Author + information
- Received December 26, 2015
- Revision received April 28, 2016
- Accepted May 2, 2016
- Published online August 29, 2016.
- Rene L. Begay, BSa,
- Charles A. Tharp, MDa,
- August Martinb,c,
- Sharon L. Graw, PhDa,
- Gianfranco Sinagra, MDd,
- Daniela Miani, MDe,
- Mary E. Sweet, BAa,
- Dobromir B. Slavov, PhDa,
- Neil Stafford, MDb,c,f,
- Molly J. Zellerb,c,
- Rasha Alnefaieb,c,
- Teisha J. Rowland, PhDa,
- Francesca Brun, MDd,
- Kenneth L. Jones, PhDg,
- Katherine Gowang,
- Luisa Mestroni, MDa,
- Deborah M. Garrity, PhDb,c and
- Matthew R.G. Taylor, MD, PhDa,∗ ()
- aCardiovascular Institute and Adult Medical Genetics Program, University of Colorado Denver, Aurora, Colorado
- bCenter for Cardiovascular Research, Colorado State University, Fort Collins, Colorado
- cDepartment of Biology, Colorado State University, Fort Collins, Colorado
- dCardiovascular Department, Ospedali Riuniti and University of Trieste, Trieste, Italy
- eDepartment of Cardiothoracic Science, University Hospital S. Maria della Misericordia, Udine, Italy
- fCardiovascular and Biofluid Mechanics Laboratory, Colorado State University, Fort Collins, Colorado
- gDepartment of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, Colorado
- ↵∗Reprint requests and correspondence:
Dr. Matthew R.G. Taylor, Adult Medical Genetics Program, University of Colorado Denver, 12700 East 19th Avenue, F442, Room 8022, Aurora, Colorado 80045.
• Deoxyribonucleic acid obtained from 2 large DCM families was studied using whole-exome sequencing and cosegregation analysis resulting in the identification of a novel disease gene, FLNC. The 2 families, from the same Italian region, harbored the same FLNC splice-site mutation (FLNC c.7251+1G>A).
• A third U.S. family was then identified with a novel FLNC splice-site mutation (FLNC c.5669-1delG) that leads to haploinsufficiency as shown by the FLNC Western blot analysis of the heart muscle.
• The FLNC ortholog flncb morpholino was injected into zebrafish embryos, and when flncb was knocked down caused a cardiac dysfunction phenotype.
• On electron microscopy, the flncb morpholino knockdown zebrafish heart showed defects within the Z-discs and sarcomere disorganization.
A genetic etiology has been identified in 30% to 40% of dilated cardiomyopathy (DCM) patients, yet only 50% of these cases are associated with a known causative gene variant. Thus, in order to understand the pathophysiology of DCM, it is necessary to identify and characterize additional genes. In this study, whole exome sequencing in combination with segregation analysis was used to identify mutations in a novel gene, filamin C (FLNC), resulting in a cardiac-restricted DCM pathology. Here we provide functional data via zebrafish studies and protein analysis to support a model implicating FLNC haploinsufficiency as a mechanism of DCM.
This study was supported by the National Institutes of Health grants UL1 RR025780, UL1 TR001082, R01 HL69071, R01 116906 to Dr. Mestroni, and Colorado Clinical and Translational Sciences Institute grants K23 JL067915 and R01HL109209 to Dr. Taylor. The human cardiac tissue bank was supported by National Institutes of Health/National Center for Advancing Translational Sciences Colorado Clinical and Translational Science Awards grant UL1 TR001082. Funding was also received from CRTrieste Foundation and GENERALI Foundation to Dr. Sinagra. This work was supported in part by a Trans-Atlantic Network of Excellence grant from the Leducq Foundation (14-CVD 03). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received December 26, 2015.
- Revision received April 28, 2016.
- Accepted May 2, 2016.
- The Authors