Differential proteomic analysis of abnormal intramyoplasmic aggregates in desminopathy

Maerkens, A.; Kley, Rudolf A.; Olivé, Montse; Theis, Verena; Ven, Peter F.M. van der; Reimann, Jens; Milting, Hendrik; Schreiner, Anja; Uszkoreit, Julian; Eisenacher, Martin; Barkovits, Katalin; Güttsches, Anne‐Katrin; Tonillo, Jason; Kuhlmann, Katja; Meyer, Helmut E.; Schröder, Rolf; Tegenthoff, Martin; Fürst, Dieter O.; Müller, Thorsten; Goldfarb, Lev G.; Vorgerd, Matthias; Marcus, Katrin

doi:10.1016/j.jprot.2013.04.026

Cited by 63 publications

(76 citation statements)

References 50 publications

(88 reference statements)

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“…It is possible that mutant filamin C is also present and is precipitating the aggregation phenotype, which could attract other proteins to the complex as well as bystanders. This would be consistent with the Maerkens et al [32] (2013) that filamin C (presumably normal protein sequence) was found in abundance in desminopathy deposits, along with a multitude of other proteins that appear to have also been trapped. It may be the gradual accumulation of these aggregates that are the underlying cause of cardiac muscle tissue failure, with such aggregates only forming in the presence of an abnormal protein, as seen in cardiac amyloidosis associated with missense mutations in the transthyretin (TTR) gene [33] .…”

Section: Discussionsupporting

confidence: 90%

“…This has been termed "filaminopathy" similar to the situation in "desminopathy". While that term now applies to a condition with abnormal tissue deposits in patients with DES mutations, including mutant desmin protein (e.g., Maerkens et al [32] , 2013), in early studies it was a descriptive term indicating presence and/ or dominance of desmin in the tissue aggregate, without knowledge of underlying genetic cause. In the family described here, the desmin gene sequence is normal [19] , yet cardiac aggregates containing desmin were seen.…”

Section: Discussionmentioning

confidence: 99%

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Exome sequencing identifies FLNC and ADD3 variants in a family with cardiomyopathy

Sanoja¹,

Li²,

Fricker³

et al. 2018

JTGG

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Aim: Idiopathic cardiomyopathy is often genetic in origin, typically autosomal dominant, and restrictive cardiomyopathy (RCM) is the rarest form. Clinically, RCM prognosis is poor with most patients requiring heart transplant due to impaired diastolic function leading to heart failure. In some cases, desminopathy is also observed, whereby desmin protein aggregates in the myocardium. Many genes are known to be involved in cardiomyopathy, and we sought to find the pathogenic mutation of a four-generation family with RCM and desminopathy. Methods:We employed whole exome sequence analysis of four RCM patients from the family, to identify the underlying pathogenic mutation(s).Results: Analysis of the exome data led to identification of two putative pathogenic variants. One, a nonsense mutation in ADD3, encoding adducin 3, was found in the proband and his affected daughter, but not other family members. The other was a missense mutation (G1546S) in the gene encoding filamin C (FLNC), found in all of the affected individuals. Both of these proteins interact with proteins involved in sarcomere function, and are expressed in both heart and skeletal muscle. FLNC has recently been implicated as a cardiomyopathy gene, but ADD3 has not at this point. Conclusion:We present bioinformatic analyses that suggest that the FLNC variant is the major pathogenic variant affecting this family, but cannot rule out some contribution of the ADD3 mutation in at least two patients.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Exome sequencing identifies FLNC and ADD3 variants in a family with cardiomyopathy

Sanoja¹,

Li²,

Fricker³

et al. 2018

JTGG

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show abstract

“…Indeed, within the abnormal DRM linked protein inclusions, desmin co-aggregates consistently with numerous proteins, associated directly or indirectly with the desmin network, including αB-crystallin, hsp27, synemin, syncoilin, nestin, plectin, filamin C, hsp72/73, myotilin, dystrophin, utrophin, α & β-dystroglycan, α, β, γ & δ-sarcoglycans, caveolin, dysferlin, actin, actinin, N-CAM, NOS, collagen VI, laminin, β-spectrin, and ubiquitin (reviewed in [7]). Some of these data were recently confirmed by a proteomic analysis of skeletal muscle biopsies of DRM patients which identified 22 proteins significantly over-represented in the aggregates, with desmin and filamin C having the highest spectral index, followed by Xirp2, αB-crystallin, N-RAP, Xin and Hsp27 [28]. On the other hand, besides desmin, human mutations in most of the above proteins and some additional ones (such as myotubularin [29] and the nuclear lamins A/C, emerin and LAP2a), lead to myopathy and cardiomyopathy, strongly suggesting that desmin might be a common denominator in most of these cases, regardless of the mutated protein.…”

Section: Mechanisms Of Desmin Related Disease Developmentmentioning

confidence: 88%

Desmin related disease: a matter of cell survival failure

Capetanaki

Papathanasiou

Diokmetzidou

et al. 2015

Current Opinion in Cell Biology

114

126

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Maintenance of the highly organized striated muscle tissue requires a cell-wide dynamic network that through interactions with all vital cell structures, provides an effective mechanochemical integrator of morphology and function, absolutely necessary for intra- and intercellular coordination of all muscle functions. A good candidate for such a system is the desmin intermediate filament cytoskeletal network. Human desmin mutations and post-translational modifications cause disturbance of this network, thus leading to loss of function of both desmin and its binding partners, as well as potential toxic effects of the formed aggregates. Both loss of normal function and gain of toxic function are linked to mitochondrial defects, cardiomyocyte death, muscle degeneration and development of skeletal myopathy and cardiomyopathy.

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“…41 Furthermore, a quantitative proteomic assessment of aggregates in desminopathy identified filamin C as the second most abundant protein in these aggregates, providing additional support for the role of filamin C as a mediator of cardiomyopathy. 42 The FLNC mutation identified in DCM-AAY02 is located 1bp from a splice-acceptor, is absent from the 1000Genomes database, is predicted to be strongly deleterious by MaxENT, and is not present in an unaffected sibling. While further functional studies are required to confirm the pathogenicity of this variant, these data underscore the utility of having a mutable super gene-set that allows for the interrogation of putative cardiomyopathy genes.…”

Section: Discussionmentioning

confidence: 99%

Targeted Analysis of Whole Genome Sequence Data to Diagnose Genetic Cardiomyopathy

Golbus

Puckelwartz

Dellefave‐Castillo

et al. 2014

Circ Cardiovasc Genet

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Background Cardiomyopathy is highly heritable but genetically diverse. At present, genetic testing for cardiomyopathy uses targeted sequencing to simultaneously assess the coding regions of more than 50 genes. New genes are routinely added to panels to improve the diagnostic yield. With the anticipated $1000 genome, it is expected that genetic testing will shift towards comprehensive genome sequencing accompanied by targeted gene analysis. Therefore, we assessed the reliability of whole genome sequencing and targeted analysis to identify cardiomyopathy variants in 11 subjects with cardiomyopathy. Methods and Results Whole genome sequencing with an average of 37× coverage was combined with targeted analysis focused on 204 genes linked to cardiomyopathy. Genetic variants were scored using multiple prediction algorithms combined with frequency data from public databases. This pipeline yielded 1-14 potentially pathogenic variants per individual. Variants were further analyzed using clinical criteria and/or segregation analysis. Three of three previously identified primary mutations were detected by this analysis. In six subjects for whom the primary mutation was previously unknown, we identified mutations that segregated with disease, had clinical correlates, and/or had additional pathological correlation to provide evidence for causality. For two subjects with previously known primary mutations, we identified additional variants that may act as modifiers of disease severity. In total, we identified the likely pathological mutation in 9 of 11 (82%) subjects. Conclusions These pilot data demonstrate that ~30-40× coverage whole genome sequencing combined with targeted analysis is feasible and sensitive to identify rare variants in cardiomyopathy-associated genes.

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Differential proteomic analysis of abnormal intramyoplasmic aggregates in desminopathy

Cited by 63 publications

References 50 publications

Exome sequencing identifies FLNC and ADD3 variants in a family with cardiomyopathy

Exome sequencing identifies FLNC and ADD3 variants in a family with cardiomyopathy

Desmin related disease: a matter of cell survival failure

Targeted Analysis of Whole Genome Sequence Data to Diagnose Genetic Cardiomyopathy

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