Frank, Derk, Rangrez, Ashraf Yusuf, Friedrich, Corinna, Dittmann, Sven, Stallmeyer, Birgit, Yadav, Pankaj ORCID: 0000-0001-7160-9209, Bernt, Alexander, Borlepawar, Ellen Schulze-Bahr Ankush, Zimmermann, Wolfram-Hubertus, Peischard, Stefan, Seebohm, Guiscard, Linke, Wolfgang A., Baba, Hideo A., Krueger, Marcus, Unger, Andreas, Usinger, Philip, Frey, Norbert ORCID: 0000-0001-7611-378X and Schulze-Bahr, Eric (2019). Cardiac alpha-Actin (ACTC1) Gene Mutation Causes Atrial-Septal Defects Associated With Late-Onset Dilated Cardiomyopathy. Circ.-Genom. Precis. Med., 12 (8). PHILADELPHIA: LIPPINCOTT WILLIAMS & WILKINS. ISSN 1942-325X

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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 alpha-actin. Methods: We combined a genome-wide linkage analysis with cell biology, microscopy, and molecular biology tools to characterize a novel ACTC1 (cardiac alpha-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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Frank, DerkUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rangrez, Ashraf YusufUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Friedrich, CorinnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dittmann, SvenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stallmeyer, BirgitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yadav, PankajUNSPECIFIEDorcid.org/0000-0001-7160-9209UNSPECIFIED
Bernt, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Borlepawar, Ellen Schulze-Bahr AnkushUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zimmermann, Wolfram-HubertusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peischard, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seebohm, GuiscardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Linke, Wolfgang A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baba, Hideo A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krueger, MarcusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Unger, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Usinger, PhilipUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frey, NorbertUNSPECIFIEDorcid.org/0000-0001-7611-378XUNSPECIFIED
Schulze-Bahr, EricUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-145117
DOI: 10.1161/CIRCGEN.119.002491
Journal or Publication Title: Circ.-Genom. Precis. Med.
Volume: 12
Number: 8
Date: 2019
Publisher: LIPPINCOTT WILLIAMS & WILKINS
Place of Publication: PHILADELPHIA
ISSN: 1942-325X
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
HEART; APOPTOSIS; TBX20; GATA4; MICEMultiple languages
Cardiac & Cardiovascular Systems; Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/14511

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