TPM1-p.E181K mutation suppresses CaMKII/HDAC4 signaling pathway leading to pediatric restrictive cardiomyopathy
Jia Fu, Jing Zhang, Youxian Zhang, Dongming Sun, Kun Xia, Ruigeng Wang, Xiaoyuan Feng, Aiguo Zhai, Yufeng Huang, Xiaobin Li, Wenjun Yu, Yong Zhang
TL;DR
This study identifies a TPM1 mutation that causes pediatric restrictive cardiomyopathy by disrupting a key signaling pathway.
Contribution
The study is the first to link the TPM1-p.E181K mutation to sporadic RCM and reveals its molecular mechanism.
Findings
TPM1-p.E181K suppresses CaMKII/HDAC4 phosphorylation and intracellular calcium transients.
The mutation leads to sarcomere disruption and myocardial hypercontractility.
The CaMKII/HDAC4 pathway is identified as a potential therapeutic target for RCM.
Abstract
This study aims to elucidate the pathogenicity of the TPM1 mutation (NM_001018005.2:c.541G>A, p. Glu181Lys) in restrictive cardiomyopathy (RCM), establish its ACMG pathogenicity classification, and report for the first time its association with sporadic RCM and underlying molecular mechanisms. The research focuses on delineating how this mutation triggers myocardial pathology via disruption of the CaMKII/HDAC4 signaling pathway. Protein 3D modeling predicted structural alterations induced by the mutation. TPM1-wild-type (WT) and mutant (p.E181K) plasmids were transfected into AC16 cardiomyocyte cell lines. Quantitative PCR (qPCR) and Western blotting (WB) analyzed gene/protein expression levels. Intracellular calcium transients were detected using Rhod-2 AM fluorescent probes. F-actin cytoskeletal reorganization was assessed by Phalloidin-488 staining. Phosphorylation status of key…
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FIGURE 5| Mutation | Domain location | Exon | Phenotype | Amino acid change | Pathogenic mechanism |
|---|---|---|---|---|---|
| c.184G > C | N-terminal stability (1-80aa) | 2 | Hypertrophic/RCM | Glu62Gln | Impaired actin binding → sarcomeric hypercontractility |
| c.842 T > C | C-terminal tail (∼Stop codon) | 9 | Met281Thr | Tropomyosin destabilization → sarcomeric structural disruption | |
| c.541G>A | Central functional domain (tropomyosin core) | 5 | RCM | Glu181Lys | Calcium dysregulation → CaMKII/HDAC4 suppression |
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Taxonomy
TopicsHistone Deacetylase Inhibitors Research · Signaling Pathways in Disease · Cardiomyopathy and Myosin Studies
Introduction
1
Restrictive cardiomyopathy (RCM) is a rare form of cardiomyopathy characterized by impaired diastolic function with preserved systolic function, left atrial or biatrial enlargement, elevated atrial pressure, and normal or near-normal ventricular wall thickness (Dadson et al., 2017; Elliott et al., 2008). Although RCM accounts for a relatively low proportion of childhood cardiomyopathies (approximately 2%–5%), its prognosis is extremely poor, with a 2-year mortality rate as high as 50% (including sudden cardiac death) in pediatric patients, imposing a substantial burden on families and society (Webber et al., 2012). RCM exhibits significant genetic heterogeneity, with over 19 disease-associated genes currently reported (Chintanaphol et al., 2022). These genes primarily encode two categories of proteins: sarcomeric proteins (e.g., TNNI3, TNNT2, TNNC1, TPM1, MYH7, MYBPC3, MYPN) and non-sarcomeric proteins (e.g., TTN, DES, FLNC, LMNA, CRYAB, BAG3, ABCC9). Notably, while mutations in TPM1 (encoding the α-tropomyosin chain) have been well-established in hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) (Rivenes et al., 2000; Lipshultz et al., 2019), definitive pathogenic evidence linking it to RCM remains exceptionally rare, and the specific molecular mechanisms are unclear. This knowledge gap underscores the critical need to explore the pathogenic mechanisms of rare genetic variants in RCM, which is essential for precise diagnosis and targeted therapeutic development.
In an 11-year-old boy with severe sporadic RCM (negative family history), we identified a de novo missense mutation (TPM1 NM_001018005.2: c.541G>A, p. Glu181Lys). This case report has been published in the Chinese Journal of Pediatrics (Fu et al., 2022). The mutation site (Glu181) exhibits high cross-species conservation, suggesting its critical role in TPM1 protein function. This finding strongly implicated TPM1-p.Glu181Lys in sporadic RCM pathogenesis; however, its definitive pathogenicity and molecular mechanisms required experimental validation. Therefore, the objectives of this study were to establish the functional association between TPM1-p.Glu181Lys and the RCM phenotype and to elucidate its molecular mechanisms in inducing cardiomyopathy. Given TPM1’s central role in regulating myofilament calcium sensitivity, we specifically investigated whether this mutation disrupted calcium homeostasis, thereby impairing key signaling pathways (e.g., CaMKII/HDAC4), which ultimately led to sarcomeric structural and functional abnormalities (e.g., hypercontractility, diastolic dysfunction). This study aimed to provide in vitro functional evidence supporting the pathogenicity of TPM1-p.Glu181Lys and to evaluate its clinical significance according to the ACMG guidelines.
This study is the first to systematically explore and reveal the mechanistic link between TPM1 mutations and RCM pathogenesis (particularly via the CaMKII/HDAC4 axis), offering new insights into the genetic etiology of RCM and identifying potential therapeutic targets.
Materials and methods
2
Study subjects and ethical compliance
2.1
This study was approved by the Medical Ethics Committee of Wuhan Children’s Hospital (Approval No.: 2024R043-E01), and written informed consent was obtained from both the patient’s legal guardians and his parents. The study subject was an 11-year-old male RCM patient who met the diagnostic criteria below and had no family history of cardiomyopathy.
Diagnostic criteria for restrictive cardiomyopathy
2.2
RCM diagnosis strictly adhered to the 2019 American Heart Association (AHA) classification criteria for cardiomyopathies (Rivenes et al., 2000; Lipshultz et al., 2019) and the American Society of Echocardiography (ASE) guidelines for diastolic function assessment (Nagueh et al., 2016).
TPM1 mutation analysis
2.3
Genomic DNA was extracted from peripheral blood samples of the proband, parents, and sister. Whole-exome sequencing (WES) was performed using the MGISEQ-2000 platform (150-bp paired-end reads, mean depth >100×). Variants with population frequency >0.1% (gnomAD/1000 Genomes) were filtered out. Variant interpretation followed the ACMG/AMP 2015 guidelines using InterVar v2.0.
Plasmid construction
2.4
The wild-type TPM1 gene (NM_001018005.2) was cloned into the pCMV-3XFlag-Neo (EGFP) vector (Provided by Bioeagle Biotech Company) using EcoRI/BamHI restriction sites. Site-directed mutagenesis to introduce the c.541G>A variant was performed with the QuikChange II XL Kit using the following primers:
Forward: 5′-CTGGAACGTGCAGAGAAGCGGGCTGAGCTC-3′
Reverse: 5′-GAGCTCAGCCCGCTTCTCTGCACGTTCCAG-3′
Successful mutagenesis was confirmed by bidirectional Sanger sequencing with T7 promoter and terminator primers.
Cell culture and transfection
2.5
AC16 human cardiomyocytes were cultured in DMEM/F12 medium supplemented with 15 mM HEPES, 10% fetal bovine serum, and 1% penicillin/streptomycin at 37 °C under 5% CO_2_. For transfection, 5 × 10^5^ cells/well were seeded in 6-well plates. Transfection complexes were prepared at a DNA (µg): Lipofectamine 2000 (µL) ratio of 1:2. After 6 h, the medium was replaced with complete growth medium, followed by 48-h incubation.
Gene expression analysis
2.6
Total RNA was isolated using TRIzol reagent, followed by cDNA synthesis with the PrimeScript RT Reagent Kit. Quantitative PCR (qPCR) was performed on the QuantStudio 6 Flex Real-Time PCR System using UltraSYBR Green PCR SuperMix and gene-specific primers (forward: 5′-AGTCGAGCCCAAAAAGATGA-3′; reverse: 5′-CCTGAGCCTCCAGTGACTTC-3′), with the amplification cycle performed according to the manufacturer’s instructions.
Mitochondrial function and calcium signaling assays
2.7
ATP levels were quantified using the ATP Assay Kit (Jiancheng Bio, Cat# A095-1) via phosphomolybdate colorimetry. Absorbance at 636 nm was measured with a microplate reader (Molecular Devices, SpectraMax CMax Plus), and ATP content was calculated as µmol/g protein. For calcium detection, transfected cells were incubated with 5 µM Rhod-2 AM in the dark at 37 °C for 30 min. Fluorescent images were captured using an inverted fluorescence microscope (Olympus IX51), and fluorescence intensity was quantified with ImageJ v1.53.
Phosphorylation analysis of signaling pathways
2.8
Transfected AC16 cells were lysed in RIPA buffer (Aspen, Cat# AS1004). Proteins (20 µg) were resolved on 10% SDS-PAGE (100V, 120 min), transferred to Polyvinylidene fluoride (PVDF) membranes (300mA, 120 min), and blocked with 5% skim milk. Membranes were incubated with primary antibodies: p-CaMKII(Thr286) (1:1000, abcam, Cat# ab320638), CaMKII (1:1000, Cell Signaling Technology [CST], Cat# 50049), p-HDAC4(Ser632) (1:500, abcam, Cat# ab39408), HDAC4 (1:1000, abcam, Cat# ab39408), and GAPDH (1:10000, abcam, Cat# ab181602). After washing, the membranes were incubated with HRP-conjugated secondary antibodies: HRP-Goat anti-Rabbit (1:10000, ASPEN, Cat# AS1107) and HRP-Goat anti-Mouse (1:10000, ASPEN, Cat# AS1106). Protein expression was quantified using AlphaEaseFC software.
Morphological analysis
2.9
After transfection, cells were fixed with 4% paraformaldehyde for 20 min and permeabilized with 0.1% Triton X-100 for 10 min. Subsequently, the cells were stained with Phalloidin-488 (1:200 dilution) for 60 min to visualize F-actin, followed by DAPI (1 μg/mL) for 5 min to label the nuclei. Finally, the samples were imaged using an inverted microscope (Olympus IX51) to evaluate sarcomeric organization and structural integrity.
Statistical analysis
2.10
Data are expressed as mean ± standard deviation (SD). Intergroup comparisons used Student’s t-test. Analyses were performed in SPSS v20.0; figures were generated with GraphPad Prism v9.0. P ≤ 0.05 was considered statistically significant.
Results
3
RCM Pedigree and Proband Clinical Phenotype
3.1
The 11-year-old male proband presented with short stature (height: 125 cm, <3rd percentile). Pedigree analysis (Figure 1A) identified a heterozygous TPM1 c.541G>A (p.Glu181Lys) mutation in the proband (II-1), while Sanger sequencing confirmed wild-type genotypes in both parents (I-1, I-2) and sister (II-2), establishing the mutation’s de novo status (Figure 1C). Clinical evaluation revealed significant cardiac abnormalities: cardiac MRI documented biatrial enlargement (Figure 1D); echocardiography demonstrated marked left atrial dilation with mild right atrial enlargement (Figure 1B); electrocardiography showed sinus rhythm with ST-segment depression >0.15 mV in leads V4-V6 and QTc prolongation to 477 ms (Figure 1E). Diastolic dysfunction was evidenced by a mitral inflow E/A ratio of 1.7. The patient exhibited no respiratory symptoms (fever, cough, vomiting, or diarrhea) or exertional cardiorespiratory complaints (dyspnea or cyanosis). This phenotypic profile—characterized by biatrial dilation and diastolic impairment—fulfilled diagnostic criteria for sporadic restrictive cardiomyopathy (RCM).
Integrated Analysis of RCM Pedigree and Proband Clinical Phenotype (A) Pedigree analysis identified the proband (II-2) as heterozygous for the TPM1 c.541G>A mutation, while parents (I-1 and I-2) and sister (II-1) showed the wild-type sequence. (B) Echocardiography revealed: biatrial enlargement (apical four-chamber view, LA marked); preserved left ventricular systolic function by M-mode (EF = 70.6%); and diastolic dysfunction evidenced by mitral inflow patterns (E/A = 1.7; E/e’ = 11, LAVI = 40 mL/m2). (C) Sanger sequencing confirmed this heterozygosity in the proband (red box indicating c.541G>A site) versus parental wild-type genotypes. (D) Cardiac MRI (four-chamber view) demonstrated biatrial enlargement with predominant left atrial dilation. (E) Electrocardiography showed sinus rhythm with QT prolongation (QTc: 477 ms) and ST-segment changes (arrows). (Imaging parameters: Philips EPIQ5 ultrasound (S8-3 probe); ECG: Philips PagewriterTC (25 mm/s); MRI: Philips Ingenia 3.0T CX).
Structural impact of TPM1-p.E181K mutation
3.2
Multidimensional computational analyses assessed the effects of the TPM1 p. Glu181Lys mutation on protein structure. AlphaFold2 modeling coupled with PyMOL structural analysis demonstrated that this mutation induces remodeling of critical hydrogen bond networks (Figure 2A). This conformational perturbation potentially destabilizes the α-helical integrity within the tropomyosin functional domain (residues 170–190). SOPMA secondary structure prediction further confirmed increased structural rigidity: the alpha helix (Hh) proportion rose from 98.59% (wild-type) to 98.94%, while random coil (Cc) content decreased from 1.41% (wild-type) to 1.06%, indicating abnormal flexibility due to altered α-helix-to-coil ratios. Surface electrostatic potential analysis (ChimeraX/APBS) revealed charge polarity reversal: wild-type Glu181 exhibited strong negative charge (−8 kT/e, red regions), whereas mutant Lys181 displayed positive potential (+6 kT/e, blue regions), disrupting electrostatic complementarity at the actin-binding interface (Figure 2B).
Structural and electrostatic alterations induced by TPM1-p.E181K (A) Conformational changes at the mutation site (position 181) extend the backbone hydrogen bond distance between Lys181 and Glu177 from 2.9 Å in wild-type to 3.0 Å (Δ = 0.1 Å), while maintaining the Leu185 hydrogen bond distance (3.0 Å). (B) APBS-based surface electrostatic potential mapping demonstrates a reversal of charge polarity, with the negative potential (red) changing to positive potential (blue).
Effect of TPM1-p.E181K on basal expression and calcium homeostasis
3.3
qPCR analysis revealed comparable TPM1 mRNA levels in AC16 cardiomyocytes transfected with TPM1-p.Glu181Lys versus wild-type (98.5% ± 8.1%; t = 0.43, P = 0.67, n = 3) (Figure 3A). Western blot quantification confirmed no significant difference in protein expression (relative grayscale: 99.7% ± 2.1%; t = 0.38, P = 0.72, n = 3) (Figures 3B,C). Colorimetric ATP measurements showed no statistical difference between mutant and wild-type cells (WT: 44.9 ± 4.4 μmol/g prot; Mut: 51.1 ± 5.9 μmol/g prot; t = 1.45, P = 0.22, n = 3) (Figure 3D), indicating no direct impact on energetic metabolism homeostasis. Rhod-2 AM fluorescent probe detection demonstrated significantly reduced intracellular Ca^2+^ concentration in mutant cells versus wild-type (t = 6.17, P < 0.0035, n = 50 cells/group) (Figures 3E,F). Fluorescence microscopy visibly demonstrated diminished red fluorescence intensity in mutant cells (Figure 3E), a phenotype concordant with pathological calcium dysregulation in restrictive cardiomyopathy.
Impact of TPM1-p.E181K mutation on basal cellular function (A) Relative TPM1 mRNA expression (qPCR, n = 6). (B) Representative Western blotting bands. (C) Protein quantification by grayscale analysis. (D) Intracellular ATP concentration (μmol/g protein). (E) Rhod-2 staining demonstrating diminished calcium signals (pseudocolored red; scale bar = 50 μm). (F) Quantitative analysis of calcium fluorescence intensity expressed as Integrated Optical Density (IOD), a measure of total fluorescence signal within the measured area. Data are presented as arbitrary units (Wild-type: 5352.04 ± 943.84; Mutant: 1844.7 ± 271.06).
Suppression of CaMKII/HDAC4 phosphorylation cascade by TPM1-p.E181K
3.4
Western blot quantification revealed significantly reduced phosphorylation levels of CaMKII in mutant versus wild-type cells (P = 0.021), with an even more pronounced reduction in HDAC4 phosphorylation (P = 0.0003) (Figures 4A–C). Mechanistically, diminished calcium signaling (Figure 3E) impaired CaMKII kinase activity, thereby suppressing HDAC4 phosphorylation.
TPM1-p.E181K suppresses phosphorylation signaling and induces sarcomeric remodeling (A) Western blot showing reduced p-CaMKII and p-HDAC4 expression. (B) p-CaMKII/CaMKII grayscale quantification (α-subunit: 50 kDa; loading control: β-actin). (C) p-HDAC4/HDAC4 quantification (α-subunit: 130 kDa). (D) Western blot demonstrating decreased p-cTnI expression. (E) p-cTnI grayscale quantification (α-subunit: 24 kDa; loading control: β-actin). (F) Immunofluorescence co-staining: F-actin (Phalloidin-488, green), nuclei (DAPI, blue) (scale bar: 20 μm). (G) Cell surface area quantification (WT: 681.3 ± 92.0 μm2 vs. Mut: 2073.6 ± 182.1 μm2).
Impaired troponin phosphorylation validates contractile dysregulation
3.5
Phosphorylated troponin I (p-TnI) expression decreased by 57.3% ± 11.9% in mutant cells (relative levels: WT: 0.67 ± 0.07 vs. Mut: 1.00 ± 0.12; t = 4.83, P = 0.0084, n = 6) (Figures 4D,E), indicating that the TPM1 mutation disrupts myofilament contractile regulation via the CaMKII-TnI signaling axis.
Morphological evidence of pathological remodeling in cardiomyocytes
3.6
Phalloidin-488/DAPI confocal imaging demonstrated increased cell surface area in mutants. Quantitative analysis confirmed a mean increase of 1392 ± 117.7 μm^2^ (t = 11.83, P = 0.0003, n = 50 cells/group) (Figures 4F,G).
Discussion
4
Tropomyosin (TM), an actin-binding protein composed of two α-helical chains forming coiled-coil structures, serves as a critical regulator of muscle contraction. It exists as multiple isoforms across eukaryotic cells and aligns with actin filaments to modulate actin-actin interactions. In mammals, 4 TM genes (TPM1, TPM2, TPM3, TPM4) encode over 20 TM isoforms (Perry, 2001). The TPM1-p.E181K missense mutation localizes to exon 5 of chromosome 15 (residue 181/284aa) within the conserved tropomyosin functional domain—a key actin-binding region. Therefore, mutations in the TPM1 gene exclusively cause cardiomyopathy without associated clinical myopathy—despite its expression in skeletal muscle—likely mediated by C-terminal alternative splicing of tissue-specific isoforms (Redwood and Robinson, 2013). Pathogenic TPM1 mutations account for 1%–2% of dilated cardiomyopathy (DCM) cases (Hershberger et al., 2010; Shen et al., 2022), 5% of hypertrophic cardiomyopathy (HCM) cases (Watkins et al., 1995; Coviello et al., 1997; Tardiff, 2005), and 3% of restrictive cardiomyopathy (RCM) cases, based on limited cohort evidence (Gallego-Delgado et al., 2016).
Genetic sequencing of a pediatric RCM case revealed the de novo TPM1-p.E181K mutation. Pathogenicity predictions unanimously indicated deleterious effects: SIFT (D), PolyPhen2_HDIV (D), PolyPhen2_HVAR (D), REVEL (0.844). Structural modeling (Figure 2) further supported functional disruption. The variant was absent from ClinVar, and its de novo origin was confirmed by parental sequencing. Per ACMG guidelines (Richards et al., 2015), this variant is classified as Likely Pathogenic.
Functionally, the TPM1-p.E181K mutation significantly suppressed the phosphorylation of both CaMKII (P < 0.05) and HDAC4 (P < 0.001) (Figures 4A–C). We propose that calcium dysregulation is a key upstream event driving this signaling suppression. The mechanism may involve two aspects: direct inhibition of CaMKII autophosphorylation due to reduced cytosolic Ca^2+^ levels, and diminished troponin I phosphorylation (Figures 4D,E), which might impair the scaffolding or allosteric activation of CaMKII at the sarcomere. Consequently, HDAC4 hypophosphorylation is expected to promote its nuclear accumulation. Nuclear accumulation of HDAC4 is known to repress transcription of genes important for cardiac relaxation, such as KLF4 and SERCA2a. Thus, it is hypothesized that this signaling cascade represents a potential mechanistic link between the TPM1-E181K mutation and the diastolic impairment characteristic of RCM (Figures 4F,G).
The α-tropomyosin encoded by TPM1 is a core regulatory protein for cardiac sarcomeric structure and function, coordinating calcium-dependent contraction-relaxation cycles through synergistic interactions with actin and the troponin complex (Keyt et al., 2022). While TPM1 mutations are predominantly reported in hypertrophic (HCM) and dilated cardiomyopathy (DCM)—attributed to sarcomeric hypercontractility (HCM) or actin destabilization (DCM) (Perry, 2001; Halder et al., 2024)—and while the E181K mutant was shown to cause hypercontractility in vitro by (Gupte et al., 2015), our study in a clinical RCM context reveals that its unique pathogenicity is mediated specifically through calcium-CaMKII-HDAC4 signaling axis disruption. This study further demonstrates that the E181K mutation, though not altering TPM1 expression levels (Figure 3C), impairs troponin phosphorylation (Figures 4D,E), and significantly reduces calcium affinity and diminishes intracellular Ca^2+^ transient amplitude (Figures 3E,F) This phenotype fundamentally differs from the RCM caused by compound heterozygous TPM1 mutations (E62Q/M281T) as reported by Dorsch et al. (Mazzarotto et al., 2020), In their report, E62Q (N-terminal domain) induces sarcomeric hypercontractility via disrupted actin binding, whereas E181K (central functional domain/Tropomyosin core) primarily disrupts calcium signaling rather than sarcomeric stability (Table 1). These findings demonstrate that mutations in distinct TPM1 domains drive phenotypic heterogeneity through divergent molecular mechanisms, suggesting unique signaling networks underlie RCM pathogenesis.
Current therapeutic strategies for restrictive cardiomyopathy (RCM) primarily adhere to general heart failure management principles (Cimiotti et al., 2021), including angiotensin-converting enzyme inhibitors, β-blockers, calcium channel blockers, and anticoagulation. However, these approaches lack etiology-specific interventions. Based on our findings, targeted activation of CaMKII or inhibition of HDAC4 nuclear translocation emerges as a potential therapeutic avenue (Figure 5). However, it is important to note that this study did not functionally evaluate the reversal of pathological phenotypes through such modulation, which represents a key limitation and a necessary next step to validate these targets.
Proposed mechanism of the TPM1-p.E181K mutation in troponin and CaMKII/HDAC4 signaling.
In summary, this study first establishes the association between the TPM1-p.E181K mutation and sporadic RCM, demonstrating that its pathogenesis is mediated through a cascade of events: calcium dyshomeostasis leads to suppression of CaMKII/HDAC4 phosphorylation, which subsequently causes sarcomeric disruption, and ultimately results in myocardial hypercontractility. This mechanistic insight provides novel therapeutic perspectives for RCM. Future studies investigating interventions targeting this pathway will be crucial to assess their potential in overcoming current treatment limitations.
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