Filamin C: a novel component of the KCNE2 interactome during hypoxia

Neethling, Annika; Mouton, Jomien; Loos, Ben; Corfield, Valerie A.; Villiers, Carin de; Kinnear, Craig

doi:10.5830/cvja-2015-049

Cited by 8 publications

(4 citation statements)

References 80 publications

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“…Neethling, et al reported that KCNE2, which is a voltage-gated potassium channel and functions in ven-tricular repolarization, interacted with FLNC. 28) Given the collective evidence, the sudden deaths in this family might be attributed to a case of incidental malignant arrhythmia. However, FLNC p.A1979T has failed to elucidate the DCM of the mother.…”

Section: Discussionmentioning

confidence: 90%

FLNC and MYLK2 Gene Mutations in a Chinese Family with Different Phenotypes of Cardiomyopathy

Qin

et al. 2021

Int. Heart J.

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Mutations in the sarcomeric protein filamin C (FLNC) gene have been linked to hypertrophic cardiomyopathy (HCM), as they have been determined to increase the risk of ventricular arrhythmia and sudden death. Thus, in this study, we identified a novel missense mutation of FLNC in a Chinese family with HCM, and, interestingly, a second novel truncating mutation of MYLK2 was discobered in one family member with different phenotype.We performed whole-exome sequencing in a Chinese family with HCM of unknown cause. To determine and confirm the function of a novel mutation of FLNC, we introduced the mutant and wild-type gene into AC 16 cells (human cardiomyocytes): we then used western blotting to analyze the expression of FLNC in subcellular fractions, and confocal microscope to observe the subcellular distribution of the protein.As per our findings, we were able to identify a novel missense single nucleotide variant (FLNC c.G5935A [p.A1979T]) in the family, which segregates with the disease. FLNC expression levels were observed to be equivalent in both wild-type and p.A1979T cardiomyocytes. However, the expression of the mutant protein has resulted in cytoplasmic protein aggregations, in contrast to wild-type FLNC, which was distributed in the cytoplasm and did not form aggregates. Unexpectedly, a second truncating mutation, NM_033118:exon8:c.G1138T: p.E380X of the MYLK2 gene, was identified in the mother of the proband with dilated cardiomyopathy, which was not found in other subjects.We then identified the FLNC A1979T mutation as a novel pathogenic variant associated with HCM in a Chinese family as well as a second causal mutation in a family member with a distinct phenotype. The possibility that there is more than one causal mutation in cardiomyopathy warrants clinical attention, especially for patients with atypical clinical features.

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Section: Discussionmentioning

confidence: 90%

FLNC and MYLK2 Gene Mutations in a Chinese Family with Different Phenotypes of Cardiomyopathy

Qin

et al. 2021

Int. Heart J.

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“…The association of FLNC with channelopathies has been described by Neethling et al in 2016 who reported an interaction between FLNC and KCNE2 (potassium voltage-gated channel) known to be causative for LQTS. In particular, they stressed this functional modulation under conditions of hypoxia and concluded that this pathway is likely to be involved in LQTS pathogenesis [ 43 ]. It is worth noting that in our patients with long QT, we did not observe likely pathogenic, nor pathogenic variants of the gene panels for congenital LQTS.…”

Section: Discussionmentioning

confidence: 99%

Cardiovascular Involvement in Pediatric FLNC Variants: A Case Series of Fourteen Patients

Baban

Alesi

Magliozzi

et al. 2022

JCDD

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Filamin C is a protein specifically expressed in myocytes and cardiomyocytes and is involved in several biological functions, including sarcomere contractile activity, signaling, cellular adhesion, and repair. FLNC variants are associated with different disorders ranging from striated muscle (myofibrillar distal or proximal) myopathy to cardiomyopathies (CMPs) (restrictive, hypertrophic, and dilated), or both. The outcome depends on functional consequences of the detected variants, which result either in FLNC haploinsufficiency or in an aberrant protein, the latter affecting sarcomere structure leading to protein aggregates. Cardiac manifestations of filaminopathies are most often described as adult onset CMPs and limited reports are available in children or on other cardiac spectrums (congenital heart defects—CHDs, or arrhythmias). Here we report on 13 variants in 14 children (2.8%) out of 500 pediatric patients with early-onset different cardiac features ranging from CMP to arrhythmias and CHDs. In one patient, we identified a deletion encompassing FLNC detected by microarray, which was overlooked by next generation sequencing. We established a potential genotype–phenotype correlation of the p.Ala1186Val variant in severe and early-onset restrictive cardiomyopathy (RCM) associated with a limb-girdle defect (two new patients in addition to the five reported in the literature). Moreover, in three patients (21%), we identified a relatively frequent finding of long QT syndrome (LQTS) associated with RCM (n = 2) and a hypertrabeculated left ventricle (n = 1). RCM and LQTS in children might represent a specific red flag for FLNC variants. Further studies are warranted in pediatric cohorts to delineate potential expanding phenotypes related to FLNC.

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“…Under conditions of stress, ECM proteins can drive cell biological responses with an important role in the tissue remodeling ( Jourdan-Lesaux et al, 2010 ; Frangogiannis, 2017 ; Frangogiannis, 2019 ). Under hypoxic stress, filamin-C interacted with other molecules to restore cellular membrane integrity, thereby promoting cellular survival during these conditions ( Leber et al, 2016 ; Neethling et al, 2016 ). Overall, it may be envisioned that ribosomal proteins, apoptosis related proteins and ECM proteins are secreted from MSCs and involved in the repair process of HLI.…”

Section: Discussionmentioning

confidence: 99%

Deciphering the in vivo Dynamic Proteomics of Mesenchymal Stem Cells in Critical Limb Ischemia

Yan

et al. 2021

Front. Cell Dev. Biol.

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ObjectiveRegenerative therapy using mesenchymal stem cells (MSC) is a promising therapeutic method for critical limb ischemia (CLI). To understand how the cells are involved in the regenerative process of limb ischemia locally, we proposed a metabolic protein labeling method to label cell proteomes in situ and then decipher the proteome dynamics of MSCs in ischemic hind limb.Methods and ResultsIn this study, we overexpressed mutant methionyl-tRNA synthetase (MetRS), which could utilize azidonorleucine (ANL) instead of methionine (Met) during protein synthesis in MSCs. Fluorescent non-canonical amino-acid tagging (FUNCAT) was performed to detect the utilization of ANL in mutant MSCs. Mice with hindlimb ischemia (HLI) or Sham surgery were treated with MetRSmut MSCs or PBS, followed by i.p. administration of ANL at days 0, 2 6, and 13 after surgery. FUNCAT was also performed in hindlimb tissue sections to demonstrate the incorporation of ANL in transplanted cells in situ. At days 1, 3, 7, and 14 after the surgery, laser doppler imaging were performed to detect the blood reperfusion of ischemic limbs. Ischemic tissues were also collected at these four time points for histological analysis including HE staining and vessel staining, and processed for click reaction based protein enrichment followed by mass spectrometry and bioinformatics analysis. The MetRSmut MSCs showed strong green signal in cell culture and in HLI muscles as well, indicating efficient incorporation of ANL in nascent protein synthesis. By 14 days post-treatment, MSCs significantly increased blood reperfusion and vessel density, while reducing inflammation in HLI model compared to PBS. Proteins enriched by click reaction were distinctive in the HLI group vs. the Sham group. 34, 31, 49, and 26 proteins were significantly up-regulated whereas 28, 32, 62, and 27 proteins were significantly down-regulated in HLI vs. Sham at days 1, 3, 7, and 14, respectively. The differentially expressed proteins were more pronounced in the pathways of apoptosis and energy metabolism.ConclusionIn conclusion, mutant MetRS allows efficient and specific identification of dynamic cell proteomics in situ, which reflect the functions and adaptive changes of MSCs that may be leveraged to understand and improve stem cell therapy in critical limb ischemia.

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Filamin C: a novel component of the KCNE2 interactome during hypoxia

Cited by 8 publications

References 80 publications

<i>FLNC</i> and <i>MYLK2</i> Gene Mutations in a Chinese Family with Different Phenotypes of Cardiomyopathy

<i>FLNC</i> and <i>MYLK2</i> Gene Mutations in a Chinese Family with Different Phenotypes of Cardiomyopathy

Cardiovascular Involvement in Pediatric FLNC Variants: A Case Series of Fourteen Patients

Deciphering the in vivo Dynamic Proteomics of Mesenchymal Stem Cells in Critical Limb Ischemia

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