title: Uncovering the rare variants of DLC1 isoform 1 and their functional effects in a Chinese sporadic congenital heart disease cohort.
abstract: Congenital heart disease (CHD) is the most common birth defect affecting the structure and function of fetal hearts. Despite decades of extensive studies, the genetic mechanism of sporadic CHD remains obscure. Deleted in liver cancer 1 (DLC1) gene, encoding a GTPase-activating protein, is highly expressed in heart and essential for heart development according to the knowledge of Dlc1-deficient mice. To determine whether DLC1 is a susceptibility gene for sporadic CHD, we sequenced the coding region of DLC1 isoform 1 in 151 sporadic CHD patients and identified 13 non-synonymous rare variants (including 6 private variants) in the case cohort. Importantly, these rare variants (8/13) were enriched in the N-terminal region of the DLC1 isoform 1 protein. Seven of eight amino acids at the N-terminal variant positions were conserved among the primates. Among the 9 rare variants that were predicted as "damaging", five were located at the N-terminal region. Ensuing in vitro functional assays showed that three private variants (Met360Lys, Glu418Lys and Asp554Val) impaired the ability of DLC1 to inhibit cell migration or altered the subcellular location of the protein compared to wild-type DLC1 isoform 1. These data suggest that DLC1 might act as a CHD-associated gene in addition to its role as a tumor suppressor in cancer.
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) and Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, People's Republic of China.
authors.forename: Bin
authors.initials: B
authors.lastname: Lin
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) and Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, People's Republic of China.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Diagnosis and Treatment Center of Congenital Heart Disease, the First Hospital of Hebei Medical University, Shijiazhuang, Hebei, People's Republic of China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Diagnosis and Treatment Center of Congenital Heart Disease, the First Hospital of Hebei Medical University, Shijiazhuang, Hebei, People's Republic of China.
authors.forename: Huilian
authors.initials: H
authors.lastname: Tan
authors.affiliation: Clinical Laboratory, Affiliated Hospital of Binzhou Medical College, Binzhou, Shandong, People's Republic of China.
authors.forename: Xianghua
authors.initials: X
authors.lastname: Kong
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) and Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, People's Republic of China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Shu
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) and Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, People's Republic of China.
authors.forename: Yuchao
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) and Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, People's Republic of China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Huang
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) and Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, People's Republic of China.
authors.forename: Yufei
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) and Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, People's Republic of China.
authors.forename: Heng
authors.initials: H
authors.lastname: Xu
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) and Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, People's Republic of China.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Wang
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) and Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, People's Republic of China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Medical Genomics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Guang
authors.initials: G
authors.lastname: Ning
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) and Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, People's Republic of China ; State Key Laboratory of Medical Genomics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Xiangyin
authors.initials: X
authors.lastname: Kong
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) and Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, People's Republic of China.
authors.forename: Guohong
authors.initials: G
authors.lastname: Hu
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) and Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, People's Republic of China ; State Key Laboratory of Medical Genomics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Landian
authors.initials: L
authors.lastname: Hu
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D002648:Child; D002675:Child, Preschool; D017124:Conserved Sequence; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics*; D006331:Heart Diseases / Q000151:congenital / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D011323:Primates / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics; D017434:Protein Structure, Tertiary; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: C112352:DLC1 protein, human; D020690:GTPase-Activating Proteins; D020033:Protein Isoforms; D025521:Tumor Suppressor Proteins