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Filamin C in cardiomyopathy: from physiological roles to DNA variants

Abstract

Cardiomyopathy affects approximately 1 in 500 adults and is the leading cause of death. Familial cases are common, and mutations in many genes are involved in cardiomyopathy, especially those in genes encoding cytoskeletal, sarcomere, and nuclear envelope proteins. Filamin C is an actin-binding protein encoded by filamin C (FLNC) gene and participates in sarcomere stability maintenance. FLNC was first demonstrated to be a causal gene of myofibrillar myopathy; recently, it has been found that FLNC mutation plays a critical role in the pathogenesis of cardiomyopathy. In this review, we summarized the physiological roles of filamin C in cardiomyocytes and the genetic evidence for links between FLNC mutations and cardiomyopathies. Truncated FLNC is enriched in dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy. Non-truncated FLNC is enriched in hypertrophic cardiomyopathy and restrictive cardiomyopathy. Two major pathomechanisms in FLNC-related cardiomyopathy have been described: protein aggregation resulting from non-truncating mutations and haploinsufficiency triggered by filamin C truncation. Therefore, it is important to understand the cellular biology and molecular regulation of FLNC to design new therapies to treat patients with FLNC-related cardiomyopathy.

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Acknowledgements

We thank Dr. Haobin Jiang for his aid in figure drawing and Zhuyun Qin for her help in English language editing.

Funding

This work was supported by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (CIFMS, 2016-I2M-1–015), the National Key Research and Development Project of China (2016YFC1300900 and 2019YFA0801500), and the National Natural Science Foundation of China (81900343 and 31801068).

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Shengshou Hu and Yu Nie had the idea for the article. Shen Song and Anteng Shi performed the literature search and data analysis and drafted the article. Hong Lian revised the manuscript. All authors approved the final version of the manuscript.

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Correspondence to Shengshou Hu or Yu Nie.

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Shen Song and Anteng Shi are co-first author.

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Song, S., Shi, A., Lian, H. et al. Filamin C in cardiomyopathy: from physiological roles to DNA variants. Heart Fail Rev 27, 1373–1385 (2022). https://doi.org/10.1007/s10741-021-10172-z

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Keywords

  • Filamins
  • Cardiomyopathy
  • FLNC
  • Cardiomyocytes