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CLINICAL RESEARCH: GENETICS/GENOMICS

ANKRD1, the Gene Encoding Cardiac Ankyrin Repeat Protein, Is a Novel Dilated Cardiomyopathy Gene

Mousumi Moulik, MD, Matteo Vatta, PhD^_*, Stephanie H. Witt, PhD, Anita M. Arola, MD, PhD^_*, Ross T. Murphy, MD, William J. McKenna, MD^||, Aladin M. Boriek, PhD, Kazuhiro Oka, PhD, Siegfried Labeit, MD, Neil E. Bowles, PhD, Takuro Arimura, DVM, PhD^¶, Akinori Kimura, MD, PhD^¶,# and Jeffrey A. Towbin, MD^_**,_*

^_* Department of Pediatrics, Section of Cardiology, Baylor College of Medicine, Houston, Texas
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
Department of Pulmonology, Baylor College of Medicine, Houston, Texas
Medical Faculty Mannnheim, University of Heidelberg, Heidelberg, Germany
^|| Institute of Cardiovascular Science, University College London, London, United Kingdom
^¶ Department of Molecular Pathogenesis, Medical Research Institute, Tokyo, Japan
^# Laboratory of Genome Diversity, School of Biomedical Science, Tokyo Medical and Dental University, Tokyo, Japan
^_** Heart Institute, Department of Pediatrics and Pediatric Cardiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
Department of Pediatrics, Division of Cardiology, University of Texas Medical School Houston, Houston, Texas
Department of Cardiology, St. James Hospital, Dublin, Ireland
Department of Pediatrics, Division of Cardiology, University of Utah, Salt Lake City, Utah

Manuscript received August 25, 2008; revised manuscript received February 5, 2009, accepted February 16, 2009.

^_* Reprint requests and correspondence: Dr. Jeffrey A. Towbin, The Heart Institute and Pediatric Cardiology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229 (Email: jeffrey.towbin{at}cchmc.org).

Objectives: We evaluated ankyrin repeat domain 1 (ANKRD1), the gene encoding cardiac ankyrin repeat protein (CARP), as a novel candidate gene for dilated cardiomyopathy (DCM) through mutation analysis of a cohort of familial or idiopathic DCM patients, based on the hypothesis that inherited dysfunction of mechanical stretch-based signaling is present in a subset of DCM patients.

Background: CARP, a transcription coinhibitor, is a member of the titin-N2A mechanosensory complex and translocates to the nucleus in response to stretch. It is up-regulated in cardiac failure and hypertrophy and represses expression of sarcomeric proteins. Its overexpression results in contractile dysfunction.

Methods: In all, 208 DCM patients were screened for mutations/variants in the coding region of ANKRD1 using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct deoxyribonucleic acid sequencing. In vitro functional analyses of the mutation were performed using yeast 2-hybrid assays and investigating the effect on stretch-mediated gene expression in myoblastoid cell lines using quantitative real-time reverse transcription–polymerase chain reaction.

Results: Three missense heterozygous ANKRD1 mutations (P105S, V107L, and M184I) were identified in 4 DCM patients. The M184I mutation results in loss of CARP binding with Talin 1 and FHL2, and the P105S mutation in loss of Talin 1 binding. Intracellular localization of mutant CARP proteins is not altered. The mutations result in differential stretch-induced gene expression compared with wild-type CARP.

Conclusions: ANKRD1 is a novel DCM gene, with mutations present in 1.9% of DCM patients. The ANKRD1 mutations may cause DCM as a result of disruption of the normal cardiac stretch-based signaling.

Key Words: DCM • CARP • ANKRD1 • mutations

Abbreviations and Acronyms   ANKRD1 = ankyrin repeat domain 1   CARP = cardiac ankyrin repeat protein   cDNA = complementary deoxyribonucleic acid   CHF = chronic heart failure   DCM = dilated cardiomyopathy   DNA = deoxyribonucleic acid   FHL2 = 4-and-a-half LIM domains 2   FS = fractional shortening   LVEDD = left ventricular end-diastolic diameter   NYHA = New York Heart Association   PCR = polymerase chain reaction   RNA = ribonucleic acid   TGF = transforming growth factor

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