PUBLICATION
HBEGF, SRA1, and IK: Three cosegregating genes as determinants of cardiomyopathy
- Authors
- Friedrichs, F., Zugck, C., Rauch, G.J., Ivandic, B., Weichenhan, D., Muller-Bardorff, M., Meder, B., El Mokhtari, N.E., Regitz-Zagrosek, V., Hetzer, R., Schafer, A., Schreiber, S., Chen, J., Neuhaus, I., Ji, R., Siemers, N.O., Frey, N., Rottbauer, W., Katus, H.A., and Stoll, M.
- ID
- ZDB-PUB-081218-7
- Date
- 2009
- Source
- Genome research 19(3): 395-403 (Journal)
- Registered Authors
- Meder, Benjamin, Rauch, Gerd-Jörg, Rottbauer, Wolfgang
- Keywords
- complex genetics, comparative genomics, linkage disequilibrium, genomic rearrangements
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Cardiomyopathies/genetics*
- Case-Control Studies
- Cell Line
- Chromosome Mapping
- Chromosome Segregation/physiology*
- Chromosomes, Human, Pair 5
- Cluster Analysis
- Cytokines/genetics*
- Cytokines/physiology
- Embryo, Nonmammalian
- Genetic Markers/physiology
- Heparin-binding EGF-like Growth Factor
- Humans
- Inflammation/genetics
- Intercellular Signaling Peptides and Proteins/genetics*
- Intercellular Signaling Peptides and Proteins/physiology
- Linkage Disequilibrium
- Polymorphism, Single Nucleotide
- RNA, Long Noncoding
- RNA, Untranslated/genetics*
- RNA, Untranslated/physiology
- Ventricular Function, Left/genetics
- Zebrafish/embryology
- Zebrafish/genetics
- PubMed
- 19064678 Full text @ Genome Res.
Citation
Friedrichs, F., Zugck, C., Rauch, G.J., Ivandic, B., Weichenhan, D., Muller-Bardorff, M., Meder, B., El Mokhtari, N.E., Regitz-Zagrosek, V., Hetzer, R., Schafer, A., Schreiber, S., Chen, J., Neuhaus, I., Ji, R., Siemers, N.O., Frey, N., Rottbauer, W., Katus, H.A., and Stoll, M. (2009) HBEGF, SRA1, and IK: Three cosegregating genes as determinants of cardiomyopathy. Genome research. 19(3):395-403.
Abstract
Human dilated cardiomyopathy (DCM), a disorder of the cardiac muscle, causes considerable morbidity and mortality and is one of the major causes of sudden cardiac death. Genetic factors play a role in the aetiology and pathogenesis of DCM. Disease-associated genetic variations identified to date have been identified in single families or single sporadic patients and explain a minority of the aetiology of DCM (Karkkainen and Peuhkurinen 2007). We show that a 600 kilobase (kb) region of linkage disequilibrium (LD) on 5q31.2-3, harboring multiple genes, is associated with cardiomyopathy in three independent Caucasian populations (combined P-value = 0.00087). Functional assessment in zebrafish demonstrates that at least three genes, orthologous to loci in this LD block, HBEGF, IK, and SRA1, result independently in a phenotype of myocardial contractile dysfunction when their expression is reduced with morpholino antisense reagents. Evolutionary analysis across multiple vertebrate genomes suggests that this heart failure associated LD block emerged by a series of genomic rearrangements across amphibian, avian, and mammalian genomes and is maintained as a cluster in mammals. Taken together, these observations challenge the simple notion that disease phenotypes can be traced to altered function of a single locus within a haplotype, and suggests that a more detailed assessment of causality can be necessary.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping