FLNC Gene Splice Mutations Cause Dilated Cardiomyopathy

• Published in: JACC. Basic to translational science Vol. 1; no. 5; pp. 344 - 359
• Main Authors: Begay, Rene L., BS, Tharp, Charles A., MD, Martin, August, Graw, Sharon L., PhD, Sinagra, Gianfranco, MD, Miani, Daniela, MD, Sweet, Mary E., BA, Slavov, Dobromir B., PhD, Stafford, Neil, MD, Zeller, Molly J, Alnefaie, Rasha, Rowland, Teisha J., PhD, Brun, Francesca, MD, Jones, Kenneth L., PhD, Gowan, Katherine, Mestroni, Luisa, MD, Garrity, Deborah M., PhD, Taylor, Matthew R.G., MD, PhD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-08-2016; Elsevier
• Subjects: Cardiovascular; cardiovascular genetics; dilated cardiomyopathy; filamin C; heart failure; PRE-CLINICAL RESEARCH; zebrafish; LoF; ribonucleic acid; loss-of-function; RNA; WES; filamin C; myofibrillar myopathy; filamin Ca; filamin Cb; GFP; deoxyribonucleic acid; MFM; flnca; RT-PCR; flncb; days post-fertilization; dpf; FLNC; transmission electron microscopy; morpholino; dilated cardiomyopathy; hpf; cardiovascular genetics; heart failure; MO; SV; retrograde fraction; real-time polymerase chain reaction; hours post-fertilization; green fluorescent protein; whole exome sequencing; DCM; stroke volume; HCM; RF; DNA; hypertrophic cardiomyopathy; zebrafish; TEM
• ISSN: 2452-302X; 2452-302X
• DOI: 10.1016/j.jacbts.2016.05.004

Summary 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.