# The Cardiac Role of Filamin C

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $394,375

## Abstract

PROJECT SUMMARY
Filamin C (FLNC) is a muscle-specific actin-binding protein, which localizes to the Z-disc and intercalated disc
of cardiac muscle, and interacts with β1 integrin and sarcoglycans at the costamere. Multiple mutations in
FLNC are associated with human cardiomyopathies, highlighting its importance for cardiac function. Individuals
with compound heterozygous variants in the FLNC gene (F106L/R991*(a null allele)) develop pediatric dilated
cardiomyopathy (DCM). Interestingly, individuals carrying only one FLNC (F106L or R991*) variant do not
exhibit any signs of cardiomyopathy; suggesting that F106L is a loss-of-function mutation. Little is known as to
the specific role of FLNC in cardiomyocytes (CMs), or mechanisms by which the F106L mutation leads to loss
of function, and how individuals with FLNC F106/null compound heterozygous alleles develop DCM. Deletion
of the last 8 exons of FLNC in mice results in perinatal lethality. However, given that multiple distinct FLNC
mutations lead to cardiomyopathy, the absence of a cardiac phenotype in this FLNC-deficient mouse model is
puzzling. As the authors noted, a truncated FLNC protein is still expressed in this mutant mice, suggesting that
the mutant FLNC allele is hypomorphic. Thus, a true null FLNC mouse model and a FLNC CM-specific
knockout (KO) mouse model are essential to comprehensively understand the role of FLNC in the heart. In
addition, studies in CMs and in vivo animal models are essential to understand the molecular basis underlying
the DCM caused by the F106L/null mutations in FLNC. To address these questions, we have generated a
floxed FLNC mouse line and used it to generate a FLNC global KO (gKO) mouse model, as well as constitutive
(cKO) and inducible (icKO) FLNC CM-specific KO mice. In contrast to the reported FLNC hypomorphic mouse,
our FLNC gKO mouse model is lethal at E10.5 and exhibits severe chest edema and decreased CM
proliferation. Moreover, FLNC cKO mice die between E10.5-E11.5 and exhibit an essentially identical
morphological phenotype as observed in FLNC gKO mice, suggesting that the primary cause of lethality in
FLNC gKO mice is due to loss of FLNC in CMs. We also observed that adult FLNC icKO mice develop DCM
and progressive heart failure. Accordingly, our hypothesis is that FLNC plays an essential role in maintaining
CM sarcomere and costamere integrity, cardiac morphogenesis, and normal cardiac function, and that the
FLNC F106L mutation is a loss-of-function mutation and impairs specific interaction between FLNC and actin.
Our Specific Aims are: 1. To determine the role of FLNC in the developing and adult myocardium by analyzing
cKO and icKO FLNC CM-specific KO mice for heart morphogenesis, structure and function, and the
progression of cardiomyopathy; and 2. To elucidate mechanisms by which the F106L FLNC mutation leads to
loss of function and how individuals with F106L/null compound heterozygous alleles develop pediatric DCM by
analysis of F107L/null and F...

## Key facts

- **NIH application ID:** 9842002
- **Project number:** 5R01HL144872-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Ju Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $394,375
- **Award type:** 5
- **Project period:** 2019-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9842002

## Citation

> US National Institutes of Health, RePORTER application 9842002, The Cardiac Role of Filamin C (5R01HL144872-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9842002. Licensed CC0.

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