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Desmin, desminopathy and the complexity of genetics.

Published on Mar 1, 2016in Journal of Molecular and Cellular Cardiology5.055
· DOI :10.1016/j.yjmcc.2016.01.017
Valerio Azzimato4
Estimated H-index: 4
(Karolinska University Hospital),
Nina Gennebäck1
Estimated H-index: 1
(Karolinska University Hospital)
+ 2 AuthorsRalph Knöll24
Estimated H-index: 24
(AstraZeneca)
Abstract
  • References (16)
  • Citations (8)
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References16
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#1Andreas Brodehl (Libin Cardiovascular Institute of Alberta)H-Index: 9
#2Mareike Dieding (Bielefeld University)H-Index: 7
Last. Hendrik Milting (RUB: Ruhr University Bochum)H-Index: 27
view all 13 authors...
Abstract Background Dilated cardiomyopathy (DCM) could be caused by mutations in more than 40 different genes. However, the pathogenic impact of specific mutations is in most cases unknown complicating the genetic counseling of affected families. Therefore, functional studies could contribute to distinguish pathogenic mutations and benign variants. Here, we present a novel heterozygous DES missense variant (c.407C > T; p.L136P) identified by next generation sequencing in a DCM patient. DES encod...
18 CitationsSource
#1Olaf Bergmann (KI: Karolinska Institutet)H-Index: 17
#2Sofia Zdunek (KI: Karolinska Institutet)H-Index: 8
Last. Jonas Frisén (KI: Karolinska Institutet)H-Index: 68
view all 18 authors...
Summary The contribution of cell generation to physiological heart growth and maintenance in humans has been difficult to establish and has remained controversial. We report that the full complement of cardiomyocytes is established perinataly and remains stable over the human lifespan, whereas the numbers of both endothelial and mesenchymal cells increase substantially from birth to early adulthood. Analysis of the integration of nuclear bomb test-derived 14 C revealed a high turnover rate of en...
296 CitationsSource
#1Sue Richards (OHSU: Oregon Health & Science University)H-Index: 5
#2Nazneen Aziz (Boston Children's Hospital)H-Index: 6
Last. Heidi L. Rehm (Harvard University)H-Index: 51
view all 12 authors...
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology
4,410 CitationsSource
#1Nilgun Cetin (Hacettepe University)H-Index: 1
#2Burcu Balci-Hayta (Hacettepe University)H-Index: 4
Last. Pervin Dincer (Hacettepe University)H-Index: 11
view all 10 authors...
Background Autosomal recessive limb girdle muscular dystrophy (LGMD2) is a heterogeneous group of myopathies characterised by progressive muscle weakness involving proximal muscles of the shoulder and pelvic girdles including at least 17 different genetic entities. Additional loci have yet to be identified as there are families which are unlinked to any of the known loci. Here we have investigated a consanguineous family with LGMD2 with two affected individuals in order to identify the causative...
36 CitationsSource
#1Snigdha Tripathi (MHH: Hannover Medical School)H-Index: 5
#2Imke Schultz (MHH: Hannover Medical School)H-Index: 2
Last. Theresia Kraft (MHH: Hannover Medical School)H-Index: 22
view all 13 authors...
Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disease, which in about 30% of the patients is caused by missense mutations in one allele of the β-myosin heavy chain (β-MHC) gene (MYH7). To address potential molecular mechanisms underlying the family-specific prognosis, we determined the relative expression of mutant versus wild-type MYH7-mRNA. We found a hitherto unknown mutation-dependent unequal expression of mutant to wild-type MYH7-mRNA, which is paralleled by similar un...
34 CitationsSource
#1Baerbel KlaukeH-Index: 7
#2Sabine KossmannH-Index: 1
Last. Hendrik MiltingH-Index: 27
view all 16 authors...
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease, frequently accompanied by sudden cardiac death and terminal heart failure. Genotyping of ARVC patients might be used for palliative treatment of the affected family. We genotyped a cohort of 22 ARVC patients referred to molecular genetic screening in our heart center for mutations in the desmosomal candidate genes JUP, DSG2, DSC2, DSP and PKP2 known to be associated with ARVC. In 43% of the cohort, we fo...
95 CitationsSource
#1Ellen Otten (UMCG: University Medical Center Groningen)H-Index: 9
#2Angeliki Asimaki (BIDMC: Beth Israel Deaconess Medical Center)H-Index: 22
Last. Tintelen van J. P (UMCG: University Medical Center Groningen)H-Index: 41
view all 11 authors...
Background Mutations in the gene encoding desmin ( DES ), an intermediate filament protein, underlie a heterogeneous phenotype, which is referred to as desmin-related myopathy (DRM). Right ventricular involvement including an arrhythmogenic right ventricular cardiomyopathy (ARVC)(-like) phenotype has occasionally been described in DES mutation-carrying patients. Objective To determine the effects of a DES missense mutation on the structure of different intercalated disk proteins, to evaluate rig...
74 CitationsSource
Muscle fiber deterioration resulting in progressive skeletal muscle weakness, heart failure, and respiratory distress occurs in more than 20 inherited myopathies. As discussed in this Review, one of the newly identified myopathies is desminopathy, a disease caused by dysfunctional mutations in desmin, a type III intermediate filament protein, or αB-crystallin, a chaperone for desmin. The range of clinical manifestations in patients with desminopathy is wide and may overlap with those observed in...
146 CitationsSource
#1Patryk Konieczny (University of Vienna)H-Index: 3
#2Peter Fuchs (University of Vienna)H-Index: 13
Last. Gerhard Wiche (University of Vienna)H-Index: 13
view all 9 authors...
Dysfunction of plectin, a 500-kD cytolinker protein, leads to skin blistering and muscular dystrophy. Using conditional gene targeting in mice, we show that plectin deficiency results in progressive degenerative alterations in striated muscle, including aggregation and partial loss of intermediate filament (IF) networks, detachment of the contractile apparatus from the sarcolemma, profound changes in myofiber costameric cytoarchitecture, and decreased mitochondrial number and function. Analysis ...
103 CitationsSource
Abstract Desmin, the muscle-specific intermediate filament protein, surrounds the Z disks and links the entire contractile apparatus to the sarcolemmal cytoskeleton, cytoplasmic organelles, and the nucleus. In an attempt to explore the molecular mechanisms of these associations, we performed a yeast two-hybrid screening of a cardiac cDNA library. We showed that the desmin amino-terminal domain (N-(1-103)) binds to a 413-kDa TRIM-like protein, myospryn, originally identified as the muscle-specifi...
46 CitationsSource
Cited By8
Newest
#1Xiaoming Zhou (UTSW: University of Texas Southwestern Medical Center)H-Index: 1
#2Yi Lin (UTSW: University of Texas Southwestern Medical Center)H-Index: 5
Last. Steven L. McKnight (UTSW: University of Texas Southwestern Medical Center)H-Index: 79
view all 10 authors...
Low complexity (LC) head domains 92 and 108 residues in length are, respectfully, required for assembly of neurofilament light (NFL) and desmin intermediate filaments (IFs). As studied in isolation, these IF head domains interconvert between states of conformational disorder and labile,β-strand-enriched polymers. Solid state nuclear magnetic resonance (ss-NMR) spectroscopic studies of NFL and desmin head domain polymers reveal spectral patterns consistent with structural order. A combination of ...
Source
#1Lin Chen (HMU: Harbin Medical University)
#2Li Wang (HMU: Harbin Medical University)
Last. Lu Fu (HMU: Harbin Medical University)H-Index: 8
view all 8 authors...
Abstract Aim Mechanoelectric feedback (MEF) was related to malignant arrhythmias in heart failure (HF). Desmin is a cytoskeleton protein and could be involved in MEF as a mechanoelectrical transducer. In this study, we will discuss the role of desmin alterations in mechanical electrical feedback in heart failure and its mechanisms. Methods We used both an in vivo rat model and an in vitro cardiomyocyte model to address this issue. For the in vivo experiments, we establish a sham group, an HF gro...
Source
#1Andreas BrodehlH-Index: 9
#2Pour Hakimi SaH-Index: 1
Last. Hendrik MiltingH-Index: 27
view all 10 authors...
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. Consequen...
2 CitationsSource
#1Adam Jarmuła (Nencki Institute of Experimental Biology)H-Index: 7
#2Anna Łusakowska (Medical University of Warsaw)H-Index: 5
Last. Maria Jolanta Redowicz (Nencki Institute of Experimental Biology)H-Index: 14
view all 14 authors...
LGMD2L is a subtype of limb-girdle muscular dystrophy (LGMD), caused by recessive mutations in ANO5, encoding anoctamin-5 (ANO5). We present the analysis of five patients with skeletal muscle weakness for whom heterozygous mutations within ANO5 were identified by whole exome sequencing (WES). Patients varied in the age of the disease onset (from 22 to 38 years) and severity of the morphological and clinical phenotypes. Out of the nine detected mutations one was novel (missense p.Lys132Met, accom...
1 CitationsSource
#1Mary Tsikitis (Academy of Athens)H-Index: 6
#2Zoi Galata (Academy of Athens)H-Index: 3
Last. Yassemi Capetanaki (Academy of Athens)H-Index: 28
view all 5 authors...
Intermediate filament (IF) proteins are critical regulators in health and disease. The discovery of hundreds of mutations in IF genes and posttranslational modifications has been linked to a plethora of human diseases, including, among others, cardiomyopathies, muscular dystrophies, progeria, blistering diseases of the epidermis, and neurodegenerative diseases. The major IF proteins that have been linked to cardiomyopathies and heart failure are the muscle-specific cytoskeletal IF protein desmin...
6 CitationsSource
#1Shafiul Alam (LSU Health Sciences Center Shreveport)H-Index: 13
#2Chowdhury S. Abdullah (LSU Health Sciences Center Shreveport)H-Index: 4
Last. Md. Shenuarin Bhuiyan (LSU Health Sciences Center Shreveport)H-Index: 17
view all 10 authors...
Background Desmin filament proteins interlink the contractile myofibrillar apparatus with mitochondria, nuclei and the sarcolemma. Mutations in the human desmin gene cause cardiac disease, remodeli...
2 CitationsSource
#1Ilona Schirmer (RUB: Ruhr University Bochum)H-Index: 3
#2Mareike Dieding (Bielefeld University)H-Index: 7
Last. Hendrik Milting (RUB: Ruhr University Bochum)H-Index: 27
view all 11 authors...
Background DES mutations cause different cardiac and skeletal myopathies. Most of them are missense mutations. Methods Using a next-generation sequencing cardiac 174 gene panel, we identified a novel heterozygous in-frame indel mutation (DES-c.493_520del28insGCGT, p.Q165_A174delinsAS) in a Caucasian patient with cardiomyopathy in combination with atrioventricular block and skeletal myopathy. This indel mutation is located in the coding region of the first exon. Family anamnesis revealed a histor...
4 CitationsSource
#1Francisco José Bermúdez-Jiménez (UGR: University of Granada)H-Index: 3
#2Víctor Carriel (UGR: University of Granada)H-Index: 17
Last. Juan Jiménez-Jáimez (UGR: University of Granada)H-Index: 9
view all 14 authors...
Background —Desmin ( DES ) mutations cause severe skeletal and cardiac muscle disease with heterogeneous phenotypes. Recently, DES mutations were described in patients with inherited arrhythmogenic right ventricular cardiomyopathy/dysplasia (iARVC/D), although their cellular and molecular pathomechanisms are not precisely known. Our aim is to describe clinically and functionally the novel DES -p.Glu401Asp mutation as a cause of inherited left ventricular arrhythmogenic cardiomyopathy/dysplasia (...
12 CitationsSource
#1Andreas Brodehl (RUB: Ruhr University Bochum)H-Index: 9
#2Hendrik Milting (RUB: Ruhr University Bochum)H-Index: 27
Source
#1Christine A. Henderson (UA: University of Arizona)H-Index: 2
#2Christopher G. Gomez (UA: University of Arizona)H-Index: 1
Last. Carol C. Gregorio (UA: University of Arizona)H-Index: 37
view all 5 authors...
Abstract Cardiac and skeletal striated muscles are intricately designed machines responsible for muscle contraction. Coordination of the basic contractile unit, the sarcomere, and the complex cytoskeletal networks are critical for contractile activity. The sarcomere is comprised of precisely organized individual filament systems that include thin (actin), thick (myosin), titin, and nebulin. Connecting the sarcomere to other organelles (e.g., mitochondria and nucleus) and serving as the scaffold ...
20 CitationsSource