Genetic and ultrastructural studies in dilated cardiomyopathy patients: a large deletion in the lamin A/C gene is associated with cardiomyocyte nuclear envelope disruption

Autosomal recessive mandibuloacral dysplasia [mandibuloacral dysplasia type A (MADA); Online Mendelian Inheritance in Man (OMIM) no. 248370 ] is caused by a mutation in LMNA encoding lamin A/C. Here we show that this mutation causes accumulation of the lamin A precursor protein, a marked alteration of the nuclear architecture and, hence, chromatin disorganization. Heterochromatin domains are altered or completely lost in MADA nuclei, consistent with the finding that heterochromatin-associated protein HP1β and histone H3 methylated at lysine 9 and their nuclear envelope partner protein lamin B receptor (LBR) are delocalized and solubilized. Both accumulation of lamin A precursor and chromatin defects become more severe in older patients. These results strongly suggest that altered chromatin remodeling is a key event in the cascade of epigenetic events causing MADA and could be related to the premature-aging phenotype.

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New mutation in lamin A/C gene associated with severe dilated cardiomyopathy

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(02)80574-5 ◽

2002 ◽

Vol 39 ◽

pp. 131

Author(s):

Manual Hermida ◽

Lorenzo Monserrat ◽

Sandra Barral ◽

Rafael Laredo ◽

Beatriz Bouzas ◽

...

Keyword(s):

Dilated Cardiomyopathy ◽

Lamin A ◽

New Mutation

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Electrophysiological and Histopathological Characteristics of Progressive Atrioventricular Block Accompanied by Familial Dilated Cardiomyopathy Caused by a Novel Mutation of Lamin A/C Gene

Journal of Cardiovascular Electrophysiology ◽

10.1046/j.1540-8167.2004.40096.x ◽

2005 ◽

Vol 16 (2) ◽

pp. 137-145 ◽

Cited By ~ 42

Author(s):

JUN OTOMO ◽

SHIGEO KURE ◽

TOMOKO SHIBA ◽

AKIHIKO KARIBE ◽

TSUYOSHI SHINOZAKI ◽

...

Keyword(s):

Dilated Cardiomyopathy ◽

Atrioventricular Block ◽

Novel Mutation ◽

Lamin A ◽

Familial Dilated Cardiomyopathy

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Abstract MP175: Disruption of the Genome Architecture at the PRRX1 Locus is Associated With the Pathogenesis of LMNA -related Dilated Cardiomyopathy

Circulation Research ◽

10.1161/res.127.suppl_1.mp175 ◽

2020 ◽

Vol 127 (Suppl_1) ◽

Author(s):

Yuan Zhang ◽

Mohamed Ameen ◽

Isaac Perea Gil ◽

Jennifer Arthur ◽

Alexandra A Gavidia ◽

...

Keyword(s):

Dilated Cardiomyopathy ◽

Single Cell ◽

Genome Organization ◽

Molecular Mechanisms ◽

Critical Role ◽

Lamin A ◽

Candidate Locus ◽

Gene Encoding ◽

Gene Dysregulation

Background: LMNA , a gene encoding A-type lamin proteins (abbreviated as lamin A), is one of the most frequently mutated genes in dilated cardiomyopathy (DCM). The molecular mechanisms underlying cardiomyocyte dysfunction in LMNA -related DCM remain elusive, translating to the lack of disease-specific therapies. Lamin A has been shown to play a critical role in genome organization via interactions with the chromatin at specific regions called lamina-associated domains (LADs). However, little is known about whether DCM-causing LMNA mutations rearrange the genome conformation and chromosome accessibility. The overarching goal of this study is to define the role of genome organization in LMNA -related DCM. Methods: LMNA -related DCM was modeled in vitro using cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs) from DCM patients carrying a frameshift mutation in the LMNA gene (c. 348_349insG; p. K117fs) and isogenic controls. We combined genome-wide single cell functional genomic and epigenomic mapping analyses to define the gene regulation and cis-regulatory interactions in isogenic iPSC-CMs. Results: Single-cell RNA-seq revealed global gene dysregulation in LMNA mutant compared to isogenic control iPSC-CMs. The homeodomain transcription factor PRRX1 was significantly upregulated in mutant cells. We showed that LAD integrity is disrupted at the PRRX1 locus in mutant iPSC-CMs. In agreement, DNA fluorescence in situ hybridization (FISH) revealed that the PRRX1 locus loses peripheral association and relocates towards the transcriptionally active nuclear interior in mutant iPSC-CMs. Correspondingly, single-cell assay for transposase accessible chromatin (ATAC)-seq showed increased chromatin co-accessibility at the PRRX1 locus, providing a plausible explanation for ectopic activation of PRRX1 in LMNA mutant iPSC-CMs. Conclusion: Our data suggest that LMNA haploinsufficiency disrupts the structure of LADs, leading to ectopic promoter interactions and altered gene expression in LMNA -related DCM iPSC-CMs. We identified PRRX1 as a promising candidate locus linking changes in LAD organization with gene dysregulation in LMNA -related DCM.

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Molecular signatures of Emery–Dreifuss muscular dystrophy

Biochemical Society Transactions ◽

10.1042/bst0361354 ◽

2008 ◽

Vol 36 (6) ◽

pp. 1354-1358 ◽

Cited By ~ 19

Author(s):

Matthew A. Wheeler ◽

Juliet A. Ellis

Keyword(s):

Muscular Dystrophy ◽

Dilated Cardiomyopathy ◽

Molecular Mechanisms ◽

Autosomal Dominant ◽

Signalling Pathways ◽

Lamin A ◽

Degenerative Diseases ◽

Hypertrophic Growth ◽

Genes Encoding

Mutations in genes encoding the nuclear envelope proteins emerin and lamin A/C lead to a range of tissue-specific degenerative diseases. These include dilated cardiomyopathy, limb-girdle muscular dystrophy and X-linked and autosomal dominant EDMD (Emery–Dreifuss muscular dystrophy). The molecular mechanisms underlying these disorders are poorly understood; however, recent work using animal models has identified a number of signalling pathways that are altered in response to the deletion of either emerin or lamin A/C or expression of Lmna mutants found in patients with laminopathies. A distinguishing feature of patients with EDMD is the association of a dilated cardiomyopathy with conduction defects. In the present article, we describe several of the pathways altered in response to an EDMD phenotype, which are known to be key mediators of hypertrophic growth, and focus on a possible role of an emerin–β-catenin interaction in the pathogenesis of this disease.

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A Rapid Progressive Course of Patients with Lamin A/C Mutation Dilated Cardiomyopathy

Journal of Cardiac Failure ◽

10.1016/j.cardfail.2016.07.425 ◽

2016 ◽

Vol 22 (9) ◽

pp. S233

Author(s):

Yuki Sugiura ◽

Takahiro Okumura ◽

Tohru Kondo ◽

Akinori Sawamura ◽

Ryota Morimoto ◽

...

Keyword(s):

Dilated Cardiomyopathy ◽

Lamin A ◽

Progressive Course

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Physiological and pathological roles of LRRK2 in the nuclear envelope integrity

Human Molecular Genetics ◽

10.1093/hmg/ddz245 ◽

2019 ◽

Vol 28 (23) ◽

pp. 3982-3996 ◽

Cited By ~ 3

Author(s):

Vered Shani ◽

Hazem Safory ◽

Raymonde Szargel ◽

Ninghan Wang ◽

Tsipora Cohen ◽

...

Keyword(s):

Nuclear Envelope ◽

Cortical Neurons ◽

Nuclear Lamina ◽

Lamin A ◽

Loss Of Function ◽

Function Mechanism ◽

Disease Mutations ◽

Lrrk2 G2019s ◽

Sporadic Parkinson’S Disease ◽

Seven In Absentia

Abstract Mutations in LRRK2 cause autosomal dominant and sporadic Parkinson’s disease, but the mechanisms involved in LRRK2 toxicity in PD are yet to be fully understood. We found that LRRK2 translocates to the nucleus by binding to seven in absentia homolog (SIAH-1), and in the nucleus it directly interacts with lamin A/C, independent of its kinase activity. LRRK2 knockdown caused nuclear lamina abnormalities and nuclear disruption. LRRK2 disease mutations mostly abolish the interaction with lamin A/C and, similar to LRRK2 knockdown, cause disorganization of lamin A/C and leakage of nuclear proteins. Dopaminergic neurons of LRRK2 G2019S transgenic and LRRK2 −/− mice display decreased circularity of the nuclear lamina and leakage of the nuclear protein 53BP1 to the cytosol. Dopaminergic nigral and cortical neurons of both LRRK2 G2019S and idiopathic PD patients exhibit abnormalities of the nuclear lamina. Our data indicate that LRRK2 plays an essential role in maintaining nuclear envelope integrity. Disruption of this function by disease mutations suggests a novel phosphorylation-independent loss-of-function mechanism that may synergize with other neurotoxic effects caused by LRRK2 mutations.

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