Derk Frank1,2, Ashraf Yusuf Rangrez1,2, Corinna Friedrich3,4, Sven Dittmann3, Birgit Stallmeyer3, Pankaj Yadav5, Alexander Bernt1,2, Ellen Schulze-Bahr3, Ankush Borlepawar1,2, Wolfram-Hubertus Zimmermann6,2, Stefan Peischard3, Guiscard Seebohm3, Wolfgang A Linke7,2, Hideo A Baba8, Marcus Krüger9, Andreas Unger3, Philip Usinger1, Norbert Frey1,2, Eric Schulze-Bahr3. 1. Department of Internal Medicine III, Cardiology and Angiology, University Medical Center Schleswig-Holstein, Campus Kiel (D.F., A.Y.R., A. Bernt, A. Borlepawar, P.U., N.F.). 2. Co-affiliated with DZHK (German Centre for Cardiovascular Research), sites Hamburg/Kiel/Lübeck and Göttingen, Germany (D.F., A.Y.R., A. Bernt, A. Borlepawar, W.H.-Z., W.A.L., N.F.). 3. Institute for Genetics of Heart Diseases (IfGH), Department of Cardiovascular Medicine (C.F., S.D., B.S., Ellen Schulze-Bahr, S.P., G.S., A.U., Eric Schulze-Bahr), University Hospital Münster. 4. Institute for Human Genetics (C.F), University Hospital Münster. 5. Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg (P.Y.). 6. Institute of Pharmacology and Toxicology, University Medical Center Göttingen (W.H.-Z.). 7. Institute of Physiology II (W.A.L.), University Hospital Münster. 8. Institute of Pathology, University of Duisburg-Essen (H.A.B.). 9. Center for Molecular Medicine Cologne (CMMC), Proteomics Facility, University of Cologne (M.K.).
Abstract
BACKGROUND: Familial atrial septal defect (ASD) has previously been attributed primarily to mutations in cardiac transcription factors. Here, we report a large, multi-generational family (78 members) with ASD combined with a late-onset dilated cardiomyopathy and further characterize the consequences of mutant α-actin. METHODS: We combined a genome-wide linkage analysis with cell biology, microscopy, and molecular biology tools to characterize a novel ACTC1 (cardiac α-actin) mutation identified in association with ASD and late-onset dilated cardiomyopathy in a large, multi-generational family. RESULTS: Using a genome-wide linkage analysis, the ASD disease locus was mapped to chromosome 15q14 harboring the ACTC1 gene. In 15 affected family members, a heterozygous, nonsynonymous, and fully penetrant mutation (p. Gly247Asp) was identified in exon 5 of ACTC1 that was absent in all healthy family members (n=63). In silico tools predicted deleterious consequences of this variant that was found absent in control databases. Ultrastructural analysis of myocardial tissue of one of the mutation carriers showed sarcomeric disarray, myofibrillar degeneration, and increased apoptosis, while cardiac proteomics revealed a significant increase in extracellular matrix proteins. Consistently, structural defects and increased apoptosis were also observed in neonatal rat ventricular cardiomyocytes overexpressing the mutant, but not native human ACTC1. Molecular dynamics studies and additional mechanistic analyses in cardiomyocytes confirmed actin polymerization/turnover defects, thereby affecting contractility. CONCLUSIONS: A combined phenotype of ASD and late-onset heart failure was caused by a heterozygous, nonsynonymous ACTC1 mutation. Mechanistically, we found a shared molecular mechanism of defective actin signaling and polymerization in both cardiac development and contractile function. Detection of ACTC1 mutations in patients with ASD may thus have further clinical implications with regard to monitoring for (late-onset) dilated cardiomyopathy.
BACKGROUND: Familial atrial septal defect (ASD) has previously been attributed primarily to mutations in cardiac transcription factors. Here, we report a large, multi-generational family (78 members) with ASD combined with a late-onset dilated cardiomyopathy and further characterize the consequences of mutant α-actin. METHODS: We combined a genome-wide linkage analysis with cell biology, microscopy, and molecular biology tools to characterize a novel ACTC1 (cardiac α-actin) mutation identified in association with ASD and late-onset dilated cardiomyopathy in a large, multi-generational family. RESULTS: Using a genome-wide linkage analysis, the ASD disease locus was mapped to chromosome 15q14 harboring the ACTC1 gene. In 15 affected family members, a heterozygous, nonsynonymous, and fully penetrant mutation (p. Gly247Asp) was identified in exon 5 of ACTC1 that was absent in all healthy family members (n=63). In silico tools predicted deleterious consequences of this variant that was found absent in control databases. Ultrastructural analysis of myocardial tissue of one of the mutation carriers showed sarcomeric disarray, myofibrillar degeneration, and increased apoptosis, while cardiac proteomics revealed a significant increase in extracellular matrix proteins. Consistently, structural defects and increased apoptosis were also observed in neonatal rat ventricular cardiomyocytes overexpressing the mutant, but not native humanACTC1. Molecular dynamics studies and additional mechanistic analyses in cardiomyocytes confirmed actin polymerization/turnover defects, thereby affecting contractility. CONCLUSIONS: A combined phenotype of ASD and late-onset heart failure was caused by a heterozygous, nonsynonymous ACTC1 mutation. Mechanistically, we found a shared molecular mechanism of defective actin signaling and polymerization in both cardiac development and contractile function. Detection of ACTC1 mutations in patients with ASD may thus have further clinical implications with regard to monitoring for (late-onset) dilated cardiomyopathy.
Authors: Ashraf Yusuf Rangrez; Lucia Kilian; Katharina Stiebeling; Sven Dittmann; Pankaj Yadav; Eric Schulze-Bahr; Norbert Frey; Derk Frank Journal: Data Brief Date: 2020-01-02
Authors: Nadeem Ul Nazeer; Mohammad Akbar Bhat; Bilal Rah; Gh Rasool Bhat; Shadil Ibrahim Wani; Adfar Yousuf; Abdul Majeed Dar; Dil Afroze Journal: Int J Environ Res Public Health Date: 2022-08-11 Impact factor: 4.614