Filamin C (FLNC)

Filamins are a family of actin-binding proteins. In humans and other mammals, there are three filamins: filamin A, filamin B, and filamin C. Filamins A and B are widely expressed, while filamin C expression appears limited to skeletal and cardiac muscle.

The figure below (adapted from [1]) shows the domain structure of filamin C.

Filamins have an amino-terminal actin-binding domain consisting of two calponin-homology (CH) domains. The rest of the protein consists of 24 immunoglobulin-like filamin domains with two hinge domains. Filamin C differs from filamins A and B in a novel domain 20 that interacts with Z disc proteins, including myotilin and myozenins. While filamin domains 1-15 form a rod, domain 20 is folded over domains 19 and 21 [2]. Filamin domain 24 is required for homodimerization.

The figure also shows the positions of human mutations associated with various types of cardiomyopathy and skeletal muscle myopathy, as summarized in the table below.

Human FLNC Alleles Associated with Cardiomyopathy
FigureaAllelebDomaincMutation TypedCitation
5R269*Filamin 1termination6
27N290KFilamin 1missense5
6R482*Filamin 3termination7
7I683Rfs*9Filamin 5frameshift1
8Y705*Filamin 5termination3
9Q707*Filamin 5termination6
28S792IFilamin 6missense8
10Y928*Filamin 7termination1
11R991*Filamin 8termination7
29A1183LFilamin 10missense9
30A1186VFilamin 10missense9
31S1194LFilamin 10missense1
12V1198Gfs*64Filamin 10frameshift1
32Y1216NFilamin 10missense10
13R1370*Filamin 12termination3
33G1424VFilamin 12missense1
14A1539TFilamin 14termination5
34A1551TFilamin 14missense8
15L1573*Filamin 14termination7
35S1624LFilamin 14missense11
36I1666TFilamin 15missense1
16G1800*Filamin 16termination3
37I1946_T1947dupFilamin 18in-frame duplication1
38R1999QFilamin 18missense8
39G2011EFilamin 18missense1
40G2039RFilamin 19missense12
17Y2100*Filamin 19frameshift duplication13
41R2133HFilamin 19missense5
42R2140QFilamin 19missense14
43G2151SFilamin 19/20missense5
44I2160FFilamin 19/20missense11
45V2297MFilamin 20missense15
46P2298LFilamin 20missense16
47G2299SFilamin 20missense1
48H2315NFilamin 21missense5
49R2318WFilamin 21missense14
50I2359TFilamin 21missense1
18Y2373Cfs*7Filamin 21frameshift1
51V2375LFilamin 21missense14
52R2410CFilamin 22missense1
53E2417PFilamin 22missense1
54A2430VFilamin 22missense5
55R2495HFilamin 22missense1
19P2513Efs*12Filamin 23frameshift17
20Q2549*Filamin 23termination1
21C2555*Filamin 23termination1
56Y2563CFilamin 23missense16
57P2643_L2645delFilamin 24in-frame deletion1
Human FLNC Alleles Associated with Skeletal Muscle Myopathy
FigureaAllelebDomaincMutation TypedCitation
Filamin 7deletion + insertion20
62V930_T933delFilamin 7in-frame deletion21
63931_935delFilamin 7in-frame deletion22
64Y1216NFilamin 10missense10
65A1630VFilamin 14missense23
22F1720Lfs*63Filamin 15frameshift24
23G1722Vfs*61Filamin 15frameshift25
66V2375IFilamin 21missense26
67T2419MFilamin 22missense27
24W2710*Filamin 24termination28
Equine FLNC Alleles Associated with Skeletal Muscle Myopathye
FigureaAllelebDomaincMutation TypedCitation
E753K+A1207T (P3)Filamin 6, 11missenseEquiSeq

aAbbreviation used in Figure.

bAllele nomenclature shows the single-letter code for the wild-type amino acid, the amino acid position in the protein, and the substituted amino acid (for missense alleles) or “*” to indicate a termination codon. Frameshift alleles indicate the identity of the amino acid at the site of the frameshift, the amino acid position, the new amino acid at that position, the designation “fs,” and the number of amino acids before the new termination (*) is reached. For example, E238Rfs*14 means that the glutamic acid (E) at position 238 is now arginine (R), and that there are 14 amino acids from an incorrect reading frame before a termination codon is reached. For more complex alleles (insertions, deletions, etc.), please see the citation for a description.

cDomains in filamin C are as follows: Actin-binding domain (ABD), Filamin repeat (Filamin).

dAllele types are missense (substitution of a different amino acid at that position), termination (mutation of an amino acid codon to a termination codon), frameshift, or more complex types like insertions and deletions.

eThe equine protein model differs from the human protein model, so that equine E753K corresponds to human E793K (Filamin 6 domain) and equine A1207T corresponds to human A1247T (Filamin 11 domain).

Mutations in FLNC may be categorized as truncating (termination codons and frameshift alleles leading to truncation) or non-truncating (missense alleles and in-frame duplications and deletions). Truncating mutations associated with cardiomyopathy are distributed across the length of the protein, while truncating mutations associated with skeletal muscle myopathy occur only in filamin domains 15 and 24. Non-truncating mutations associated with cardiomyopathy and skeletal muscle myopathy are both distributed across the length of the protein.

Some human patients initially identified as having skeletal muscle myopathy also develop cardiomyopathy [16].

A targeted mutation of FLNC in mice, Flnctm1.1Rsdf, is a gene truncation lacking Ig-like repeats 20 through 24 [29]. The Flnctm1.1Rsdf allele destabilizes Flnc mRNA and produces only a trace amount of truncated FLNC protein that is likely inactive. Mice homozygous for Flnctm1.1Rsdf die within minutes of birth from respiratory insufficiency and show multiple defects in skeletal muscle tissue. These include decreased muscle mass, centrally located nuclei, and infiltration of connective tissue, showing that the FLNC protein is essential for normal muscle development [29].

The 24th filamin domain is required for dimerization. A well-studied human allele, W2710*, has a mutation to a termination codon in the 24th Ig-like domain. This mutation is associated with Myofibrillar Myopathy 5 (MFM5) in humans [28]. The mutant protein is unable to dimerize, but nevertheless localizes to the Z disc [30]. In addition, ectopic aggregates of Z disc proteins, including filamin, myotilin, and desmin, form within myofibrils [28, 30]. Electron microscopy shows ultrastructural defects including breaks in the Z disc and Z disc streaming [28, 30].

The table also shows an equine allele nicknamed P3 that bears two missense mutations: E753K, corresponding to human E793K (Filamin 6 domain) and A1270T, corresponding to human A1247T (Filamin 11 domain). These two missense mutations are a haplotype discovered in a horse diagnosed with Myofibrillar Myopathy (MFM) through the identification of desmin-positive inclusions observed in muscle tissue. The two missense mutations are a haplotype in that when one is detected, the other is also detected, in samples of hundreds of horses. P3/P3 homozygotes have been observed and appear to be more severely affected; there is no evidence of cardiomyopathy (EquiSeq, unpublished).

Evidence that the equine P3 allele is pathogenic will be presented in a subsequent blog post.


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