The Novel Desmin Variant p.Leu115Ile Is Associated With a Unique Form of Biventricular Arrhythmogenic Cardiomyopathy

Protonotarios, Alexandros; Brodehl, Andreas; Asimaki, Angeliki; Jager, Joanna; Quinn, Ellie; Stanasiuk, Caroline; Ratnavadivel, Sandra; Futema, Marta; Akhtar, Mohammed; Gossios, Thomas D.; Ashworth, Michael; Savvatis, Konstantinos; Walhorn, Volker; Anselmetti, Dario; Elliott, Perry; Syrris, Petros; Lopes, Luís Rocha

doi:10.1016/j.cjca.2020.11.017

Cited by 35 publications

(38 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Members of the Lebanese family did not have evidence of significant skeletal myopathies. A more comprehensive review of all known mutations throughout the DES gene indicated that on average 49% develop cardiomyopathy (DCM, arrhythmogenic cardiomyopathy, restrictive cardiomyopathy, and non‐compaction cardiomyopathy), 36% develop conduction disease requiring pacemaker placement, and a minority (<10%) develop AF (Brodehl et al, 2018, 2019; Marakhonov et al, 2019; Protonotarios et al, 2020; van Spaendonck‐Zwarts et al, 2011). While the incidence of cardiomyopathy in the Lebanese pedigree (50%) was similar to that reported in the literature, the incidence of heart block (67%) requiring pacemaker and AF (83%) were much greater.…”

Section: Resultsmentioning

confidence: 99%

Epistatic interaction of PDE4DIP and DES mutations in familial atrial fibrillation with slow conduction

et al. 2021

View full text Add to dashboard Cite

The genetic causes of atrial fibrillation (AF) with slow conduction are unknown. Eight kindreds with familial AF and slow conduction, including a family affected by early‐onset AF, heart block, and incompletely penetrant nonischemic dilated cardiomyopathy (DCM) underwent whole exome sequencing. A known pathogenic mutation in the desmin (DES) gene resulting in p.S13F substitution (NM_001927.3:c.38C>T) at a PKC phosphorylation site was identified in all four members of the kindred with early‐onset AF and heart block, while only two developed DCM. Higher penetrance for AF and heart block prompted a genetic screening for DES modifier(s). A deleterious mutation in the phosphodiesterase‐4D‐interacting‐protein (PDE4DIP) gene resulting in p.A123T substitution (NM_001002811:c.367G>A) was identified that segregated with early‐onset AF, heart block, and the DES mutation. Three additional novel deleterious PDE4DIP mutations were identified in four other unrelated kindreds. Characterization of PDE4DIPA123T in vitro suggested impaired compartmentalization of PKA and PDE4D characterized by reduced colocalization with PDE4D, increased cAMP activation leading to higher PKA phosphorylation of the β2‐adrenergic‐receptor, and decreased PKA phosphorylation of desmin after isoproterenol stimulation. Our findings identify PDE4DIP as a novel gene for slow AF and unravel its epistatic interaction with DES mutations in development of conduction disease and arrhythmia.

show abstract

Section: Resultsmentioning

confidence: 99%

Epistatic interaction of PDE4DIP and DES mutations in familial atrial fibrillation with slow conduction

et al. 2021

View full text Add to dashboard Cite

show abstract

“…DES encodes the cardiac intermediate filament (IF) protein desmin, and missense mutations in this gene cause right or biventricular forms of ACM [50][51][52]. However, the phenotypes associated with DES mutations are heterogeneous and range from isolated skeletal myopathies to different cardiomyopathies including DCM, left ventricular non-compaction (LVNC), and restrictive cardiomyopathy (RCM) [53].…”

Section: Z-band Proteinsmentioning

confidence: 99%

Insights Into Genetics and Pathophysiology of Arrhythmogenic Cardiomyopathy

Gerull¹,

Brodehl

2021

Curr Heart Fail Rep

Self Cite

View full text Add to dashboard Cite

Purpose of Review Arrhythmogenic cardiomyopathy (ACM) is a genetic disease characterized by life-threatening ventricular arrhythmias and sudden cardiac death (SCD) in apparently healthy young adults. Mutations in genes encoding for cellular junctions can be found in about half of the patients. However, disease onset and severity, risk of arrhythmias, and outcome are highly variable and drug-targeted treatment is currently unavailable. Recent Findings This review focuses on advances in clinical risk stratification, genetic etiology, and pathophysiological concepts. The desmosome is the central part of the disease, but other intercalated disc and associated structural proteins not only broaden the genetic spectrum but also provide novel molecular and cellular insights into the pathogenesis of ACM. Signaling pathways and the role of inflammation will be discussed and targets for novel therapeutic approaches outlined. Summary Genetic discoveries and experimental-driven preclinical research contributed significantly to the understanding of ACM towards mutation- and pathway-specific personalized medicine.

show abstract

“…A recent report of the largest family of a single DES mutation (DES E401D) causing predominantly inherited ARVC suggested that the prevalence of desmin mutations in ARVC may be higher than expected [67]. In fact, a recent study reported a single L115 DES mutation as the cause of ACM in three patients [68]. Interestingly, a patient carrying single heterozygous missense mutations both in LMNA and DES genes presented at 14 years of age with a rapidly progressive HCM [69].…”

Section: Clinical Aspects Of Cardiac Involvement In Desminopathiesmentioning

confidence: 99%

Skeletal and Cardiac Muscle Disorders Caused by Mutations in Genes Encoding Intermediate Filament Proteins

Maggi

Mavroidis

Psarras

et al. 2021

IJMS

View full text Add to dashboard Cite

Intermediate filaments are major components of the cytoskeleton. Desmin and synemin, cytoplasmic intermediate filament proteins and A-type lamins, nuclear intermediate filament proteins, play key roles in skeletal and cardiac muscle. Desmin, encoded by the DES gene (OMIM *125660) and A-type lamins by the LMNA gene (OMIM *150330), have been involved in striated muscle disorders. Diseases include desmin-related myopathy and cardiomyopathy (desminopathy), which can be manifested with dilated, restrictive, hypertrophic, arrhythmogenic, or even left ventricular non-compaction cardiomyopathy, Emery–Dreifuss Muscular Dystrophy (EDMD2 and EDMD3, due to LMNA mutations), LMNA-related congenital Muscular Dystrophy (L-CMD) and LMNA-linked dilated cardiomyopathy with conduction system defects (CMD1A). Recently, mutations in synemin (SYNM gene, OMIM *606087) have been linked to cardiomyopathy. This review will summarize clinical and molecular aspects of desmin-, lamin- and synemin-related striated muscle disorders with focus on LMNA and DES-associated clinical entities and will suggest pathogenetic hypotheses based on the interplay of desmin and lamin A/C. In healthy muscle, such interplay is responsible for the involvement of this network in mechanosignaling, nuclear positioning and mitochondrial homeostasis, while in disease it is disturbed, leading to myocyte death and activation of inflammation and the associated secretome alterations.

show abstract

The Novel Desmin Variant p.Leu115Ile Is Associated With a Unique Form of Biventricular Arrhythmogenic Cardiomyopathy

Cited by 35 publications

References 35 publications

Epistatic interaction of PDE4DIP and DES mutations in familial atrial fibrillation with slow conduction

Epistatic interaction of PDE4DIP and DES mutations in familial atrial fibrillation with slow conduction

Insights Into Genetics and Pathophysiology of Arrhythmogenic Cardiomyopathy

Skeletal and Cardiac Muscle Disorders Caused by Mutations in Genes Encoding Intermediate Filament Proteins

Contact Info

Product

Resources

About