title: Exome Sequencing Identified a Novel FBN2 Mutation in a Chinese Family with Congenital Contractural Arachnodactyly.
abstract: 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 ofFBN2. Our results may also provide new insights into the cause and diagnosis of CCA and may have implications for genetic counseling and clinical management.
authors.affiliation: Department of Laboratory Medicine, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China. youguoling@126.com.
authors.forename: Guoling
authors.initials: G
authors.lastname: You
authors.affiliation: Department of Laboratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200127, China. zubailing@126.com.|Department of Clinical Laboratory, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 200127, China. zubailing@126.com.
authors.forename: Bailing
authors.initials: B
authors.lastname: Zu
authors.affiliation: Department of Laboratory Medicine, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China. wangbao@scmc.com.cn.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Pediatric Orthopedics, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China. wangzhigang@scmc.com.cn.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Pediatric Orthopedics, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China. xu.yunlan@hotmail.com.
authors.forename: Yunlan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Laboratory Medicine, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China. qihuafu@126.com.
authors.forename: Qihua
authors.initials: Q
authors.lastname: Fu
mesh_terms: D000293:Adolescent; D000328:Adult; D054119:Arachnodactyly / Q000235:genetics*; D044466:Asian People / Q000235:genetics*; D001665:Binding Sites; D002648:Child; D002681:China; D003286:Contracture / Q000235:genetics*; D059472:Exome; D005260:Female; D000071840:Fibrillin-2 / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D017510:Protein Folding; D017422:Sequence Analysis, DNA / Q000379:methods*
chemical_list: C000605723:FBN2 protein, human; D000071840:Fibrillin-2
keywords: congenital contractural arachnodactyly; exome sequencing; fibrillin-2 (FBN2) gene