Filamin C (FLNC)

Paul Szauter, PhD, Chief Scientific Officer, EquiSeq

January 13, 2020

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.

FLNC alleles

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
Figurea Alleleb Domainc Mutation Typed Citation
1 Y7Tfs*51 ABD frameshift 1
2 Y83* ABD termination 3
25 F106L ABD missense 4
3 E108* ABD termination 5
26 V123A ABD missense 5
4 E238Rfs*14 ABD frameshift 1
5 R269* Filamin 1 termination 6
27 N290K Filamin 1 missense 5
6 R482* Filamin 3 termination 7
7 I683Rfs*9 Filamin 5 frameshift 1
8 Y705* Filamin 5 termination 3
9 Q707* Filamin 5 termination 6
28 S792I Filamin 6 missense 8
10 Y928* Filamin 7 termination 1
11 R991* Filamin 8 termination 7
29 A1183L Filamin 10 missense 9
30 A1186V Filamin 10 missense 9
31 S1194L Filamin 10 missense 1
12 V1198Gfs*64 Filamin 10 frameshift 1
32 Y1216N Filamin 10 missense 10
13 R1370* Filamin 12 termination 3
33 G1424V Filamin 12 missense 1
14 A1539T Filamin 14 termination 5
34 A1551T Filamin 14 missense 8
15 L1573* Filamin 14 termination 7
35 S1624L Filamin 14 missense 11
36 I1666T Filamin 15 missense 1
16 G1800* Filamin 16 termination 3
37 I1946_T1947dup Filamin 18 in-frame duplication 1
38 R1999Q Filamin 18 missense 8
39 G2011E Filamin 18 missense 1
40 G2039R Filamin 19 missense 12
17 Y2100* Filamin 19 frameshift duplication 13
41 R2133H Filamin 19 missense 5
42 R2140Q Filamin 19 missense 14
43 G2151S Filamin 19/20 missense 5
44 I2160F Filamin 19/20 missense 11
45 V2297M Filamin 20 missense 15
46 P2298L Filamin 20 missense 16
47 G2299S Filamin 20 missense 1
48 H2315N Filamin 21 missense 5
49 R2318W Filamin 21 missense 14
50 I2359T Filamin 21 missense 1
18 Y2373Cfs*7 Filamin 21 frameshift 1
51 V2375L Filamin 21 missense 14
52 R2410C Filamin 22 missense 1
53 E2417P Filamin 22 missense 1
54 A2430V Filamin 22 missense 5
55 R2495H Filamin 22 missense 1
19 P2513Efs*12 Filamin 23 frameshift 17
20 Q2549* Filamin 23 termination 1
21 C2555* Filamin 23 termination 1
56 Y2563C Filamin 23 missense 16
57 P2643_L2645del Filamin 24 in-frame deletion 1

Human FLNC Alleles Associated with Skeletal Muscle Myopathy
Figurea Alleleb Domainc Mutation Typed Citation
58 A193T ABD missense 18
59 M222V ABD missense 19
60 M251T ABD missense 18
61 K899_V904del,
Filamin 7 deletion + insertion 20
62 V930_T933del Filamin 7 in-frame deletion 21
63 931_935del Filamin 7 in-frame deletion 22
64 Y1216N Filamin 10 missense 10
65 A1630V Filamin 14 missense 23
22 F1720Lfs*63 Filamin 15 frameshift 24
23 G1722Vfs*61 Filamin 15 frameshift 25
66 V2375I Filamin 21 missense 26
67 T2419M Filamin 22 missense 27
24 W2710* Filamin 24 termination 28

Equine FLNC Alleles Associated with Skeletal Muscle Myopathye
Figurea Alleleb Domainc Mutation Typed Citation
E753K+A1207T (P3) Filamin 6, 11 missense EquiSeq

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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