Noncompaction cardiomyopathy is caused by a novel in‐frame desmin ( DES ) deletion mutation within the 1A coiled‐coil rod segment leading to a severe filament assembly defect

Abstract

Mutations in DES, encoding desmin protein, are associated with different kinds of skeletal and/or cardiac myopathies. However, it is unknown, whether DES mutations are associated with left ventricular hypertrabeculation (LVHT). Here, we performed a clinical examination and subsequent genetic analysis in a family, with two individuals presenting LVHT with conduction disease and skeletal myopathy. The genetic analysis revealed a novel small in‐frame deletion within the DES gene, p.Q113_L115del, affecting the α‐helical rod domain. Immunohistochemistry analysis of explanted myocardial tissue from the index patient revealed an abnormal cytoplasmic accumulation of desmin and a degraded sarcomeric structure. Cell transfection experiments with wild‐type and mutant desmin verified the cytoplasmic aggregation and accumulation of mutant desmin. Cotransfection experiments were performed to model the heterozygous state of the patients and revealed a dominant negative effect of the mutant desmin on filament assembly. DES:p.Q113_L115del is classified as a pathogenic mutation associated with dilated cardiomyopathy with prominent LVHT.

Desminopathy: Novel Desmin Variants, a New Cardiac Phenotype, and Further Evidence for Secondary Mitochondrial Dysfunction

“…In addition to known cardiac phenotypes of desminopathy like DCM, RCM HCM, and ACM [1,28,29], we observed LVNC as a relatively novel phenotype. So far, DES variants have been associated with LVNC just in a few individuals [34][35][36][37]. The first report from Arbustini et al [34] described a family with a segregation of DES variant p.(G84S) with non-obstructive hypertrophic cardiomyopathy and one case of LVNC.…”

“…Another group [35] reported one sporadic case of LVNC in a child with a DES variant p.(L398P). An occurrence of two cases of LVNC in one family has been recently associated with an in-frame mutation of desmin p.(Q113_L115del) affecting the α-helical rod domain [36] with a formation of typical desmin-immunoreactive aggregates. We expanded the available evidence by a description of another familial occurrence of two cases of LVNC associated with the desmin variant p.(Q364H) with a decreased myocardial expression of desmin and absent desmin aggregates in myocardial/skeletal biopsy.…”

Genetic Animal Models for Arrhythmogenic Cardiomyopathy

“…Although desmin is not directly a Z-band protein, it forms cytoplasmic IF and is involved in connection of the Z-bands ( Hijikata et al, 1999 ), desmosomes ( Choi et al, 2002 ), mitochondria ( Capetanaki, 2002 ), and also the nuclei ( Heffler et al, 2020 ) in cardiomyocytes. Mutations in DES cause different skeletal and cardiac myopathies, including DCM ( Li et al, 1999 ; Brodehl et al, 2016a ), HCM ( Harada et al, 2018 ), RCM ( Brodehl et al, 2019c ), LVNC ( Marakhonov et al, 2019 ; Kubanek et al, 2020 ), and also ACM ( Klauke et al, 2010 ; Bermudez-Jimenez et al, 2018 ). Desmin consists of a central α-helical rod domain flanked by nonhelical head and tail domains.…”

Human Induced Pluripotent Stem-Cell-Derived Cardiomyocytes as Models for Genetic Cardiomyopathies

“…Of note, the spectrum of affected genes and mutations partially overlaps between the different non-ischemic cardiomyopathies (Figure 1). For example, mutations in DES , encoding the muscle specific intermediate filament protein desmin, might cause DCM [23,24], HCM [25], ACM [26,27], RCM [28], or NCCM [29,30,31]. Similarly, mutations in TTN , encoding the giant sarcomere protein titin, can also cause different types of structural, non-ischemic cardiomyopathies [32,33,34].…”