title: Novel point mutations in GDF5 associated with two distinct limb malformations in Chinese: brachydactyly type C and proximal symphalangism.
abstract: Growth/differentiation factor 5 (GDF5) is a secreted growth factor that plays a key regulatory role in embryonic skeletal and joint development. Mutations in the GDF5 gene can cause different types of skeletal dysplasia, including brachydactyly type C (BDC) and proximal symphalangism (SYM1). We report two novel mutations in the GDF5 gene in Chinese families with distinct limb malformations. In one family affected with BDC, we identified a novel nonsense mutation, c.1461T > G (p.Y487X), which is predicted to truncate the GDF5 precursor protein by deleting 15 amino acids at its C-terminus. In one family with SYM1, we found a novel missense mutation, c.1118T > G (p.L373R), which changes a highly conserved amino acid in the prodomain of GDF5. We transfected COS-7 cells with retroviral constructs to express human wild-type or mutant GDF5 cDNAs. The mature GDF5 protein was detected, as in the wild-type, in supernatant derived from the p.L373R mutant GDF5 transfected cells, but not in the supernatant from the p.Y487X mutant transfected cells, indicating that the two mutations led to different fates of the mutant GDF5 proteins, thereby producing distinct limb phenotypes.
authors.affiliation: Department of Medical Genetics and National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 5 Dong Dan San Tiao, Beijing, 100005, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.affiliation: The Research Center for Medical Genomics, China Medical University, Shenyang, 110001, China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Cao
authors.affiliation: Department of Dermatology, Shenyang No.7 People's Hospital, Shenyang, Liaoning, China.
authors.forename: Wenli
authors.initials: W
authors.lastname: Liu
authors.affiliation: The Research Center for Medical Genomics, China Medical University, Shenyang, 110001, China.
authors.forename: Li
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Department of Medical Genetics and National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 5 Dong Dan San Tiao, Beijing, 100005, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Sun
authors.affiliation: Department of Medical Genetics and National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 5 Dong Dan San Tiao, Beijing, 100005, China.
authors.forename: Dai
authors.initials: D
authors.lastname: Zhang
authors.affiliation: The Research Center for Medical Genomics, China Medical University, Shenyang, 110001, China.
authors.forename: Shusen
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Medical Genetics and National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 5 Dong Dan San Tiao, Beijing, 100005, China.
authors.forename: Wilson H Y
authors.initials: WHY
authors.lastname: Lo
authors.affiliation: The Research Center for Medical Genomics, China Medical University, Shenyang, 110001, China. luoyangjj@sina.com.
authors.forename: Yang
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Department of Medical Genetics and National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 5 Dong Dan San Tiao, Beijing, 100005, China. xuezhang@pumc.edu.cn.
authors.forename: Xue
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D044466:Asian People / Q000235:genetics*; D001483:Base Sequence; D015153:Blotting, Western; D019485:Bone Morphogenetic Proteins / Q000235:genetics*; D019556:COS Cells; D002522:Chlorocebus aethiops; D017931:DNA Primers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055428:Growth Differentiation Factor 5; D006801:Humans; D017880:Limb Deformities, Congenital / Q000000981:diagnostic imaging / Q000235:genetics*; D008969:Molecular Sequence Data; D010375:Pedigree; D017354:Point Mutation / Q000235:genetics*; D011859:Radiography; D017422:Sequence Analysis, DNA
chemical_list: D019485:Bone Morphogenetic Proteins; D017931:DNA Primers; C525893:GDF5 protein, human; D055428:Growth Differentiation Factor 5