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1.
Circ Cardiovasc Genet ; 8(6): 752-64, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26499333

ABSTRACT

BACKGROUND: E193, a heterozygous truncating mutation in the human transcription cofactor Eyes absent 4 (Eya4), causes hearing impairment followed by dilative cardiomyopathy. METHODS AND RESULTS: In this study, we first show Eya4 and E193 alter the expression of p27(kip1) in vitro, suggesting Eya4 is a negative regulator of p27. Next, we generated transgenic mice with cardiac-specific overexpression of Eya4 or E193. Luciferase and chromatin immunoprecipitation assays confirmed Eya4 and E193 bind and regulate p27 expression in a contradictory manner. Activity and phosphorylation status of the downstream molecules casein kinase-2α and histone deacetylase 2 were significantly elevated in Eya4- but significantly reduced in E193-overexpressing animals compared with wild-type littermates. Magnetic resonance imaging and hemodynamic analysis indicate Eya4-overexpression results in an age-dependent development of hypertrophy already under baseline conditions with no obvious functional effects, whereas E193 animals develop onset of dilative cardiomyopathy as seen in human E193 patients. Both cardiac phenotypes were aggravated on pressure overload. Finally, we identified a new heterozygous truncating Eya4 mutation, E215, which leads to similar clinical features of disease and a stable myocardial expression of the mutant protein as seen with E193. CONCLUSIONS: Our results implicate Eya4/Six1 regulates normal cardiac function via p27/casein kinase-2α/histone deacetylase 2 and indicate that mutations within this transcriptional complex and signaling cascade lead to the development of cardiomyopathy.


Subject(s)
Base Sequence , Cardiomegaly/metabolism , Cyclin-Dependent Kinase Inhibitor p27/biosynthesis , Sequence Deletion , Trans-Activators/metabolism , Animals , Cardiomegaly/genetics , Cardiomegaly/pathology , Cyclin-Dependent Kinase Inhibitor p27/genetics , Gene Expression Regulation/genetics , Humans , Mice , Mice, Transgenic , Rats , Trans-Activators/genetics
2.
Clin Res Cardiol ; 100(12): 1087-93, 2011 Dec.
Article in English | MEDLINE | ID: mdl-21789513

ABSTRACT

Two sons of a consanguineous marriage developed biventricular cardiomyopathy. One boy died of severe heart failure at the age of 6 years, the other was transplanted because of severe heart failure at the age of 10 years. In addition, focal palmoplantar keratoderma and woolly hair were apparent in both boys. As similar phenotypes have been described in Naxos disease and Carvajal syndrome, respectively, the genes for plakoglobin (JUP) and desmoplakin (DSP) were screened for mutations using direct genomic sequencing. A novel homozygous 2 bp deletion was identified in an alternatively spliced region of DSP. The deletion 5208_5209delAG led to a frameshift downstream of amino acid 1,736 with a premature truncation of the predominant cardiac isoform DSP-1. This novel homozygous truncating mutation in the isoform-1 specific region of the DSP C-terminus caused Carvajal syndrome comprising severe early-onset heart failure with features of non-compaction cardiomyopathy, woolly hair and an acantholytic form of palmoplantar keratoderma in our patient. Congenital hair abnormality and manifestation of the cutaneous phenotype in toddler age can help to identify children at risk for cardiac death.


Subject(s)
Cardiomyopathies/genetics , Desmoplakins/genetics , Frameshift Mutation , Hair Diseases/genetics , Isolated Noncompaction of the Ventricular Myocardium/genetics , Keratoderma, Palmoplantar/genetics , Sequence Deletion , Age of Onset , Base Sequence , Cardiomyopathies/diagnosis , Cardiomyopathy, Dilated , Child , Child, Preschool , DNA Mutational Analysis , Fatal Outcome , Genetic Predisposition to Disease , Hair Diseases/diagnosis , Heart Failure/genetics , Homozygote , Humans , Isolated Noncompaction of the Ventricular Myocardium/diagnosis , Keratoderma, Palmoplantar/diagnosis , Male , Molecular Sequence Data , Pedigree , Phenotype , Severity of Illness Index
3.
Eur J Heart Fail ; 13(11): 1185-92, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21750094

ABSTRACT

AIMS: Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) can both be due to mutations in the genes encoding ß-myosin heavy chain (MYH7) or cardiac myosin-binding protein C (MYBPC3). The aim of the present study was to determine the prevalence and spectrum of mutations in both genes in German HCM and DCM patients and to establish novel genotype-to-phenotype correlations. METHODS AND RESULTS: Coding exons and intron flanks of the two genes MYH7 and MYBPC3 of 236 patients with HCM and 652 patients with DCM were sequenced by conventional and array-based means. Clinical records were established following standard protocols. Mutations were detected in 41 and 11% of the patients with HCM and DCM, respectively. Differences were observed in the frequency of splice site and frame-shift mutations in the gene MYBPC3, which occurred more frequently (P< 0.02, P< 0.001, respectively) in HCM than in DCM, suggesting that cardiac myosin-binding protein C haploinsufficiency predisposes to hypertrophy rather than to dilation. Additional novel genotype-to-phenotype correlations were found in HCM, among these a link between MYBPC3 mutations and a particularly large thickness of the interventricular septum (P= 0.04 vs. carriers of a mutation in MYH7). Interestingly, this correlation and a link between MYH7 mutations and a higher degree of mitral valve regurgitation held true for both HCM and DCM, indicating that the gene affected by a mutation may determine the magnitude of structural and functional alterations in both HCM and DCM. CONCLUSION: A large clinical-genetic study has unravelled novel genotype-to-phenotype correlations in HCM and DCM which warrant future investigation of both the underlying mechanisms and the prognostic use.


Subject(s)
Cardiomyopathy, Dilated/genetics , Cardiomyopathy, Hypertrophic/genetics , Cardiomyopathy, Dilated/epidemiology , Cardiomyopathy, Hypertrophic/epidemiology , Genetic Predisposition to Disease , Humans , Mutation , Phenotype
4.
Med Klin (Munich) ; 103(3): 166-74, 2008 Mar 15.
Article in German | MEDLINE | ID: mdl-18344067

ABSTRACT

The pathogenesis of most cardiovascular disorders is multifactorial and incompletely understood. Besides genetic influences that often arise from multiple genetic loci, the specific nutritional and environmental influences do contribute to the dysfunctional development. Nevertheless, a rather small number of cardiovascular diseases exhibits Mendelian traits, since they are caused by a single gene defect. Examples are familial cardiomyopathies, primary arrhythmias and connective tissues disorders of vessels. More detailed investigations reveal that even these entities are usually not purely monogenic, as they do not appear with the same intensity in all mutation carriers. Hence, there must be further modifying factors that influence the penetrance of the disease. Despite this limitation monogenic diseases allow the identification of the underlying genetic defects and thereby a deeper insight into the pathophysiology. Predictive genetic diagnostics, on the other hand, permit a better adaptation of medical care to the individual risk of offspring that are not yet affected.


Subject(s)
Heart Diseases/genetics , Adult , Arrhythmias, Cardiac/genetics , Arrhythmogenic Right Ventricular Dysplasia/diagnosis , Arrhythmogenic Right Ventricular Dysplasia/genetics , Cardiomyopathy, Dilated/genetics , Cardiomyopathy, Dilated/therapy , Cardiomyopathy, Hypertrophic/genetics , Coronary Disease/genetics , Death, Sudden, Cardiac/etiology , Electrocardiography , Female , Genetic Diseases, Inborn , Genetic Predisposition to Disease , Heart Defects, Congenital/genetics , Heart Diseases/diagnosis , Heart Diseases/etiology , Heart Diseases/mortality , Heart Diseases/physiopathology , Heart Valve Diseases/genetics , Humans , Hypertension/genetics , Infant, Newborn , Male , Mutation , Mutation, Missense , Phenotype , Polymorphism, Genetic , Prognosis , Randomized Controlled Trials as Topic
5.
N Engl J Med ; 356(8): 809-19, 2007 Feb 22.
Article in English | MEDLINE | ID: mdl-17314340

ABSTRACT

BACKGROUND: The Björnstad syndrome, an autosomal recessive disorder associated with sensorineural hearing loss and pili torti, is caused by mutation of a previously unidentified gene on chromosome 2q34-36. METHODS: Refined genetic mapping and DNA sequencing of 44 genes between D2S2210 and D2S2244 revealed BCS1L mutations. Functional analyses elucidated how BCS1L mutations cause the Björnstad syndrome. RESULTS: BCS1L encodes a member of the AAA family of ATPases that is necessary for the assembly of complex III in the mitochondria. In addition to the Björnstad syndrome, BCS1L mutations cause complex III deficiency and the GRACILE syndrome, which in neonates are lethal conditions that have multisystem and neurologic manifestations typifying severe mitochondrial disorders. Patients with the Björnstad syndrome have mutations that alter residues involved in protein-protein interactions, whereas mutations in patients with complex III deficiency alter ATP-binding residues, as deduced from the crystal structure of a related AAA-family ATPase. Biochemical studies provided evidence to support this model: complex III deficiency mutations prevented ATP-dependent assembly of BCS1L-associated complexes. All mutant BCS1L proteins disrupted the assembly of complex III, reduced the activity of the mitochondrial electron-transport chain, and increased the production of reactive oxygen species. However, only mutations associated with complex III deficiency increased mitochondrial content, which further increased the production of reactive oxygen species. CONCLUSIONS: BCS1L mutations cause disease phenotypes ranging from highly restricted pili torti and sensorineural hearing loss (the Björnstad syndrome) to profound multisystem organ failure (complex III deficiency and the GRACILE syndrome). All BCS1L mutations disrupted the assembly of mitochondrial respirasomes (the basic unit for respiration in human mitochondria), but the clinical expression of the mutations was correlated with the production of reactive oxygen species. Mutations that cause the Björnstad syndrome illustrate the exquisite sensitivity of ear and hair tissues to mitochondrial function, particularly to the production of reactive oxygen species.


Subject(s)
Electron Transport Complex III/genetics , Hair Diseases/genetics , Hearing Loss, Sensorineural/genetics , Mutation, Missense , ATPases Associated with Diverse Cellular Activities , Bacterial Proteins/chemistry , Child, Preschool , DNA Mutational Analysis , Electron Transport Complex III/chemistry , Female , Humans , Male , Mitochondria , Pedigree , Protein Structure, Tertiary , Sequence Homology, Amino Acid , Syndrome , Yeasts
6.
Hum Genet ; 118(3-4): 451-7, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16228230

ABSTRACT

Inherited dilated cardiomyopathy (DCM) is a genetically and phenotypically very heterogeneous disease. DCM is caused by mutations in multiple genes encoding proteins that are involved in force generation, force transmission, energy production and several signalling pathways. Thus, the pathophysiology of heart failure is complex and not yet fully understood. Familial forms of DCM let the way to identify new key proteins by positional cloning and to study respective pathomechanisms that are critical for normal cardiac function, but may not have been correlated with heart disease before. Here we report a three-generation pedigree including 16 individuals affected by dilated cardiomyopathy without additional phenotypes. The pedigree is consistent with autosomal-dominant inheritance and age-related penetrance. A genome-wide linkage analysis excluded linkage to all known DCM genes and loci, whereas several close markers on chromosome 7q22.3-31.1 segregated with the disease (maximum logarithm of odds score, 4.20 at D7S471 and D7S501). The disease causing mutation lies in a 9.73 Mb interval between markers D7S2545 and D7S2554 that contains no known cytoskeletal genes. Coding exons of the candidate genes LAMB1, LAMB4 and PIK3CG were screened but no mutations were identified.


Subject(s)
Cardiomyopathy, Dilated/genetics , Chromosomes, Human, Pair 7 , Adolescent , Adult , Age of Onset , Aged , DNA Mutational Analysis , Female , Genetic Linkage , Humans , Inheritance Patterns , Male , Middle Aged , Pedigree , Phenotype
7.
Nat Genet ; 37(4): 418-22, 2005 Apr.
Article in English | MEDLINE | ID: mdl-15735644

ABSTRACT

We identified a human mutation that causes dilated cardiomyopathy and heart failure preceded by sensorineural hearing loss (SNHL). Unlike previously described mutations causing dilated cardiomyopathy that affect structural proteins, this mutation deletes 4,846 bp of the human transcriptional coactivator gene EYA4. To elucidate the roles of eya4 in heart function, we studied zebrafish embryos injected with antisense morpholino oligonucleotides. Attenuated eya4 transcript levels produced morphologic and hemodynamic features of heart failure. To determine why previously described mutated EYA4 alleles cause SNHL without heart disease, we examined biochemical interactions of mutant Eya4 peptides. Eya4 peptides associated with SNHL, but not the shortened 193-amino acid peptide associated with dilated cardiomyopathy and SNHL, bound wild-type Eya4 and associated with Six proteins. These data define unrecognized and crucial roles for Eya4-Six-mediated transcriptional regulation in normal heart function.


Subject(s)
Cardiomyopathy, Dilated/genetics , Hearing Loss, Sensorineural/genetics , Mutation/genetics , Trans-Activators/genetics , Zebrafish/metabolism , Animals , Blotting, Northern , Embryo, Nonmammalian/cytology , Embryo, Nonmammalian/metabolism , Exons/genetics , Eye Proteins/genetics , Heart/physiopathology , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Humans , Immunoprecipitation , In Situ Hybridization , Mice , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Oligonucleotides, Antisense/pharmacology , Peptide Fragments/genetics , Peptide Fragments/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Zebrafish/embryology , Homeobox Protein SIX3
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