Dilated cardiomyopathy (DCM) is a heritable, genetically heterogeneous disorder causing congestive heart failure. Current medical therapy has minimal impact on prognosis and cardiac transplantation is the only definitive treatment for end-stage disease. The molecular and cellular mechanisms underlying DCM are poorly defined, but the importance of single gene defects in disease pathogenesis is becoming increasingly apparent. The objective of this study is to identify novel DCM genes by genetic linkage and mutational analyses.
The first aim i s to determine the chromosomal location of novel familial DCM genes. This will be accomplished by genome-wide genotyping and genetic linkage analyses in 3 large families with autosomal dominant DCM. Previously identified DCM genes have been excluded in these families.
The second aim i s to identify mutations in novel genes that cause familial DCM by linkage and sequence analyses of candidate genes mapping to DCM loci. Once novel genes for familial DCM are identified, the third aim will be to determine the role of these genes in a large cohort of unrelated patients with familial and sporadic DCM. High throughput DNA sequence analyses will be performed to identify additional inherited and de novo mutations. The long-term objectives of this work are to gain new insights into molecular mechanisms for heart failure and to improve prediction, prevention, and treatment of DCM.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL071225-02
Application #
6611030
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Fabsitz, Richard
Project Start
2002-07-15
Project End
2005-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
2
Fiscal Year
2003
Total Cost
$252,875
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Ding, Yonghe; Long, Pamela A; Bos, J Martijn et al. (2017) A modifier screen identifies DNAJB6 as a cardiomyopathy susceptibility gene. JCI Insight 2:
Long, Pamela A; Theis, Jeanne L; Shih, Yu-Huan et al. (2017) Recessive TAF1A mutations reveal ribosomopathy in siblings with end-stage pediatric dilated cardiomyopathy. Hum Mol Genet 26:2874-2881
Long, Pamela A; Evans, Jared M; Olson, Timothy M (2017) Diagnostic Yield of Whole Exome Sequencing in Pediatric Dilated Cardiomyopathy. J Cardiovasc Dev Dis 4:
Long, Pamela A; Zimmermann, Michael T; Kim, Maengjo et al. (2016) De novo RRAGC mutation activates mTORC1 signaling in syndromic fetal dilated cardiomyopathy. Hum Genet 135:909-917
Ding, Yonghe; Long, Pamela A; Bos, J Martijn et al. (2016) A modifier screen identifies DNAJB6 as a cardiomyopathy susceptibility gene. JCI Insight 1:
Long, Pamela A; Evans, Jared M; Olson, Timothy M (2015) Exome sequencing establishes diagnosis of Alström syndrome in an infant presenting with non-syndromic dilated cardiomyopathy. Am J Med Genet A 167A:886-90
Long, Pamela A; Larsen, Brandon T; Evans, Jared M et al. (2015) Exome Sequencing Identifies Pathogenic and Modifier Mutations in a Child With Sporadic Dilated Cardiomyopathy. J Am Heart Assoc 4:
Theis, Jeanne L; Zimmermann, Michael T; Larsen, Brandon T et al. (2014) TNNI3K mutation in familial syndrome of conduction system disease, atrial tachyarrhythmia and dilated cardiomyopathy. Hum Mol Genet 23:5793-804
Terzic, Andre; Alekseev, Alexey E; Yamada, Satsuki et al. (2011) Advances in cardiac ATP-sensitive K+ channelopathies from molecules to populations. Circ Arrhythm Electrophysiol 4:577-85
Theis, Jeanne L; Sharpe, Katharine M; Matsumoto, Martha E et al. (2011) Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy. Circ Cardiovasc Genet 4:585-94

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