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In vitro analysis of arrhythmogenic cardiomyopathy associated desmoglein-2 (DSG2) mutations reveals diverse glycosylation patterns

Published on Apr 1, 2019in Journal of Molecular and Cellular Cardiology5.055
· DOI :10.1016/j.yjmcc.2019.03.014
Jana Davina Debus1
Estimated H-index: 1
(RUB: Ruhr University Bochum),
Hendrik Milting27
Estimated H-index: 27
(RUB: Ruhr University Bochum)
+ 4 AuthorsAnna Gaertner-Rommel6
Estimated H-index: 6
(RUB: Ruhr University Bochum)
Source
Abstract
Abstract Arrhythmogenic right ventricular cardiomyopathy is a heritable cardiac disease causing severe ventricular arrhythmias, heart failure and sudden cardiac death. It is mainly caused by mutations in genes encoding several structural proteins of the cardiac desmosomes including the DSG2 gene encoding the desmosomal cadherin desmoglein-2. Although the molecular structure of the extracellular domain of desmoglein-2 is known, it remains an open question, how mutations in DSG2 contribute to the pathogenesis of arrhythmogenic right ventricular cardiomyopathy. In the present study, we analyzed the impact of different DSG2 mutations on the glycosylation pattern using de-glycosylation assays, lectin blot analysis and genetic inhibition studies. Remarkably, wildtype and mutant desmoglein-2 displayed different glycosylation patterns, although the investigated DSG2 mutations do not directly affect the consensus sequences of the N-glycosylation sites. Our study reveals complex molecular interactions between DSG2 mutations and N-glycosylations of desmoglein-2, which may contribute to the molecular understanding of the patho-mechanisms associated with arrhythmogenic right ventricular cardiomyopathy.
  • References (38)
  • Citations (1)
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References38
Newest
#1Ivan GudeljH-Index: 10
#2Gordan Lauc (University of Zagreb)H-Index: 38
Purpose of Review Protein glycosylation has been observed to associate with different diseases, including cardiovascular diseases (CVDs). Most of these observations are related to O-glycosylation, yet N-glycosylation changes have recently gained more attention.
3 CitationsSource
#1Mareike DiedingH-Index: 7
#2Jana Davina Debus (RUB: Ruhr University Bochum)H-Index: 1
Last. Dario AnselmettiH-Index: 37
view all 7 authors...
Cadherins are calcium dependent adhesion proteins that establish the intercellular mechanical contact by bridging the gap to adjacent cells. Desmoglein-2 (Dsg2) is a specific cadherin of the cell-cell contact in cardiac desmosomes. Mutations in the DSG2-gene are regarded to cause arrhythmogenic (right ventricular) cardiomyopathy (ARVC) which is a rare but severe heart muscle disease. The molecular pathomechanisms of the vast majority of DSG2 mutations, however, are unknown. Here, we investigated...
8 CitationsSource
#1Ida Signe Bohse Larsen (UCPH: University of Copenhagen)H-Index: 6
#2Yoshiki Narimatsu (UCPH: University of Copenhagen)H-Index: 10
Last. Adnan Halim (UCPH: University of Copenhagen)H-Index: 5
view all 13 authors...
The cadherin (cdh) superfamily of adhesion molecules carry O-linked mannose (O-Man) glycans at highly conserved sites localized to specific β-strands of their extracellular cdh (EC) domains. These O-Man glycans do not appear to be elongated like O-Man glycans found on α-dystroglycan (α-DG), and we recently demonstrated that initiation of cdh/protocadherin (pcdh) O-Man glycosylation is not dependent on the evolutionary conserved POMT1/POMT2 enzymes that initiate O-Man glycosylation on α-DG. Here,...
22 CitationsSource
#1Ida Signe Bohse Larsen (UCPH: University of Copenhagen)H-Index: 6
#2Yoshiki Narimatsu (UCPH: University of Copenhagen)H-Index: 10
Last. Adnan Halim (UCPH: University of Copenhagen)H-Index: 20
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Abstract Protein O-mannosylation is found in yeast and metazoans and a family of conserved orthologous protein O-mannosyltransferases is believed to initiate this important post-translational modification. We recently discovered that the cadherin superfamily carries O-linked mannose (O-Man) glycans at highly conserved residues in specific extracellular cadherin domains, and it was suggested that the function of E-cadherin was dependent on the O-Man glycans. Deficiencies in enzymes catalyzing O-M...
15 CitationsSource
#1Peter D. Stenson (Cardiff University)H-Index: 41
#2Matthew Mort (Cardiff University)H-Index: 31
Last. David Neil Cooper (Cardiff University)H-Index: 92
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The Human Gene Mutation Database (HGMD®) constitutes a comprehensive collection of published germline mutations in nuclear genes that underlie, or are closely associated with human inherited disease. At the time of writing (March 2017), the database contained in excess of 203,000 different gene lesions identified in over 8000 genes manually curated from over 2600 journals. With new mutation entries currently accumulating at a rate exceeding 17,000 per annum, HGMD represents de facto the central ...
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#1Monkol Lek (Broad Institute)H-Index: 35
#2Konrad J. Karczewski (Broad Institute)H-Index: 35
Last. Daniel G. MacArthur (Broad Institute)H-Index: 57
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Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence fo...
4,484 CitationsSource
#1Oliver J. Harrison (Columbia University)H-Index: 15
#2Julia Brasch (Columbia University)H-Index: 14
Last. Lawrence Shapiro (Columbia University)H-Index: 66
view all 7 authors...
Desmosomes are intercellular adhesive junctions that impart strength to vertebrate tissues. Their dense, ordered intercellular attachments are formed by desmogleins (Dsgs) and desmocollins (Dscs), but the nature of trans-cellular interactions between these specialized cadherins is unclear. Here, using solution biophysics and coated-bead aggregation experiments, we demonstrate family-wise heterophilic specificity: All Dsgs form adhesive dimers with all Dscs, with affinities characteristic of each...
46 CitationsSource
Targeted proteomics focusing on post-translational modifications, including glycosylation, is a useful strategy for discovering novel biomarkers. To apply this strategy effectively to cardiac hypertrophy and resultant heart failure, we aimed to characterize glycosylation profiles in the left ventricle and plasma of rats with cardiac hypertrophy. Dahl salt-sensitive hypertensive rats, a model of hypertension-induced cardiac hypertrophy, were fed a high-salt (8% NaCl) diet starting at 6 weeks. As ...
13 CitationsSource
#1Sebastian Kant (RWTH Aachen University)H-Index: 5
#2Bastian Holthöfer (RWTH Aachen University)H-Index: 3
Last. Rudolf E. Leube (RWTH Aachen University)H-Index: 40
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Background— The desmosomal cadherin desmoglein 2 (Dsg2) localizes to the intercalated disc coupling adjacent cardiomyocytes. Desmoglein 2 gene ( DSG2 ) mutations cause arrhythmogenic cardiomyopathy (AC) in human and transgenic mice. AC is characterized by arrhythmia, cardiodilation, cardiomyocyte necrosis with replacement fibrosis, interstitial fibrosis, and intercalated disc dissociation. The genetic DSG2 constellations encountered are compatible with loss of adhesion and altered signaling. To ...
24 CitationsSource
#1Angela Schlipp (LMU: Ludwig Maximilian University of Munich)H-Index: 3
#2Camilla Schinner (LMU: Ludwig Maximilian University of Munich)H-Index: 3
Last. Jens Waschke (LMU: Ludwig Maximilian University of Munich)H-Index: 28
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Aims We determined the contribution of the desmosomal cadherin desmoglein-2 to cell–cell cohesion in cardiomyocytes. In the intercalated disc, providing mechanical strength and electrical communication between adjacent cardiomyocytes, desmoglein-2 is closely associated with N-cadherin and gap junctions. Methods and results We studied intercalated discs of HL-1 cardiomyocytes by immunostaining of desmoglein-2 and N-cadherin. Cohesion was measured using a liberase-based dissociation-assay and comp...
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#1Milos KubanekH-Index: 9
#1Miloš KubánekH-Index: 2
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Background: The pleomorphic clinical presentation makes the diagnosis of desminopathy difficult. We aimed to describe the prevalence, phenotypic expression, and mitochondrial function of individuals with putative disease-causing desmin (DES) variants identified in patients with an unexplained etiology of cardiomyopathy. Methods: A total of 327 Czech patients underwent whole exome sequencing and detailed phenotyping in probands harboring DES variants. Results: Rare, conserved, and possibly pathog...
Source
#1Andreas Brodehl (RUB: Ruhr University Bochum)H-Index: 9
Last. Anna Gärtner (RUB: Ruhr University Bochum)H-Index: 1
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Abstract Aims We aimed to unravel the genetic, molecular and cellular pathomechanisms of DSC2 truncation variants leading to arrhythmogenic cardiomyopathy (ACM). Methods and results We report a homozygous 4-bp DSC2 deletion variant c.1913_1916delAGAA, p.Q638LfsX647hom causing a frameshift carried by an ACM patient. Whole exome sequencing and comparative genomic hybridization analysis support a loss of heterozygosity in a large segment of chromosome 18 indicating segmental interstitial uniparenta...
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#1Andreas BrodehlH-Index: 9
#2Pour Hakimi SaH-Index: 1
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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...
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In the last few decades, many pathogenic or likely pathogenic genetic mutations in over hundred different genes have been described for non-ischemic, genetic cardiomyopathies. However, the functional knowledge about most of these mutations is still limited because the generation of adequate animal models is time-consuming and challenging. Therefore, human induced pluripotent stem cells (iPSCs) carrying specific cardiomyopathy-associated mutations are a promising alternative. Since the original d...
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