title: Functional Analysis of Two Novel Mutations in TWIST1 Protein Motifs Found in Ventricular Septal Defect Patients.
abstract: The aim of this study was to investigate the possible genetic effect of sequence variations in TWIST1 on the pathogenesis of ventricular septal defect in humans. We examined the coding region of TWIST1 in a cohort of 196 Chinese people with non-syndromic ventricular septal defect patients and 200 healthy individuals as the controls. We identified two novel potential disease-associated mutations, NM_000474.3:c.247G>A (G83S) and NM_000474.3:c.283A>G (S95G). Both of them were identified for the first time and were not observed in the 200 controls without congenital heart disease. Using a dual-luciferase reporter assay, we showed that both of the mutations significantly down-regulated the repressive effect of TWIST1 on the E-cadherin promoter. Furthermore, a mammalian two-hybrid assay showed that both of the mutations significantly affected the interaction between TWIST1 and KAT2B. New mutations in the transcription factor TWIST1 that affect protein function were identified in 1.0 % (2/196) of Chinese patients with ventricular septal defect. Our data show, for the first time, that TWIST1 has a potential causative effect on the development of ventricular septal defect.
authors.affiliation: Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, No.36, Sanhao Street, Heping District, Shenyang, 110004, China.
authors.forename: Xiaopeng
authors.initials: X
authors.lastname: Deng
authors.affiliation: Graduate School, Peking Union Medical College, Beijing, 100080, China.|Center for Genetics, National Research Institute for Family Planning, 12 Dahuisi Road, Haidian, Beijing, 100081, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Pan
authors.affiliation: Graduate School, Peking Union Medical College, Beijing, 100080, China.|Center for Genetics, National Research Institute for Family Planning, 12 Dahuisi Road, Haidian, Beijing, 100081, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Graduate School, Peking Union Medical College, Beijing, 100080, China.|Center for Genetics, National Research Institute for Family Planning, 12 Dahuisi Road, Haidian, Beijing, 100081, China.
authors.forename: Binbin
authors.initials: B
authors.lastname: Wang
authors.affiliation: Graduate School, Peking Union Medical College, Beijing, 100080, China.|Center for Genetics, National Research Institute for Family Planning, 12 Dahuisi Road, Haidian, Beijing, 100081, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Cheng
authors.affiliation: Graduate School, Peking Union Medical College, Beijing, 100080, China.|Center for Genetics, National Research Institute for Family Planning, 12 Dahuisi Road, Haidian, Beijing, 100081, China.
authors.forename: Longfei
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Graduate School, Peking Union Medical College, Beijing, 100080, China.|Center for Genetics, National Research Institute for Family Planning, 12 Dahuisi Road, Haidian, Beijing, 100081, China.
authors.forename: Lixi
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, No.36, Sanhao Street, Heping District, Shenyang, 110004, China. fclihui@sj-hospital.org.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Graduate School, Peking Union Medical College, Beijing, 100080, China. NICGR2014@163.com.|Center for Genetics, National Research Institute for Family Planning, 12 Dahuisi Road, Haidian, Beijing, 100081, China. NICGR2014@163.com.|World Health Organization Collaborating Centre for Research in Human Reproduction, Beijing, 100081, China. NICGR2014@163.com.
authors.forename: Xu
authors.initials: X
authors.lastname: Ma
mesh_terms: D020816:Amino Acid Motifs; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D002675:Child, Preschool; D002681:China; D005260:Female; D020022:Genetic Predisposition to Disease; D006345:Heart Septal Defects, Ventricular / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D051879:Twist-Related Protein 1 / Q000235:genetics*
chemical_list: D009687:Nuclear Proteins; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1
keywords: Genetics; TWIST1; Variant; Ventricular septal defect