Familial dilated cardiomyopathy and isolated left ventricular noncompaction associated with lamin A/C gene mutations

Hermida-Prieto, Manuel; Monserrat, Lorenzo; Castro‐Beiras, Alfonso; Laredo, Rafael; Soler, Rafaela; Peteiro, Jesús; Rodrı́guez, Esther; Bouzas, Beatriz; Álvarez, Nemesio; Muñiz, Javier; Crespo-Leiro, María G.

doi:10.1016/j.amjcard.2004.03.029

Cited by 172 publications

(93 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These amino acid substitutions are analogous to human Lamin A/C R190W and G449V, respectively. Mutations in LMNA that give rise to Lamin A/C R190W are associated with progressive cardiac defect (including conduction defects) and reduced cardiac performance (Arbustini et al., 2002; Heller et al., 2017; Hermida‐Prieto et al., 2004). Mutations in LMNA that give rise to Lamin A/C G449V cause congenital muscular dystrophy, which is characterized by skeletal muscle defects in childhood and age‐dependent dilated cardiomyopathy (Dialynas et al., 2015).…”

Section: Resultsmentioning

confidence: 99%

Increasing autophagy and blocking Nrf2 suppress laminopathy‐induced age‐dependent cardiac dysfunction and shortened lifespan

et al. 2018

View full text Add to dashboard Cite

SummaryMutations in the human LMNA gene cause a collection of diseases known as laminopathies. These include myocardial diseases that exhibit age‐dependent penetrance of dysrhythmias and heart failure. The LMNA gene encodes A‐type lamins, intermediate filaments that support nuclear structure and organize the genome. Mechanisms by which mutant lamins cause age‐dependent heart defects are not well understood. To address this issue, we modeled human disease‐causing mutations in the Drosophila melanogaster Lamin C gene and expressed mutant Lamin C exclusively in the heart. This resulted in progressive cardiac dysfunction, loss of adipose tissue homeostasis, and a shortened adult lifespan. Within cardiac cells, mutant Lamin C aggregated in the cytoplasm, the CncC(Nrf2)/Keap1 redox sensing pathway was activated, mitochondria exhibited abnormal morphology, and the autophagy cargo receptor Ref2(P)/p62 was upregulated. Genetic analyses demonstrated that simultaneous over‐expression of the autophagy kinase Atg1 gene and an RNAi against CncC eliminated the cytoplasmic protein aggregates, restored cardiac function, and lengthened lifespan. These data suggest that simultaneously increasing rates of autophagy and blocking the Nrf2/Keap1 pathway are a potential therapeutic strategy for cardiac laminopathies.

show abstract

Section: Resultsmentioning

confidence: 99%

Increasing autophagy and blocking Nrf2 suppress laminopathy‐induced age‐dependent cardiac dysfunction and shortened lifespan

et al. 2018

View full text Add to dashboard Cite

show abstract

“…There are other previous reports of LMNA amino-terminal head and a-helical rod domain mutations causing overlapping phenotype of partial lipodystrophy and cardiomyopathy or cardiac conduction defects (29,30). Also, at codon 349, another variant (p.R349L) was associated with a severe familial form of isolated dilated cardiomyopathy (31).…”

Section: Discussionmentioning

confidence: 99%

Phenotypic diversity in patients with lipodystrophy associated with LMNA mutations

Mory

Crispim

Freire

et al. 2012

European Journal of Endocrinology

View full text Add to dashboard Cite

Objective: Mutations in LMNA have been linked to diverse disorders called laminopathies, which display heterogeneous phenotypes and include diseases affecting muscles, axonal neurons, progeroid syndromes, and lipodystrophies. Among the lipodystrophies, LMNA mutations have been reported most frequently in patients with familial partial lipodystrophy (FPLD) of the Dunnigan variety; however, phenotypic heterogeneity in the pattern of body fat loss has been observed. In this study, we searched for LMNA mutations in patients with various forms of lipodystrophy. Design and methods: We studied 21 unrelated individuals with lipodystrophy. Subjects underwent a complete clinical evaluation and were classified as typical FPLD (nZ12), atypical partial lipodystrophy (nZ7), or generalized lipodystrophy (nZ2). Molecular analysis of LMNA gene, analysis of body fat by dual-energy X-ray absorptiometry, and biochemical measurements were performed.

show abstract

“…Twelve exon sequences of the LMNA gene were analyzed in proband, individual 201, of family A and a unique sequence variant which cause amino acid change at position 190 from Arg to Trp in exon 3 was identified (Figure 2). This mutation, Arg190Trp, was previously reported (Arbustini et al, 2002;Anan et al, 2002;Hermida-Prieto et al, 2004) and predicted to alter residues in the -helical rod domain of the peptide. Previously 10 missense mutations identified in the -helical rod domain of the LMNA were reported to be disease-causing mutations in Caucasians with FDC and DCM.…”

Section: Mutation Analysis Of a Candidate Genementioning

confidence: 99%

Lamin A/C mutations associated with familial and sporadic cases of dilated cardiomyopathy in Koreans

Song

Dubé²,

Lim³

et al. 2007

Exp Mol Med

View full text Add to dashboard Cite

Dilated cardiomyopathy (DCM) is characterized by cardiac dilation and systolic dysfunction. So far sixteen genes have been shown to cause autosomal dominant familial dilated cardiomyopathy (FDC). We identified a large Korean family from the Jeju island showing a clear Mendelian inheritance of FDC. A genomewide linkage scan at 9 cM marker density identified a peak multipoint LOD score of 2.82 at D1S195. Haplotyping of the region with 15 additional markers defined a candidate interval that included a known candidate gene encoding the lamin A/C (LMNA). Sequencing of the LMNA exons revealed one missense mutation at C568T (Arg190Trp) in the -helical rod domain of the LMNA gene cosegregating with FDC with conduction-system disease. The same mutation was found in patients of another Korean family with FDC without conduction-system disease. Upon screening 14 sporadic DCM cases, we found three LMNA mutations including a case having a previously described (Glu161Lys) mutation and two having novel mutations (Glu53Val and Glu186Lys). Our results suggest that variable genotypes of laminopathy are implicated in not only familial but also considerable proportion of sporadic DCM.

show abstract

Familial dilated cardiomyopathy and isolated left ventricular noncompaction associated with lamin A/C gene mutations

Cited by 172 publications

References 26 publications

Increasing autophagy and blocking Nrf2 suppress laminopathy‐induced age‐dependent cardiac dysfunction and shortened lifespan

Increasing autophagy and blocking Nrf2 suppress laminopathy‐induced age‐dependent cardiac dysfunction and shortened lifespan

Phenotypic diversity in patients with lipodystrophy associated with LMNA mutations

Lamin A/C mutations associated with familial and sporadic cases of dilated cardiomyopathy in Koreans

Contact Info

Product

Resources

About