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QUARTERLY FOCUS ISSUE: HEART FAILURE: CLINICAL RESEARCH

Familial Dilated Cardiomyopathy Caused by an Alpha-Tropomyosin Mutation

The Distinctive Natural History of Sarcomeric Dilated Cardiomyopathy

Neal K. Lakdawala, MD^_*, Lisa Dellefave, MS, CGC, Charles S. Redwood, PhD, Elizabeth Sparks, RNP, Allison L. Cirino, MS, CGC^_*, Steve Depalma, PhD, Steven D. Colan, MD^||, Birgit Funke, PhD^¶, Rebekah S. Zimmerman, PhD^¶, Paul Robinson, DPhil, Hugh Watkins, MD, PhD, Christine E. Seidman, MD^_*,,#, J.G. Seidman, PhD, Elizabeth M. McNally, MD, PhD and Carolyn Y. Ho, MD^_*,_*

^_* Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts
Department of Medicine, Section of Cardiology, The University of Chicago, Chicago, Illinois
University of Oxford, Oxford, United Kingdom
Department of Genetics, Harvard Medical School, Boston, Massachusetts
^|| Department of Cardiology, Children's Hospital Boston, Boston, Massachusetts
^¶ Harvard Medical School–Partners Healthcare Center for Personalized Genetic Medicine, Cambridge, Massachusetts
^# Howard Hughes Medical Institute, Cambridge, Massachusetts

Manuscript received August 7, 2009; revised manuscript received October 21, 2009, accepted November 9, 2009.

^_* Reprint requests and correspondence: Dr. Carolyn Y. Ho, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115 (Email: cho{at}partners.org).

Objectives: We sought to further define the role of sarcomere mutations in dilated cardiomyopathy (DCM) and associated clinical phenotypes.

Background: Mutations in several contractile proteins contribute to DCM, but definitive evidence for the roles of most sarcomere genes remains limited by the lack of robust genetic support.

Methods: Direct sequencing of 6 sarcomere genes was performed on 334 probands with DCM. A novel D230N missense mutation in the gene encoding alpha-tropomyosin (TPM1) was identified. Functional assessment was performed by the use of an in vitro reconstituted sarcomere complex to evaluate ATPase regulation and Ca²⁺ affinity as correlates of contractility.

Results: TPM1 D230N segregated with DCM in 2 large unrelated families. This mutation altered an evolutionarily conserved residue and was absent in >1,000 control chromosomes. In vitro studies demonstrated major inhibitory effects on sarcomere function with reduced Ca²⁺ sensitivity, maximum activation, and Ca²⁺ affinity compared with wild-type TPM1. Clinical manifestations ranged from decompensated heart failure or sudden death in those presenting early in life to asymptomatic left ventricular dysfunction in those diagnosed during adulthood. Notably, several affected infants had remarkable improvement.

Conclusions: Genetic segregation in 2 unrelated families and functional analyses conclusively establish a pathogenic role for TPM1 mutations in DCM. In vitro results demonstrate contrasting effects of DCM and hypertrophic cardiomyopathy mutations in TPM1, suggesting that specific functional consequences shape cardiac remodeling. Along with previous reports, our data support a distinctive, age-dependent phenotype with sarcomere-associated DCM where presentation early in life is associated with severe, sometimes lethal, disease. These observations have implications for the management of familial DCM.

Key Words: cardiomyopathy • heart failure • genetics

Abbreviations and Acronyms   DCM = dilated cardiomyopathy   HCM = hypertrophic cardiomyopathy   HF = heart failure   LV = left ventricular/ventricle   LVIDD = left ventricular end-diastolic internal diameter   LVEF = left ventricular ejection fraction

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