A mutation update for the
            <i>FLNC</i>
            gene in myopathies and cardiomyopathies

Verdonschot, Job A.J.; Vanhoutte, Els K.; Claes, Godelieve R F; Enden, Apollonia T J M Helderman-van den; Hoeijmakers, Janneke G. J.; Hellebrekers, Debby M.E.I.; Haan, Amber de; Christiaans, Imke; Deprez, Ronald H. Lekanne; Boen, Hanne M; Craenenbroeck, Emeline M. Van; Loeys, Bart; Hoedemaekers, Yvonne M.; Marcelis, Carlo; Kempers, Marlies; Brusse, Esther; Waning, Jaap I. van; Baas, Annette F.; Dooijes, Dennis; Asselbergs, Folkert W.; Barge-Schaapveld, Daniela Q.C.M.; Koopman, Pieter; Wijngaard, Arthur van den; Heymans, Stéphane; Krapels, Ingrid P.C.; Brunner, Han G.

doi:10.1002/humu.24004

Cited by 108 publications

(124 citation statements)

References 88 publications

(94 reference statements)

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“…Until now more than 200 dominant human mutations in the FLNC gene have been identified to be associated with a great variety of myopathies and cardiomyopathies [ 83 ]. In addition, very recently a first case of a homozygous, recessive FLNC mutation (NM_001458.4:c.1325C > G; p.P442R) was reported to cause a severe congenital myopathy associated with degenerated myofibrils, advanced sarcomeric lesions and protein aggregates containing FLNc, Xin and XIRP2 in patient muscle fibers [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

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Homozygous expression of the myofibrillar myopathy-associated p.W2710X filamin C variant reveals major pathomechanisms of sarcomeric lesion formation

Schuld

Orfanos

Chevessier

et al. 2020

acta neuropathol commun

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Filamin C (FLNc) is mainly expressed in striated muscle cells where it localizes to Z-discs, myotendinous junctions and intercalated discs. Recent studies have revealed numerous mutations in the FLNC gene causing familial and sporadic myopathies and cardiomyopathies with marked clinical variability. The most frequent myopathic mutation, p.W2710X, which is associated with myofibrillar myopathy, deletes the carboxy-terminal 16 amino acids from FLNc and abolishes the dimerization property of Ig-like domain 24. We previously characterized “knock-in” mice heterozygous for this mutation (p.W2711X), and have now investigated homozygous mice using protein and mRNA expression analyses, mass spectrometry, and extensive immunolocalization and ultrastructural studies. Although the latter mice display a relatively mild myopathy under normal conditions, our analyses identified major mechanisms causing the pathophysiology of this disease: in comparison to wildtype animals (i) the expression level of FLNc protein is drastically reduced; (ii) mutant FLNc is relocalized from Z-discs to particularly mechanically strained parts of muscle cells, i.e. myotendinous junctions and myofibrillar lesions; (iii) the number of lesions is greatly increased and these lesions lack Bcl2-associated athanogene 3 (BAG3) protein; (iv) the expression of heat shock protein beta-7 (HSPB7) is almost completely abolished. These findings indicate grave disturbances of BAG3-dependent and -independent autophagy pathways that are required for efficient lesion repair. In addition, our studies reveal general mechanisms of lesion formation and demonstrate that defective FLNc dimerization via its carboxy-terminal domain does not disturb assembly and basic function of myofibrils. An alternative, more amino-terminally located dimerization site might compensate for that loss. Since filamins function as stress sensors, our data further substantiate that FLNc is important for mechanosensing in the context of Z-disc stabilization and maintenance.

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Section: Discussionmentioning

confidence: 99%

“…A very recent extensive review provides a complete overview of the currently known approximately 325 FLNC variants. A large part of those are associated with skeletal myopathies and cardiomyopathies [ 83 ].…”

Section: Introductionmentioning

confidence: 99%

Homozygous expression of the myofibrillar myopathy-associated p.W2710X filamin C variant reveals major pathomechanisms of sarcomeric lesion formation

Schuld

Orfanos

Chevessier

et al. 2020

acta neuropathol commun

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“…Functional studies supported FLNC haploinsufficiency as the mechanism driving arrhythmogenic DCM [68,69]. Multiple groups have reported FLNCtvs in probands and families with DCM and ventricular arrhythmias [68][69][70][71][72][73][74], which provides strong evidence for FLNCtv pathogenicity in arrhythmogenic DCM.…”

Section: Desmoplakinmentioning

confidence: 85%

Clinical Implications of the Genetic Architecture of Dilated Cardiomyopathy

Wilsbacher

2020

Curr Cardiol Rep

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Purpose of Review Dilated cardiomyopathy (DCM) frequently involves an underlying genetic etiology, but the clinical approach for genetic diagnosis and application of results in clinical practice can be complex. Recent Findings International sequence databases described the landscape of genetic variability across populations, which informed guidelines for the interpretation of DCM gene variants. New evidence indicates that loss-of-function mutations in filamin C (FLNC) contribute to DCM and portend high risk of ventricular arrhythmia. Summary A clinical framework aids in referring patients for DCM genetic testing and applying results to patient care. Results of genetic testing can change medical management, particularly in a subset of genes that increase risk for life-threatening ventricular arrhythmias, and can influence decisions for defibrillator therapy. Clinical screening and cascade genetic testing of family members should be diligently pursued to identify those at risk of developing DCM.

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“…Patients with pathogenic mutations in the DSP gene frequently presented with a comparable triad of clinical features consisting of DCM, wooly hair, and palmoplantar keratoderma, which is known as Carvajal syndrome (MIM, #605676) ( Protonotarios and Tsatsopoulou, 2004 ). An additional skeletal muscle myopathy can contribute to the phenotype of patients with mutations in DES or FLNC ( Klauke et al, 2010 ; Verdonschot et al, 2020 ).…”

Section: Animal Models For Acm Associated With Mutations In Desmosomamentioning

confidence: 99%

Genetic Animal Models for Arrhythmogenic Cardiomyopathy

Gerull

Brodehl

2020

Front. Physiol.

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Arrhythmogenic cardiomyopathy has been clinically defined since the 1980s and causes right or biventricular cardiomyopathy associated with ventricular arrhythmia. Although it is a rare cardiac disease, it is responsible for a significant proportion of sudden cardiac deaths, especially in athletes. The majority of patients with arrhythmogenic cardiomyopathy carry one or more genetic variants in desmosomal genes. In the 1990s, several knockout mouse models of genes encoding for desmosomal proteins involved in cell–cell adhesion revealed for the first time embryonic lethality due to cardiac defects. Influenced by these initial discoveries in mice, arrhythmogenic cardiomyopathy received an increasing interest in human cardiovascular genetics, leading to the discovery of mutations initially in desmosomal genes and later on in more than 25 different genes. Of note, even in the clinic, routine genetic diagnostics are important for risk prediction of patients and their relatives with arrhythmogenic cardiomyopathy. Based on improvements in genetic animal engineering, different transgenic, knock-in, or cardiac-specific knockout animal models for desmosomal and nondesmosomal proteins have been generated, leading to important discoveries in this field. Here, we present an overview about the existing animal models of arrhythmogenic cardiomyopathy with a focus on the underlying pathomechanism and its importance for understanding of this disease. Prospectively, novel mechanistic insights gained from the whole animal, organ, tissue, cellular, and molecular levels will lead to the development of efficient personalized therapies for treatment of arrhythmogenic cardiomyopathy.

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A mutation update for the FLNC gene in myopathies and cardiomyopathies

Abstract: Filamin C (FLNC) variants are associated with cardiac and muscular phenotypes. Originally, FLNC variants were described in myofibrillar myopathy (MFM) patients.

Cited by 108 publications

References 88 publications

Homozygous expression of the myofibrillar myopathy-associated p.W2710X filamin C variant reveals major pathomechanisms of sarcomeric lesion formation

Homozygous expression of the myofibrillar myopathy-associated p.W2710X filamin C variant reveals major pathomechanisms of sarcomeric lesion formation

Clinical Implications of the Genetic Architecture of Dilated Cardiomyopathy

Genetic Animal Models for Arrhythmogenic Cardiomyopathy

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