Expanding the central nervous system disease spectrum associated with <i>FLNC</i> mutation

Previtali, Stefano C.; Scarlato, Marina; Vezzulli, Paolo; Ruggieri, Alessandra; Velardo, Daniele; Benedetti, Sara; Torini, Giacomo; Colombo, Bruno; Maggi, Lorenzo; Bella, Daniela Di; Gellera, Cinzia; Mora, Marina

doi:10.1002/mus.26443

Cited by 3 publications

(2 citation statements)

References 15 publications

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“…In some patients, cardiac and skeletal muscle features were combined with the involvement of the central and peripheral nervous systems, mainly presenting as signs from the pyramid tract. Together with the cases reported by Tasca et al and Previtali et al, this underlines the importance of filamin C in neuronal cells despite the low expression level and the existence of other filamins, namely filamin A and B [35,50].…”

Section: Discussionsupporting

confidence: 81%

Rare clinical phenotype of filaminopathy presenting as restrictive cardiomyopathy and myopathy in childhood

Muravyev

Вершинина

Tesner

et al. 2022

Orphanet J Rare Dis

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Background FLNC is one of the few genes associated with all types of cardiomyopathies, but it also underlies neuromuscular phenotype. The combination of concomitant neuromuscular and cardiac involvement is not often observed in filaminopathies and the impact of this on the disease prognosis has hitherto not been analyzed. Results Here we provide a detailed clinical, genetic, and structural prediction analysis of distinct FLNC-associated phenotypes based on twelve pediatric cases. They include early-onset restrictive cardiomyopathy (RCM) in association with congenital myopathy. In all patients the initial diagnosis was established during the first year of life and in five out of twelve (41.7%) patients the first symptoms were observed at birth. RCM was present in all patients, often in combination with septal defects. No ventricular arrhythmias were noted in any of the patients presented here. Myopathy was confirmed by neurological examination, electromyography, and morphological studies. Arthrogryposes was diagnosed in six patients and remained clinically meaningful with increasing age in three of them. One patient underwent successful heart transplantation at the age of 18 years and two patients are currently included in the waiting list for heart transplantation. Two died due to congestive heart failure. One patient had ICD instally as primary prevention of SCD. In ten out of twelve patients the disease was associated with missense variants and only in two cases loss of function variants were detected. In half of the described cases, an amino acid substitution A1186V, altering the structure of IgFLNc10, was found. Conclusions The present description of twelve cases of early-onset restrictive cardiomyopathy with congenital myopathy and FLNC mutation, underlines a distinct unique phenotype that can be suggested as a separate clinical form of filaminopathies. Amino acid substitution A1186V, which was observed in half of the cases, defines a mutational hotspot for the reported combination of myopathy and cardiomyopathy. Several independent molecular mechanisms of FLNC mutations linked to filamin structure and function can explain the broad spectrum of FLNC-associated phenotypes. Early disease presentation and unfavorable prognosis of heart failure demanding heart transplantation make awareness of this clinical form of filaminopathy of great clinical importance.

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Section: Discussionsupporting

confidence: 81%

Rare clinical phenotype of filaminopathy presenting as restrictive cardiomyopathy and myopathy in childhood

Muravyev

Вершинина

Tesner

et al. 2022

Orphanet J Rare Dis

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“…These mutations have the distinct involvement of hand muscles and induce aggregates of F-actin in cell due to increased affinity of the mutant FLNC to F-actin although the mutant srABD per se are soluble [124]. Interestingly, the p.A193T mutation is also associated with cerebellar and spinal cord abnormalities [93]. Indeed, other studies have shown an association between FLNC and neuronal diseases [120,123,134].…”

Section: Flnc Mutation In Distal and Myofibrillar Skeletal Myopathymentioning

confidence: 99%

Structure and Function of Filamin C in the Muscle Z-Disc

Mao

Nakamura

2020

IJMS

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Filamin C (FLNC) is one of three filamin proteins (Filamin A (FLNA), Filamin B (FLNB), and FLNC) that cross-link actin filaments and interact with numerous binding partners. FLNC consists of a N-terminal actin-binding domain followed by 24 immunoglobulin-like repeats with two intervening calpain-sensitive hinges separating R15 and R16 (hinge 1) and R23 and R24 (hinge-2). The FLNC subunit is dimerized through R24 and calpain cleaves off the dimerization domain to regulate mobility of the FLNC subunit. FLNC is localized in the Z-disc due to the unique insertion of 82 amino acid residues in repeat 20 and necessary for normal Z-disc formation that connect sarcomeres. Since phosphorylation of FLNC by PKC diminishes the calpain sensitivity, assembly, and disassembly of the Z-disc may be regulated by phosphorylation of FLNC. Mutations of FLNC result in cardiomyopathy and muscle weakness. Although this review will focus on the current understanding of FLNC structure and functions in muscle, we will also discuss other filamins because they share high sequence similarity and are better characterized. We will also discuss a possible role of FLNC as a mechanosensor during muscle contraction.

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Identification of tumor antigens and immune subtypes in lower grade gliomas for mRNA vaccine development

Wang

Yang

et al. 2021

J Transl Med

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Background As an important part of tumor immunotherapy for adjunct, therapeutic tumor vaccines have been effective against multiple solid cancers, while their efficacy against lower grade glioma (LGG) remains undefined. Immunophenotyping of tumors is an essential tool to evaluate the immune function of patients with immunodeficiency or autoimmunity. Therefore, this study aims to find the potential tumor antigen of LGG and identify the suitable population for cancer vaccination based on the immune landscape. Method The genomic and clinical data of 529 patients with LGG were obtained from TCGA, the mRNA_seq data of normal brain tissue were downloaded from GTEx. Differential expression gene and mutation analysis were performed to screen out potential antigens, K-M curves were carried out to investigate the correlation between the level of potential antigens and OS and DFS of patients. TIMER dataset was used to explore the correlation between genes and immune infiltrating cells. Immunophenotyping of 529 tumor samples was based on the single-sample gene sets enrichment analysis. Cibersort and Estimate algorithm were used to explore the tumor immune microenvironment characteristics in each immune subtype. Weighted gene co-expression network analysis (WGCNA) clustered immune-related genes and screened the hub genes, and pathway enrichment analyses were performed on the hub modules related to immune subtype in the WGCNA. Results Selecting for the mutated, up-regulated, prognosis- and immune-related genes, four potential tumor antigens were identified in LGG. They were also significantly positively associated with the antigen-presenting immune cells (APCs). Three robust immune subtypes, IS1, IS2 and IS3, represented immune status "desert", "immune inhibition", and "inflamed" respectively, which might serve as a predictive parameter. Subsequently, clinicopathological features, including the codeletion status of 1p19q, IDH mutation status, tumor mutation burden, tumor stemness, etc., were significantly different among subtypes. Conclusion FCGBP, FLNC, TLR7, and CSF2RA were potential antigens for developing cancer vaccination, and the patients in IS3 were considered the most suitable for vaccination in LGG.

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Expanding the central nervous system disease spectrum associated with FLNC mutation

Cited by 3 publications

References 15 publications

Rare clinical phenotype of filaminopathy presenting as restrictive cardiomyopathy and myopathy in childhood

Rare clinical phenotype of filaminopathy presenting as restrictive cardiomyopathy and myopathy in childhood

Structure and Function of Filamin C in the Muscle Z-Disc

Identification of tumor antigens and immune subtypes in lower grade gliomas for mRNA vaccine development

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