Insights into the Role of a Cardiomyopathy-Causing Genetic Variant in ACTN2

Broadway-Stringer, Sophie; Wadmore, Kirsty; Hooper, Charlotte; Douglas, Gillian; Steeples, Violetta; Azad, Amar J.; Singer, Evie; Reyat, Jasmeet S.; Galatík, Frantisek; Ehler, Elisabeth; Bennett, Pauline M.; Kalisch-Smith, Jacinta I.; Sparrow, Duncan B.; Davies, Benjamin M; Djinović-Carugo, Kristina; Gautel, Mathias; Watkins, Hugh; Gehmlich, Katja

doi:10.3390/cells12050721

Cited by 10 publications

(8 citation statements)

References 48 publications

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“…Similarly, variants located in the ABD may cause the disease through alterations in the binding of alpha-actinin-2 with actin. 12, 16, 33, 34 However, more research is required to uncover these alternative disease mechanisms.…”

Section: Discussionmentioning

confidence: 99%

RareACTN2Frameshift Variants Resulting in Protein Extension Cause Distal Myopathy and Hypertrophic Cardiomyopathy through Protein Aggregation

Ranta-aho,

Felice,

Jonson

et al. 2024

Preprint

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Distal myopathies are a group of rare, inherited muscular disorders characterized by progressive loss of muscle fibers that begins in the distal parts of arms and legs. Recently, variants in a new disease gene,ACTN2, have been shown to cause distal myopathy.ACTN2, a gene previously only associated with cardiomyopathies, encodes alpha-actinin-2, a protein expressed in both cardiac and skeletal sarcomeres. The primary function of alpha-actinin-2 is to link actin and titin to the sarcomere Z-disk. NewACTN2variants are continuously discovered, however, the clinical significance of many variants remains unknown. Thus, lack of clear genotype-phenotype correlations inACTN2-related diseases, actininopathies, persists.ObjectiveThe objective of the study is to characterize the pathomechanisms underlying actininopathies.MethodsFunctional characterization in C2C12 cell models of severalACTN2variants is conducted, including frameshift and missense variants associated with dominant actininopathies. We assess the genotype-phenotype correlations of actininopathies using clinical data from several patients carrying these variants.ResultsThe results show that the missense variants associated with a recessive form of actininopathy do not cause detectable alpha-actinin-2 aggregates in the cell model. Conversely, dominant frameshift variants causing a protein extension do produce alpha-actinin-2 aggregates.InterpretationThe results suggest that alpha-actinin-2 aggregation is the disease mechanism underlying some dominant actininopathies, and thus we recommend that protein-extending frameshift variants inACTN2should be classified as pathogenic. However, this mechanism is likely elicited by only a limited number of variants. Alternative functional characterization methods should be explored to further investigate other molecular mechanisms underlying actininopathies.

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Section: Discussionmentioning

confidence: 99%

RareACTN2Frameshift Variants Resulting in Protein Extension Cause Distal Myopathy and Hypertrophic Cardiomyopathy through Protein Aggregation

Ranta-aho,

Felice,

Jonson

et al. 2024

Preprint

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“…CCR2 [114], IL2RB [115], CCL4 [116], CCL24 [117], FASLG (Fas ligand) [118], CD24 [119], TDGF1 [120], CD28 [121], IL7R [122], CYP11B1 [123], CCL5 [124], CCL3 [125], LTF (lactotransferrin) [126], GPNMB (glycoprotein nmb) [127], CD209 [128], IL2RG [129], CHIT1 [130], TAB2 [131], CD163 [132], ALOX15B [133], NMRK2 [134], HGF (hepatocyte growth factor) [135], TRPM8 [136], DIO3 [137], SIGLEC1 [138], TTR (transthyretin) [139], IL24 [140], F13A1 [141], IL9 [142], VEGFA (vascular endothelial growth factor A) [143], RASAL1 [144], ADM (adrenomedullin) [145], ANGPTL4 [146], CHI3L1 [147], LDB3 [148], CNP (2’,3’-cyclic nucleotide 3’ phosphodiesterase) [149], HES6 [150], CMTM5 [151], PLXNB3 [152], KLK8 [153], CDKN1C [154], INSIG1 [155], GREM1 [156], ATF3 [157], HK2 [158], MCAM (melanoma cell adhesion molecule) [159], SEMA4D [160], GLUL (glutamate-ammonia ligase) [161], S1PR5 [162], FN3K [163], MEIS1 [164], ADAMTS4 [165], BIN1 [166], BMP2 [167], LMNA (lamin A/C) [168], ERBB3 [169], DLL1 [170], THBS2 [171], GADD45B [172], MYH6 [173]. PNPLA3 [174], ACTN2 [175], MMP15 [176], SVEP1 [177], CPB2 [178], DYSF (dysferlin) [179], ADAMTSL2 [180], NINJ2 [181], LRP2 [106], PHLDA3 [182], LIPC (lipase C, hepatic type) [183], CARNS1 [184], PRODH (proline dehydrogenase 1) [185], TRPV6 [186], C...…”

Section: Discussionmentioning

confidence: 99%

Identification of candidate biomarkers and pathways associated with multiple sclerosis using bioinformatics and next generation sequencing data analysis

Vastrad,

Vastrad

2023

Preprint

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Multiple sclerosis (MS) is the main reason for disability caused by autoimmunity. However, effective biomarkers for MS have not been identified. This study explored the molecular mechanisms and potential therapeutic targets for MS occurrence and progression using bioinformatics and next generation sequencing (NGS) data analysis. NGS data GSE138614, including patients with MS and 25 normal control samples, were obtained from Gene Expression Omnibus (GEO) database Differentially expressed genes (DEGs) were filtered and subjected to gene ontology (GO) and pathway enrichment analyses. Protein–protein interaction (PPI) network and module analyses were performed based on the DEGs. MiRNA-hub gene regulatory network and TF-hub gene regulatory network analysis were built by Cytoscape to predict the underlying microRNAs (miRNAs) and transcription factors (TFs) associated with hub genes. We also validated the identified hub genes via receiver operating characteristic (ROC) curve analysis. A total of 959 DEGs (479 up regulated genes and 480 down regulated genes) were detected. The GO terms and pathways of DEGs involve immune system process, developmental process, immune system and regulation of cholesterol biosynthesis by SREBP (SREBF). The network analysis revealed that hub genes include LCK, PYHIN1, SLAMF1, DOK2, TAB2, CFTR, RHOB, LMNA, EGLN3 and ERBB3 might be involved in the development of MS. The present investigation illustrates a characteristic gene profile in MS, which might contribute to the interpretation of the progression of MS and provide novel biomarkers and therapeutic targets for MS.

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“…Moreover, based on our previous research, the homozygous deletion of ACTN2 or RYR2 would induce a fetal-lethal condition. Thus, such two genes are of great importance, and haploinsufficiency had been identified in associated patients and animal models [ 9 , 10 , 11 ]. According to previous research, ACTN2 is considered a major contributor to LVNC.…”

Section: Discussionmentioning

confidence: 99%

“…However, large depletion of RYR2 leads to severe DCM and impaired myocardial function [ 12 , 13 , 14 ]. Moreover, the animal models of ACTN2 variant were also related with DCM and LVNC [ 7 , 11 , 15 ]. Accordingly, such previous reports supported the clinical phenotype of this patient was tightly correlated with the dysfunction of ACTN2 and RYR2 .…”

Section: Discussionmentioning

confidence: 99%

Impaired Cardiomyocyte Maturation Leading to DCM: A Case Report and Literature Review

et al. 2023

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Background: The maturation of cardiomyocytes is a rapidly evolving area of research within the field of cardiovascular medicine. Understanding the molecular mechanisms underlying cardiomyocyte maturation is essential to advancing our knowledge of the underlying causes of cardiovascular disease. Impaired maturation can lead to the development of cardiomyopathy, particularly dilated cardiomyopathy (DCM). Recent studies have confirmed the involvement of the ACTN2 and RYR2 genes in the maturation process, facilitating the functional maturation of the sarcomere and calcium handling. Defective sarcomere and electrophysiological maturation have been linked to severe forms of cardiomyopathy. This report presents a rare case of DCM with myocardial non-compaction, probably resulting from allelic collapse of both the ACTN2 and RYR2 genes. Case Presentation: The proband in this case was a four-year-old male child who presented with a recurrent and aggressive reduction in activity tolerance, decreased ingestion volume, and profuse sweating. Electrocardiography revealed significant ST-T segment depression (II, III, aVF V3-V6 ST segment depression >0.05 mV with inverted T-waves). Echocardiography showed an enlarged left ventricle and marked myocardial non-compaction. Cardiac magnetic resonance imaging revealed increased left ventricular trabeculae, an enlarged left ventricle, and a reduced ejection fraction. Whole exome sequencing revealed a restricted genomic depletion in the 1q43 region (chr1:236,686,454-237,833,988/Hg38), encompassing the coding genes ACTN2, MTR, and RYR2. The identified variant resulted in heterozygous variations in these three genes, with the ACTN2 g.236,686,454-236,764,631_del and RYR2 g.237,402,134-237,833,988_del variants being the dominant contributors to the induction of cardiomyopathy. The patient was finally diagnosed with DCM and left ventricular myocardial non-compaction. Conclusions: This study reports a rare case of DCM with myocardial non-compaction caused by the allelic collapse of the ACTN2 and RYR2 genes. This case provides the first human validation of the critical role of cardiomyocyte maturation in maintaining cardiac function and stability and confirms the key findings of previous experimental research conducted by our group. This report emphasizes the connection between genes involved in regulating the maturation of cardiomyocytes and the development of cardiomyopathy.

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Insights into the Role of a Cardiomyopathy-Causing Genetic Variant in ACTN2

Cited by 10 publications

References 48 publications

RareACTN2Frameshift Variants Resulting in Protein Extension Cause Distal Myopathy and Hypertrophic Cardiomyopathy through Protein Aggregation

RareACTN2Frameshift Variants Resulting in Protein Extension Cause Distal Myopathy and Hypertrophic Cardiomyopathy through Protein Aggregation

Identification of candidate biomarkers and pathways associated with multiple sclerosis using bioinformatics and next generation sequencing data analysis

Impaired Cardiomyocyte Maturation Leading to DCM: A Case Report and Literature Review

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