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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.
AuthorsBin Lin, Yufeng Wang, Zhen Wang, Huilian Tan, Xianghua Kong, Yang Shu, Yuchao Zhang, Yun Huang, Yufei Zhu, Heng Xu, Zhiqiang Wang, Ping Wang, Guang Ning, Xiangyin Kong, Guohong Hu, Landian Hu
JournalPloS one (PLoS One) Vol. 9 Issue 2 Pg. e90215 ( 2014) ISSN: 1932-6203 [Electronic] United States
PMID24587289 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • DLC1 protein, human
  • GTPase-Activating Proteins
  • Protein Isoforms
  • Tumor Suppressor Proteins
Topics
  • Adolescent
  • Adult
  • Amino Acid Sequence
  • Animals
  • Child
  • Child, Preschool
  • Conserved Sequence
  • Female
  • GTPase-Activating Proteins (genetics)
  • Heart Diseases (congenital, genetics)
  • Humans
  • Infant
  • Male
  • Molecular Sequence Data
  • Mutation
  • Primates (genetics)
  • Protein Isoforms (genetics)
  • Protein Structure, Tertiary
  • Tumor Suppressor Proteins (genetics)

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