A/Professor Diane Fatkin, MD BSc(Med) FRACPLaboratory Head, Sr Bernice Research program in Inherited Heart Disease, Molecular Cardiology and Biophysics DivisionA/Professor, University of New South Wales
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Genetic Causes of DCM and AF
Approximately one in 3 cases of DCM and AF is caused by defective genes that can be passed from an affected person to their children. A/Professor Fatkin's group recruits families where 2 or more first-degree family members have DCM and/or AF to identify new disease-causing genes. Quite often, family members who are unaware they have heart disease or a genetic predisposition to heart disease because of a lack of symptoms are identified. They are identified via heart ultrasound testing and genetic screening performed as part of the research conducted by the laboratory.
The group also recruits healthy elderly individuals to serve as controls. Identifying disease-causing genes in families will further our understanding of the molecular basis of DCM and AF. In addition, it will help to define genetic factors that affect the susceptibility to these diseases in the general community. Consequently, therapies can be developed for the treatment and prevention of these common diseases.
A/Professor Fatkin's group is also conducting a twin study to enhance the understanding of the genetic and environmental factors contributing to AF. Identical or non-identical twin pairs where either one or both of the twins have AF are invited to participate in the study. This is a really useful way to better understand the gene changes that can predispose to AF and to look at interactions between genetic and environmental factors contributing to increased AF risk. To find out if you or someone you know might be eligible for any of these studies, please visit the research volunteers page.
New Disease Models.jpg)
The discovery of DNA sequence variants in families brings new challenges of determining how gene changes can cause disease. In addition to using conventional cell culture and mouse models to look at genetic variants, we are exploring the in vitro models and genetically manipulated zebrafish models.
The zebrafish is a versatile animal model that is gaining popularity in the study of heart disease. A unique feature of zebrafish is that they are transparent when young so that detailed visualisation of the heart?s contraction and rhythm can be performed in the live animal. Furthermore, they are amenable to transgenic analysis, such that we can breed zebrafish strains carrying human heart disease genes, to study their impact on cardiac development and function. The zebrafish cardiology group at the VCCRI is currently the only laboratory in Australia studying human adult heart disease in fish and carrying out ECG recordings on adult zebrafish. Human and zebrafish heart rates are similar, making the zebrafish a very good experimental model for both heart failure and heart rhythm disturbances.
Co-Investigators:
Arie Jacoby, PhD
Christiana Leimena, BSc Hons
Guanglan Guo, PhD
Gunjan Trivedi, BMedSci Hons
Inken Martin, MD, PhD
Leah Cannon, BVSc Hons
Li Sze Yeo, Bsc Hons
Magdalena Soka, BBiotech Hons
Molly Vale, MSc
Monique Ohanian, BMedSci Hons
Poonam Zodgekar MSW, GradDipGenCouns, BSc Hons
Robyn Otway, PhD
Vesna Nikolova-Krstevski, PhD
Collaborators:
National
International
Selected Publications:
Fatkin D, Otway R, Richmond Z. Genetics of dilated cardiomyopathy. Heart Failure Clinics 2010 (in press).
Chandar S, Yeo LS, Leimena C, Tan JC, Xiao XH, Nikolova-Krstevski V, Yasuoka Y, Gardiner-Garden M, Wu J, Kesteven S, Karlsdotter L, Natarajan S, Carlton A, Rainer S, Feneley MP, Fatkin D. Effects of Mechanical Stress and Carvedilol in Lamin A/C-Deficient Dilated Cardiomyopathy. Circulation Research 2009 (in press).
Fatkin D, Otway R, Vandenberg JI. Genes and Atrial Fibrillation: a new look at an old problem. Circulation 2007;116:782-792.
Otway R, Vandenberg JL, Guo G, Varghese A, Castro ML, Liu J, Zhao JT, Bursil JA, Wyse KR, Crotty H, Baddeley O, Walker B, Kuchar D, Thorburn C, Fatkin D. Stretch-sensitive KCNQ1 mutation: a link between genetic and environmental factors in the pathogenesis of atrial fibrillation? J Am Coll Cardiol. 2007;49:578-586.
Kirk EP, Sunde M, Costa MW, Rankin SA, Wolstein O, Castro ML, Butler TL, Hyun C, Guo G, Otway R, Mackay JP, Waddell LB, Cole AD, Hayward C, Keogh A, Macdonald P, Griffiths L, Fatkin D, Sholler GF, Zorn AM, Feneley MP, Winlaw DS, Harvey RP. Mutations in cardiac T-box factor gene TBX20 are associated with diverse cardiac pathologies, including defects of septation and valvulogenesis and cardiomyopathy. Am J Hum Genet. 2007;81:280-291.
Nikolova V, Leimena C, McMahon AC, Tan JC, Chandar S, Jogia D, Kesteven SH, Michalicek J, Otway R, Verheyen F, Rainer S, Stewart CL, Martin D, Feneley MP, Fatkin D. Defects in nuclear structure and function promote dilated cardiomyopathy in lamin A/C deficient mice. Journal of Clinical Investigation 2004; 113:357-369.
Fatkin D, Graham RM. Molecular mechanisms of inherited cardiomyopathies. Physiological Reviews 2002; 82:945-980
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