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CLINICAL RESEARCH: GENETICS/GENOMICS

Cardiac Ankyrin Repeat Protein Gene (ANKRD1) Mutations in Hypertrophic Cardiomyopathy

Takuro Arimura, DVM, PhD^_*, J. Martijn Bos, MD, Akinori Sato, MD^_*, Toru Kubo, MD, PhD, Hiroshi Okamoto, MD, PhD, Hirofumi Nishi, MD, PhD^||, Haruhito Harada, MD, PhD^¶, Yoshinori Koga, MD, PhD^¶, Mousumi Moulik, MD^#, Yoshinori L. Doi, MD, PhD, Jeffrey A. Towbin, MD^_**, Michael J. Ackerman, MD, PhD and Akinori Kimura, MD, PhD^,_*

^_* Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
Departments of Medicine, Pediatrics, and Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota
Department of Medicine and Geriatrics, Kochi Medical School, Kochi, Japan
Division of Cardiovascular Medicine, Nishi Sapporo National Hospital, Sapporo, Japan
^|| Nishi Hospital, Omuta, Japan
^¶ Division of Cardiovascular Disease, Kurume University Medical Center, Kurume, Japan
^# Department of Pediatrics, Division of Cardiology, University of Texas Medical School Houston, Houston, Texas
^_** Heart Institute, Department of Pediatrics and Pediatric Cardiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
Laboratory of Genome Diversity, School of Biomedical Science, Tokyo Medical and Dental University, Tokyo, Japan

Manuscript received August 21, 2008; revised manuscript received November 20, 2008, accepted December 3, 2008.

^_* Reprint requests and correspondence: Dr. Akinori Kimura, Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Bunkyo-Ku, Tokyo 113-8510, Japan (Email: akitis{at}mri.tmd.ac.jp).

Objectives: The purpose of this study was to explore a novel disease gene for hypertrophic cardiomyopathy (HCM) and to evaluate functional alterations caused by mutations.

Background: Mutations in genes encoding myofilaments or Z-disc proteins of the cardiac sarcomere cause HCM, but the disease-causing mutations can be found in one-half of the patients, indicating that novel HCM-susceptibility genes await discovery. We studied a candidate gene, ankyrin repeat domain 1 (ANKRD1), encoding for the cardiac ankyrin repeat protein (CARP) that is a Z-disc component interacting with N2A domain of titin/connectin and N-terminal domain of myopalladin.

Methods: We analyzed 384 HCM patients for mutations in ANKRD1 and in the N2A domain of titin/connectin gene (TTN). Interaction of CARP with titin/connectin or myopalladin was investigated using coimmunoprecipitation assay to demonstrate the functional alteration caused by ANKRD1 or TTN mutations. Functional abnormalities caused by the ANKRD1 mutations were also examined at the cellular level in neonatal rat cardiomyocytes.

Results: Three ANKRD1 missense mutations, Pro52Ala, Thr123Met, and Ile280Val, were found in 3 patients. All mutations increased binding of CARP to both titin/connectin and myopalladin. In addition, TTN mutations, Arg8500His, and Arg8604Gln in the N2A domain were found in 2 patients, and these mutations increased binding of titin/connectin to CARP. Myc-tagged CARP showed that the mutations resulted in abnormal localization of CARP in cardiomyocytes.

Conclusions: CARP abnormalities may be involved in the pathogenesis of HCM.

Key Words: hypertrophic cardiomyopathy • mutation • Z-disc • cardiac ankyrin repeat protein • titin/connectin

Abbreviations and Acronyms   Ab = antibody   ANKRD1 = ankyrin repeat domain 1   CARP = cardiac ankyrin repeat protein   cDNA = complementary deoxyribonucleic acid   Co-IP = coimmunoprecipitation   DAPI = 4'6-diamidino-2-phenylindole   DCM = dilated cardiomyopathy   HCM = hypertrophic cardiomyopathy   PCR = polymerase chain reaction   WT = wild type

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