Restrictive Cardiomyopathy is Caused by a Novel Homozygous Desmin (DES) Mutation p.Y122H Leading to a Severe Filament Assembly Defect

Abstract

Here, we present a small Iranian family, where the index patient received a diagnosis of restrictive cardiomyopathy (RCM) in combination with atrioventricular (AV) block. Genetic analysis revealed a novel homozygous missense mutation in the DES gene (c.364T > C; p.Y122H), which is absent in human population databases. The mutation is localized in the highly conserved coil-1 desmin subdomain. In silico, prediction tools indicate a deleterious effect of the desmin (DES) mutation p.Y122H. Consequently, we generated an expression plasmid encoding the mutant and wildtype desmin formed, and analyzed the filament formation in vitro in cardiomyocytes derived from induced pluripotent stem cells and HT-1080 cells. Confocal microscopy revealed a severe filament assembly defect of mutant desmin supporting the pathogenicity of the DES mutation, p.Y122H, whereas the wildtype desmin formed regular intermediate filaments. According to the guidelines of the American College of Medical Genetics and Genomics, we classified this mutation, therefore, as a novel pathogenic mutation. Our report could point to a recessive inheritance of the DES mutation, p.Y122H, which is important for the genetic counseling of similar families with restrictive cardiomyopathy caused by DES mutations.

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

“…Desmin encoding parts of all plasmids were verified by Sanger sequencing (Macrogen, Amsterdam, Netherlands). The plasmid pmRuby-N1-DES and pmRuby-N1-DES-p.(Y122C) have been previously described [19,20]. Previously reported variant DES-p.(Y122C) was used as a positive control forming abnormal cytoplasmic aggregates [20].…”

“…The plasmid pmRuby-N1-DES and pmRuby-N1-DES-p.(Y122C) have been previously described [19,20]. Previously reported variant DES-p.(Y122C) was used as a positive control forming abnormal cytoplasmic aggregates [20]. HT1080 cells, which do not express endogenous desmin and cardiomyocytes derived from human induced pluripotent stem cells (iPSC) (NP00040-8) were transfected using Lipofectamin 3000 (ThermoFisher Scientific) or nucleofection using the 4D Nucleofector (Lonza, Cologne, Germany) in combination with the P3 Primary Cell 4D Nucleofector Kit according to the manufacturer's instructions.…”

“…* p < 0.05 and ** p < 0.01. The variant DES-p.(Y122C) was used as a positive control forming abnormal cytoplasmic aggregates [20].…”

Infantile restrictive cardiomyopathy: cTnI-R170G/W impair the interplay of sarcomeric proteins and the integrity of thin filaments

“…Restrictive cardiomyopathy can have many causes: metabolic disorders like diabetes, genetically caused storage diseases like amyloidosis, and point mutations of sarcomeric proteins inherited in a dominant autosomal manner (for review see also Muchtar et al 2017 [7]). Point mutations have been identified in a number of different sarcomeric components such as the heavy myosin chain of β-myosin (MYH7), myosin binding protein C (MYBPC3), and the troponin subunits cTnC (TNNC1), cTnI (TNNI3) and cTnT (TNNT2) as well as in cytoskeletal components like filamin (FLNC), αB-crystallin (CRYAB), and desmin (DES) [3,[8][9][10][11][12][13]. A number of RCM causing point mutations were identified in cTnI (TNNI3) that are clustered in its C-terminal region [4,[14][15][16][17].…”

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.…”