Research

The overall objectives of the Wang laboratory are to use the genetic technology to identify key genes responsible for cardiovascular disease, neurological disease, and other forms of inherited human disease, and to employ transgenic and knockout mouse technology, cell biological, biochemical, biophysical and electrophysiological tools to uncover the underlying molecular mechanisms.  Dr. Wang has had a long standing interest in cardiac arrhythmias that account for more than 300,000 sudden deaths each year in the U.S. alone.  Dr. Wang has been a key pioneer in the genetic studies of inherited cardiac arrhythmias, and is responsible for discovering one of the first two genes responsible for long QT syndrome (LQTS) (the cardiac sodium channel gene SCN5A), and the molecular cloning of the KCNQ1 gene which encodes the first member of the KCNQ family of potassium channels and is responsible for the most common LQTS, and for identifying the first gene for Brugada syndrome (BrS).  These findings have driven the successful launching of the first commercial genetic test kit for cardiovascular disease, the FAMILION test, and realization of a successful case of personalized medicine in cardiovascular medicine. 

Atrial fibrillation (AF) is another major form of cardiac arrhythmias that affects more than 2.2 million people in the US, and accounts for 15% of all strokes.  Dr. Wang’s group reported the first genetic locus for autosomal recessive AF onto chromosome 5p13 in 2004, and successful identified the underlying gene in 2008.  The underlying gene is the NUP155 gene encoding a critical protein involved in exchange of macromolecules between the nucleus and cytoplasm.  The finding for the first time links the nucleocytoplasmic transport system to cardiovascular physiology and disease, and identifies a non-ion channel gene for AF. 

Besides genetics of single gene disorders, Dr. Wang’s group has a keen interest in genetics of common complex diseases, including coronary artery disease (CAD) and myocardial infarction (MI), common AF, strokes and a neurological disease restless legs syndrome (RLS).  Two candidate genes have been identified for CAD and MI, including MEF2A and LRP8.  One genetics locus for RLS was mapped to chromosome 9 (RLS3).  A new genetic variant has been identified for ischemic stroke in the Chinese population.

In 2004, Dr. Wang and colleagues reported the molecular cloning of a novel angiogenic factor AGGF1 (previously known as VG5Q) which is associated with a human vascular disease Klippel-Trenaunay syndrome (KTS).  Continued studies have focused on defining the exact molecular mechanisms by which AGGF1 promotes anagiogenesis using knockout mouse modeling and a series of biochemical and cell biological experiments. 

In 2005, Dr. Wang and colleagues reported the identification of the first gene and underlying pathologic mechanism responsible for coexistence of generalized epilepsy and paroxysmal nonkinesigenic dyskinesia. 

Dr. Wang’s group has created a new animal model for type 3 LQTS and show that extrasystoles and reentry are responsible for ventricular arrhythmias associated with LQTS and that type 3 LQTS is associated with dilated cardiomyopathy. 

Dr. Wang’s group carried out the first systematic functional characterization of TBX5 missense mutations that cause Holt-Oram syndrome and atrial septal defects, and recently showed that transcriptional factors TBX5 could interact with an mRNA splicing protein SC35 and modulate constitutive and alternative mRNA splicing.  TBX5, thus, becomes the first cardiac gene and the first human disease gene with dual roles in both transcriptional activation and pre-mRNA splicing.