. (1993). Congenital contractural arachnodactyly. Genereviews(r), University of Washington."},{"key":"ref_2","first-page":"818","article-title":"Parental somatic and germ-line mosaicism for a FBN2 mutation and analysis of FBN2 transcript levels in dermal fibroblasts","volume":"60","author":"Putnam","year":"1997","journal-title":"Am. J. Hum. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1007\/s004390050777","article-title":"A single mutation that results in an asp to his substitution and partial exon skipping in a family with congenital contractural arachnodactyly","volume":"103","author":"Babcock","year":"1998","journal-title":"Hum. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1007\/s00508-013-0358-7","article-title":"Congenital contractural arachnodactyly (Beals\u2013Hecht syndrome): A rare connective tissue disorder","volume":"125","author":"Jurko","year":"2013","journal-title":"Wien. Klin. Wochenschr."},{"key":"ref_5","first-page":"1027","article-title":"Familial occurrence of typical and severe lethal congenital contractural arachnodactyly caused by missplicing of Exon 34 of fibrillin-2","volume":"59","author":"Wang","year":"1996","journal-title":"Am. J. Hum. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1002\/humu.20794","article-title":"The FBN2 gene: New mutations, locus-specific database (universal mutation database FBN2), and genotype-phenotype correlations","volume":"30","author":"Frederic","year":"2009","journal-title":"Hum. Mutat."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1038\/352330a0","article-title":"Linkage of Marfan syndrome and a phenotypically related disorder to two different fibrillin genes","volume":"352","author":"Lee","year":"1991","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.matbio.2015.09.004","article-title":"Fibrillin microfibrils in bone physiology","volume":"52","author":"Smaldone","year":"2016","journal-title":"Matrix Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1530\/REP-16-0172","article-title":"Regulation of fibrillins and modulators of TGF\u03b2 in fetal bovine and human ovaries","volume":"152","author":"Bastian","year":"2016","journal-title":"Reproduction"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Sengle, G., Carlberg, V., Tufa, S.F., Charbonneau, N.L., Smaldone, S., Carlson, E.J., Ramirez, F., Keene, D.R., and Sakai, L.Y. (2015). Abnormal activation of BMP signaling causes myopathy in FBN2 null mice. PLoS Genet., 11.","DOI":"10.1371\/journal.pgen.1005340"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1083\/jcb.200105046","article-title":"Regulation of limb patterning by extracellular microfibrils","volume":"154","author":"Gayraud","year":"2001","journal-title":"J. Cell Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1086\/520125","article-title":"Effect of mutation type and location on clinical outcome in 1013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: An international study","volume":"81","author":"Faivre","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/S0092-8674(00)81259-3","article-title":"Solution structure of a pair of calcium-binding epidermal growth factor-like domains: Implications for the marfan syndrome and other genetic disorders","volume":"85","author":"Downing","year":"1996","journal-title":"Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"12199","DOI":"10.1074\/jbc.M208266200","article-title":"Solution structure and dynamics of a calcium binding epidermal growth factor-like domain pair from the neonatal region of human fibrillin-1","volume":"278","author":"Smallridge","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1101\/gr.107524.110","article-title":"The genome analysis toolkit: A mapreduce framework for analyzing next-generation DNA sequencing data","volume":"20","author":"McKenna","year":"2010","journal-title":"Genome Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1101\/gr.129684.111","article-title":"Varscan 2: Somatic mutation and copy number alteration discovery in cancer by exome sequencing","volume":"22","author":"Koboldt","year":"2012","journal-title":"Genome Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e164","DOI":"10.1093\/nar\/gkq603","article-title":"ANNOVAR: Functional annotation of genetic variants from high-throughput sequencing data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Res"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Adzhubei, I., Jordan, D.M., and Sunyaev, S.R. (2013). Predicting functional effect of human missense mutations using polyphen-2. Curr. Protoc. Hum. Genet.","DOI":"10.1002\/0471142905.hg0720s76"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1038\/nprot.2009.86","article-title":"Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm","volume":"4","author":"Kumar","year":"2009","journal-title":"Nat. Protoc."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1038\/nmeth0810-575","article-title":"Mutationtaster evaluates disease-causing potential of sequence alterations","volume":"7","author":"Schwarz","year":"2010","journal-title":"Nat. Methods"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1016\/j.ajhg.2016.08.016","article-title":"Revel: An ensemble method for predicting the pathogenicity of rare missense variants","volume":"99","author":"Ioannidis","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1581","DOI":"10.1038\/ng.3703","article-title":"M-CAP eliminates a majority of variants of uncertain significance in clinical exomes at high sensitivity","volume":"48","author":"Jagadeesh","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e115","DOI":"10.1093\/nar\/gks596","article-title":"Primer3\u2014New capabilities and interfaces","volume":"40","author":"Untergasser","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"D257","DOI":"10.1093\/nar\/gku949","article-title":"SMART: Recent updates, new developments and status in 2015","volume":"43","author":"Letunic","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1002\/1097-0134(20001101)41:2<224::AID-PROT70>3.0.CO;2-Z","article-title":"Rapid automatic detection and alignment of repeats in protein sequences","volume":"41","author":"Heger","year":"2000","journal-title":"Proteins"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1870","DOI":"10.1093\/molbev\/msw054","article-title":"Mega7: Molecular evolutionary genetics analysis version 7.0 for bigger datasets","volume":"33","author":"Kumar","year":"2016","journal-title":"Mol. Biol. Evol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"W252","DOI":"10.1093\/nar\/gku340","article-title":"SWISS-MODEL: Modelling protein tertiary and quaternary structure using evolutionary information","volume":"42","author":"Biasini","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2714","DOI":"10.1002\/elps.1150181505","article-title":"SWISS-MODEL and the Swiss-PdbViewer: An environment for comparative protein modeling","volume":"18","author":"Guex","year":"1997","journal-title":"Electrophoresis"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/4\/626\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:31:58Z","timestamp":1760207518000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/4\/626"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,4,5]]},"references-count":28,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2017,4]]}},"alternative-id":["ijms18040626"],"URL":"https:\/\/doi.org\/10.3390\/ijms18040626","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,4,5]]}}}