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19 pages, 2499 KB

Open AccessArticle

First Glance at Myeloid Leukaemia Factor 2 in Cardiomyocytes

by Jakob Christoph Voran, Lucia Sophie Kilian, Simone Martini, Marcin Luzarowski, Marie Isabel Noormalal, Oliver Josef Müller, Ashraf Yusuf Rangrez and Derk Frank

J. Cardiovasc. Dev. Dis. 2026, 13(1), 19; https://doi.org/10.3390/jcdd13010019 - 30 Dec 2025

Cited by 1 | Viewed by 1364

Abstract

Understanding the molecular mechanisms that maintain protein homeostasis in cardiomyocytes is fundamental for the development of causal therapies for heart failure. Chaperones, the ubiquitin–proteasome system and autophagy are major regulators of cardiac homeostasis and are crucial for cardiomyocyte function and survival. In this context, myeloid leukaemia factor 2 (MLF2) emerged as a candidate of interest, as we found it overrepresented in protein aggregates in the hearts of mouse models of desmin-related cardiomyopathies (DRM), and it has also been suggested to be associated with dilated cardiomyopathy (DCM). Here, we identified αB-crystallin (CryAB), among other proteins, as a potential interaction partner of MLF2. Functionally, MLF2 was significantly upregulated in mouse models of heart failure and in two in vitro models of cardiomyocyte hypertrophy, and its overexpression resulted in attenuation of pro-hypertrophic gene expression. Taken together, these findings provide initial evidence supporting a role for MLF2 in regulating protein homeostasis and in modulating hypertrophic signalling in cardiomyocytes. Full article

(This article belongs to the Topic Molecular and Cellular Mechanisms of Heart Disease)

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20 pages, 7399 KB

Open AccessArticle

Unraveling Desmin’s Head Domain Structure and Function

by Dimitrios Vlachakis, Konstantinos Tsilafakis, Ioanna Kostavasili, Sophia Kossida and Manolis Mavroidis

Cells 2024, 13(7), 603; https://doi.org/10.3390/cells13070603 - 29 Mar 2024

Cited by 6 | Viewed by 3008

Abstract

Understanding the structure and function of intermediate filaments (IFs) is necessary in order to explain why more than 70 related IF genes have evolved in vertebrates while maintaining such dramatically tissue-specific expression. Desmin is a member of the large multigene family of IF proteins and is specifically expressed in myocytes. In an effort to elucidate its muscle-specific behavior, we have used a yeast two-hybrid system in order to identify desmin’s head binding partners. We described a mitochondrial and a lysosomal protein, NADH ubiquinone oxidoreductase core subunit S2 (NDUFS2), and saposin D, respectively, as direct desmin binding partners. In silico analysis indicated that both interactions at the atomic level occur in a very similar way, by the formation of a three-helix bundle with hydrophobic interactions in the interdomain space and hydrogen bonds at R16 and S32 of the desmin head domain. The interactions, confirmed also by GST pull-down assays, indicating the necessity of the desmin head domain and, furthermore, point out its role in function of mitochondria and lysosomes, organelles which are disrupted in myopathies due to desmin head domain mutations. Full article

(This article belongs to the Topic Molecular and Cellular Mechanisms of Diseases: Heart Disease)

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10 pages, 1199 KB

Open AccessCase Report

Deep Characterization of a Greek Patient with Desmin-Related Myofibrillar Myopathy and Cardiomyopathy

by Constantinos Papadopoulos, Edoardo Malfatti, Corinne Métay, Boris Keren, Elodie Lejeune, Julien Buratti, Sophia Xirou, Margarita Chrysanthou-Piterou and George K. Papadimas

Int. J. Mol. Sci. 2023, 24(13), 11181; https://doi.org/10.3390/ijms241311181 - 6 Jul 2023

Cited by 4 | Viewed by 3675

Abstract

Desmin is a class III intermediate filament protein highly expressed in cardiac, smooth and striated muscle. Autosomal dominant or recessive mutations in the desmin gene (DES) result in a variety of diseases, including cardiomyopathies and myofibrillar myopathy, collectively called desminopathies. Here we describe the clinical, histological and radiological features of a Greek patient with a myofibrillar myopathy and cardiomyopathy linked to the c.734A>G,p.(Glu245Gly) heterozygous variant in the DES gene. Moreover, through ribonucleic acid sequencing analysis in skeletal muscle we show that this variant provokes a defect in exon 3 splicing and thus should be considered clearly pathogenic. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Neuromuscular Diseases and Myopathies)

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27 pages, 3248 KB

Open AccessReview

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

by Lorenzo Maggi, Manolis Mavroidis, Stelios Psarras, Yassemi Capetanaki and Giovanna Lattanzi

Int. J. Mol. Sci. 2021, 22(8), 4256; https://doi.org/10.3390/ijms22084256 - 20 Apr 2021

Cited by 54 | Viewed by 8187

Abstract

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. Full article

(This article belongs to the Special Issue Recent Advances in Intermediate Filaments)

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11 pages, 2257 KB

Open AccessArticle

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

by Andreas Brodehl, Seyed Ahmad Pour Hakimi, Caroline Stanasiuk, Sandra Ratnavadivel, Doris Hendig, Anna Gaertner, Brenda Gerull, Jan Gummert, Lech Paluszkiewicz and Hendrik Milting

Genes 2019, 10(11), 918; https://doi.org/10.3390/genes10110918 - 11 Nov 2019

Cited by 64 | Viewed by 6091

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. Full article

(This article belongs to the Section Human Genomics and Genetic Diseases)

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