Two missense mutations in the cardiac actin gene (ACTC), postulated to impair force transmission, have been associated with familial dilated cardiomyopathy (DCM).
Both DCM mutations were found to shift tropomyosin towards the periphery of thin filament and to change the affinity of tropomyosin for actin; during the ATPase cycle the amplitude of tropomyosin movement was reduced and at some stages of the cycle even reversed.
With respect to the cytoskeleton, disruption of the non-sarcomeric actin linkage at the intercalated discs via overexpressing the VASP-EHV1 domain is sufficient to cause dilated cardiomyopathy (DCM).
We have tested the hypothesis that the protein-folding pathway plays a role in disease development for two actin variants associated with DCM and six associated with HCM.
WD repeat domain 1 (WDR1), a protein that assists cofilin-mediated actin filament disassembly, is overexpressed in the invading front of invasive ductal carcinoma (IDC), but its implication of overexpression and how to be regulated have not been studied.
To test the hypothesis that actin dysfunction leads to heart failure, patients with hereditary idiopathic dilated cardiomyopathy (IDC) were examined for mutations in the cardiac actin gene (ACTC).
Mutations in metavinculin, a muscle-specific isoform of vinculin, were identified previously in DCM and shown to alter in vitro organization of actin filaments.
Mutations in exons 5 and 6 of the cardiac actin gene that have been reported in humans with familial DCM do not appear to be the cause of familial DCM in Doberman Pinschers.
We found: (1) there are substantial differences in the stoichiometry of sarcomeric MHC and actin transcripts in hearts of DCM patients as well as in ND individuals; (2) there are substantial differences between levels of total sarcomeric actin transcripts from different individual patients; (3) by and large variations in transcript levels between samples from the same heart are much less than between samples from different hearts; and (4) the ratio of MHC to sarcomeric actin proteins expressed by different ND and DCM hearts remains essentially constant.
Four of the DCM mutations lowered the duty ratio (the ATPase cycle portion when myosin strongly binds actin) because of reduced occupancy of the force-holding A·M·D complex in the steady state.
However, Ca(2+) sensitivity did not change with the level of troponin I phosphorylation in any of the DCM-mutant containing thin filaments (E40K, E54K, and D230N in α-tropomyosin; R141W and ΔK210 in cardiac troponin T; K36Q in cardiac troponin I; G159D in cardiac troponin C, and E361G in cardiac α-actin).
Our studies on Tm have demonstrated that: (1) Tm positively enhances the hydrophobic interaction between actin and myosin in the "closed state", which in turn enhances the isometric tension; (2) Tm's seven periodical repeats carry distinct functions, with the 3rd period being essential for the tension enhancement; (3) Tm mutants lead to HCM by impairing the relaxation on one hand, and lead to DCM by over inhibition of the AM interaction on the other hand.
To further test the hypothesis that mutations within functionally distinct domains of ACTC cause either DCM or HCM, we performed mutational analyses in 368 unrelated patients with familial or sporadic HCM.
The ACTC1 gene was the first sarcomeric gene whose mutation was shown to cause DCM; recent studies have indicated that the HSPB7 and ZBTB17 genes are also associated with DCM.
In conclusion, our data suggests that human G247DACTC1 mutation negatively regulates SRF-signaling likely contributing to the late-onset DCM observed in mutation carrier patients.
A group of 99 unrelated adult patients with DCM (familial n=27, sporadic n=72) were screened for the following genes: cardiac beta-myosin heavy chain, cardiac myosin-binding protein C (MYBPC3), regulatory and essential myosin light chains, alpha cardiac actin, alpha tropomyosin, cardiac troponin T, cardiac troponin I, cardiac troponin C, dystrophin, and lamin A/C.
We hypothesize that ACTC mutations affecting sarcomere contraction lead to FHC and that mutations affecting force transmission from the sarcomere to the surrounding syncytium lead to IDC.