Dysregulation of G protein Signaling in Idiopathic Ventricular Tachycardia.
Key Faculty: Bruce B. Lerman, MD (Professor), Craig T. Basson, MD, PhD (Professor)

Our laboratory studies the regulation of proteins (G proteins) that couple cell surface receptors to intracellular cAMP and their role in medicating adrenergically-dependent ventricular tachycardia. cAMP regulates phosphorylation and permeation of ion channels, which can result in intracellular calcium overload that triggers malignant arrhythmias in patients without structural heart disease. Our laboratory has identified cardiac mutations in several regulatory G proteins, which are thought to be responsible for this form of tachycardia. Mutations in these G proteins couple to either the β-adrenergic receptor of the muscarinic cholinergic receptor, and are of somatic origin, the first to be demonstrated in the heart. Transfection experiments show that these mutations increase intracellular cAMP. Our biochemical analyses has further shown that the identified mutations in the inhibitory G protein (Gαi2) impair binding of GTP, altering activation kinetics, whereas the mutations in the stimulatory G protein (Gs) cause constitutive activation, impairing hydrolysis of GTP.

Selected References

Lerman BB, Bei D, Stein KM, Markowitz SM, Linden J, Catanzaro DF. Right ventricular outflow tract tachycardia due to a somatic cell mutation in G protein subunit αI2. J Clin Invest. 1998;101:2862-2868.

Lerman BB, Dai J, Stein KM, Markowitz SM, Slotwiner DJ, Iwai S, Xu L, Das MK, Hao SC, Cohen JD. Variant of outflow tract tachycardia associated with a somatic mutation of the Gai switch 2 Region. J Am Coll Cardiol. 2003;818-2:105A.

Iwai S, Dai J, Linna X. Lerman BB. Expression of constitutively activated G-protein associated with human right ventricular tachycardia causes ventricular tachycardia in a rabbit model. Circulation. 2004;110: III-1385.

Dai J, Xu L, Steegborn C, Basson CT, Lerman BB. Constitutively activating Gsα mutation in repetitive monomorphic ventricular outflow tract tachycardia. (submitted)

Genetic Contribution to Abnormal Cardiac and Arterial Structure and Function.
Key Faculty: Richard Devereux, MD (Professor)

In this area of research, we examine the heritability, linkage and association with genetic regions of a variety of cardiac and arterial phenotypes (e.g., LV mass, indices of LV systolic and diastolic function, aortic and carotid artery diameter and wall thickness, etc.) defined by echocardiography and carotid ultrasound studies using a variety of analytical strategies. This line of investigation utilizes data from nearly 5,000 adolescents or adults in large 3-generation families (mean of >40 related individuals per family) and from nearly 6,000 adults in sibships from population-based samples of multiple ethnic groups.

Selected References
Bella JN, MacCluer JW, Roman MJ, Almasy L, North KE, Welty TK, Lee ET, Fabsitz RR, Howard BV, Devereux RB: Genetic influences on aortic size in American Indians: The Strong Heart Study. Atheroscler Thromb Vasc Biol. 2002;22:1008-1011.

North KE, MacCluer JW, Devereux RB, Howard BV, Welty TK, Best LG, Lee ET, Fabsitz RR, Roman MJ: Heritability of carotid artery structure and function: The Strong Heart Family Study. Arterioscler Thromb Vasc Biol. 2002;22:1698-1703.

Bella JN, MacCluer JW, Roman MJ, Almasy L, North KE, Best LG, Lee ET, Fabsitz RR, Howard BV, Devereux RB: Heritability of left ventricular dimensions and mass in American Indians: The Strong Heart Study. J Hypertens. 2004;22:281-286.

Molecular Genetics of the Adult Embryonic Cardiovascular System.
Key Faculty: Craig T. Basson, MD, PhD (Professor)

We seek to identify novel genetic factors that produce human cardiovascular disease and then study their contributions to embryonic and adult cardiovascular growth and development. These studies (1-3) shed light on genetic regulation of cardiovascular gene transcription and signal transduction. Trainees being mentored as part of these investigative studies include graduate and medical students, medical residents, cardiology fellows, and postdoctoral research fellows.

Selected References

Veugelers M, Bressan MA, McDermott DA, Weremowicz S, Morton CC, Mabry CC, Lefaivre JF, Zunamon A, Destree A, Chaudron JM, Basson CT. Mutation of perinatal myosin heavy chain associated with a Carney complex variant. The New England Journal of Medicine. 2004;351:460-469.

Hatcher CJ, Diman N, Kim MS, Pennisi DA, Song Y, Goldstein MM, Mikawa T, Basson CT. A role for Tbx5 in proepicardial cell migration in cardiogenesis. Physiological Genomics. 2004;18:129-140.

Veugelers M, Wilkes D, Burton KA, McDermott DA, Song Y, Goldstein MM, LaPerle K, Vaughan CJ, O'Hagan A, Bennett KR, Meyer BJ, Legius E, Karttunen M, Norio R, Kaariainen H, Lavyne M, Neau JP, Richter G, Kirali K, Farnsworth A, Stapleton K, Morelli P, Takanashi Y, Bamforth JS, Eitelberger F, Noszian I, Manfroi W, Powers J, Mochizuki Y, Imai T, Ko GTC, Driscoll DA, Goldmuntz E, Edelberg JM, Collins A, Eccles D, Irvine A, McKnight GS, Basson CT. Comparative PRKAR1A genotype-phenotype analyses in humans with Carney complex and prkar1a haploinsufficient mice. Proc Natl Acad Sci USA. 2004;101:14222-14227.

Vaughan CJ, Casey M, He J, Veugelers M, Henderson K, Guo D, Campagna R, Roman MJ, Milewicz DM, Devereux RB, Basson CT. Identification of a chromosome 11q23.2-q24 locus for familial aortic aneurysm disease, a genetically heterogeneous disorder. Circulation. 2001;103:2469-2475.

Genetic Strategies for the Treatment and Diagnosis of Cardiovascular Disease.
Key Faculty: Craig T. Basson, MD, PhD (Professor)

Advances in cardiovascular genetics and gene discovery in our laboratory have created platforms for genetic testing in cardiovascular disease. We have developed several genetic tests for structural heart diseases.

Selected References

Goldstein MM, Casey M, Carney JA, Basson CT. Molecular genetic diagnosis of the familial myxoma syndrome (Carney complex). Am J Med Genet. 1999;86:62-65.

He J, McDermott DA, Song Y, Gilbert F, Kligman I, Basson CT. Preimplantation diagnosis of Holt-Oram syndrome and congenital heart disease. American Journal of Medical Genetics. 2004;126A:93-98.

McDermott DA, Bressan MA, Je J, Lee JS, Aftimos S, Brueckner M, gilbert F, Graham GE, Hannibal MC, Innis JW, Pierpont ME, Raas-Rothschild A, Shanske AL, Smith WE, Spencer RH, St. John-Sutton MG, van Maldergem L, Waggoner DJ, Weber M, Basson CT. TBX5 genetic testing validates strict clinical criteria for Holt-Oram syndrome. Pediatric Research, in press.

Gerull B, Heuser A, Wichter T, Paul M, Basson CT, McDermott DA, Lerman BB, Markowitz SM, Ellinor PT, MacRae CA, Peters S, Grossmann KS, Drenckhahn J, Michely B, Sasse-Klassen S, Birchmeier W, Dietz R, Breithardt G, Schulze-Bahr E, Thierfelder L. Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. Nature Genetics. 2004:36:1162-1164.