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Review
. 2020 Jun;41(6):1091-1111.
doi: 10.1002/humu.24004. Epub 2020 Mar 20.

A mutation update for the FLNC gene in myopathies and cardiomyopathies

Job A J Verdonschot  1   2 , Els K Vanhoutte  1 , Godelieve R F Claes  1 , Apollonia T J M Helderman-van den Enden  1 , Janneke G J Hoeijmakers  3 , Debby M E I Hellebrekers  1 , Amber de Haan  1 , Imke Christiaans  4   5 , Ronald H Lekanne Deprez  4 , Hanne M Boen  6 , Emeline M van Craenenbroeck  6 , Bart L Loeys  7 , Yvonne M Hoedemaekers  5   8 , Carlo Marcelis  8 , Marlies Kempers  8 , Esther Brusse  9 , Jaap I van Waning  10   11 , Annette F Baas  12 , Dennis Dooijes  12 , Folkert W Asselbergs  13 , Daniela Q C M Barge-Schaapveld  14 , Pieter Koopman  15 , Arthur van den Wijngaard  1 , Stephane R B Heymans  2   16   17 , Ingrid P C Krapels  1 , Han G Brunner  1   8   18
Affiliations
Review

A mutation update for the FLNC gene in myopathies and cardiomyopathies

Job A J Verdonschot et al. Hum Mutat. 2020 Jun.

Abstract

Filamin C (FLNC) variants are associated with cardiac and muscular phenotypes. Originally, FLNC variants were described in myofibrillar myopathy (MFM) patients. Later, high-throughput screening in cardiomyopathy cohorts determined a prominent role for FLNC in isolated hypertrophic and dilated cardiomyopathies (HCM and DCM). FLNC variants are now among the more prevalent causes of genetic DCM. FLNC-associated DCM is associated with a malignant clinical course and a high risk of sudden cardiac death. The clinical spectrum of FLNC suggests different pathomechanisms related to variant types and their location in the gene. The appropriate functioning of FLNC is crucial for structural integrity and cell signaling of the sarcomere. The secondary protein structure of FLNC is critical to ensure this function. Truncating variants with subsequent haploinsufficiency are associated with DCM and cardiac arrhythmias. Interference with the dimerization and folding of the protein leads to aggregate formation detrimental for muscle function, as found in HCM and MFM. Variants associated with HCM are predominantly missense variants, which cluster in the ROD2 domain. This domain is important for binding to the sarcomere and to ensure appropriate cell signaling. We here review FLNC genotype-phenotype correlations based on available evidence.

Keywords: FLNC; cardiomyopathy; filamin; genotype-phenotype correlation; myopathy.

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Figures

Figure 1
Figure 1
Variant selection of all FLNC variants and the overview of all variants in association with their phenotype. DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; HGMD, Human Gene Mutation Database; LOVD, Leiden Open Variation Database
Figure 2
Figure 2
Schematic representation of the FLNC gene with their protein‐coding domains. Numbers inside the boxes refer to the Ig‐like domains of filamin C. Above and below the schematic are all unique variants associated with dilated cardiomyopathy. Variants are annotated at the protein level
Figure 3
Figure 3
Schematic representation of the FLNC gene with their protein‐coding domains. Numbers inside the boxes refer to the Ig‐like domains of filamin C. Above and below the schematic are all unique variants associated with hypertrophic cardiomyopathy. Variants are annotated at the protein level
Figure 4
Figure 4
Schematic representation of the FLNC gene with their protein‐coding domains. Numbers inside the boxes refer to the Ig‐like domains of filamin C. Above and below the schematic are all unique variants associated with different cardiac phenotypes. Variants are annotated at the protein level
Figure 5
Figure 5
Schematic representation of the FLNC gene with their protein‐coding domains. Numbers inside the boxes refer to the Ig‐like domains of filamin C. Above and below the schematic are all unique variants associated with myopathies. Variants are annotated at the protein level
Figure 6
Figure 6
A timeline representation of animal models generated to study FLNC variants. eGFP indicates enhanced green fluorescent protein
Figure 7
Figure 7
A summary how different variants in FLNC lead to a variety of disease mechanisms eventually giving a spectrum of clinical entities with the corresponding structural histological changes. These FLNC‐associated diseases contain specific clinical characteristics compared with other forms of the corresponding disease
See this image and copyright information in PMC

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