Nuclear envelope defects associated with<i>LMNA</i>mutations cause dilated cardiomyopathy and Emery-Dreifuss muscular dystrophy

Raharjo, Wahyu Hendrati; Enarson, Paul; Sullivan, Teresa; Stewart, Colin L.; Burke, Brian

doi:10.1242/jcs.114.24.4447

Cited by 206 publications

(20 citation statements)

References 48 publications

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“…30 Formation of intranuclear foci had been reported in HeLa cells transfected with the DCM mutant of lamin A N195K. 34 Figure 2 represents a comparison between the wild type lamin A and representative mutanttransfected cells. The transfection efficiency was between 50 and 60% for the wild type construct and between 20 and 25% consistently in the case of the mutants.…”

Section: ■ Resultsmentioning

confidence: 94%

“…The rationale behind our study is understanding how the mutations in the rod domain of the protein influence the overall structure and hence its self-association behavior at the molecular level. Various studies of samples from laminopathy-afflicted patients as well as with ectopic expression of mutant proteins in cultured cell lines ,, have shown the formation of misshapen nuclei with herniations, blebs, intranuclear foci, and aggregates with various sizes and distribution patterns. This can be attributed to the fact that mutations in lamin A could perturb self-association or homotypic interaction, heterotypic interactions with lamin B1 and B2, interactions with NE-associated and nucleoplasmic proteins, and interactions with chromatin in all possible manners.…”

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confidence: 99%

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Structural Alterations of Lamin A Protein in Dilated Cardiomyopathy

Bhattacharjee

Banerjee

et al. 2013

Biochemistry

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Lamin A protein, encoded by the LMNA gene, belongs to the type V intermediate filament protein family and is a major nuclear protein component of higher metazoan organisms, including humans. Lamin A along with B-type lamins impart structural rigidity to the nucleus by forming a lamina that is closely apposed to the inner nuclear membrane and is also present as a filamentous network in the interior of the nucleus. A vast number of mutations that lead to a diverse array of at least 11 diseases in humans, collectively termed laminopathies, are being gradually uncovered in the LMNA gene. Dilated cardiomyopathy (DCM) is one such laminopathy in which ventricular dilation leads to an increase in systolic and diastolic volumes, resulting in cardiac arrhythmia and ultimately myocardial infarction. The point mutations in lamin A protein span the entire length of the protein, with a slight preponderance in the central α-helical coiled-coil forming domain. In this work, we have focused on three such important mutations that had been previously observed in DCM-afflicted patients producing severe symptoms. This is the first report to show that these mutations entail significant alterations in the secondary and tertiary structure of the protein, hence perturbing the intrinsic self-association behavior of lamin A protein. Comparison of the enthalpy changes accompanying the deoligomerization process for the wild type and the mutants suggests a difference in the energetics of their self-association. This is further corroborated by the formation of the aggregates of different size and distribution formed inside the nuclei of transfected cells.

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Section: ■ Resultsmentioning

confidence: 94%

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confidence: 99%

Structural Alterations of Lamin A Protein in Dilated Cardiomyopathy

Bhattacharjee

Banerjee

et al. 2013

Biochemistry

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“…It is also noteworthy that the autosomal dominant LMNA EDMD mutation L530P similarly impacts both LMNA protein isoforms and fails to localize to the nuclear ruptures despite being more mobile than WT [ 77 ], but in contrast with K542N does not lead to progeria. It can be assumed that the complete loss of the Ig-like fold structure and all of its associated interactions, including the LINC complex proteins Sun1/2 [ 95 ] and emerin [ 96 ], caused by the L530P mutation would constitute a loss of function, albeit only impacting one allele, whereas the K542N mutation may only impact interaction with BAF or at least a subset of interactions of the Ig-like fold. It is also possible that the mechanisms that underlie the progeria-associated deficiency in recruitment of A-type lamins to nuclear ruptures is indicative of defects in the BAF-dependent process of nuclear envelope reformation following mitosis which could underlie disease phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of A-Type Lamin Targeting to Nuclear Ruptures Are Disrupted in LMNA- and BANF1-Associated Progerias

Sears

Roux

2022

Cells

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Mutations in the genes LMNA and BANF1 can lead to accelerated aging syndromes called progeria. The protein products of these genes, A-type lamins and BAF, respectively, are nuclear envelope (NE) proteins that interact and participate in various cellular processes, including nuclear envelope rupture and repair. BAF localizes to sites of nuclear rupture and recruits NE-repair machinery, including the LEM-domain proteins, ESCRT-III complex, A-type lamins, and membranes. Here, we show that it is a mobile, nucleoplasmic population of A-type lamins that is rapidly recruited to ruptures in a BAF-dependent manner via BAF’s association with the Ig-like β fold domain of A-type lamins. These initially mobile lamins become progressively stabilized at the site of rupture. Farnesylated prelamin A and lamin B1 fail to localize to nuclear ruptures, unless that farnesylation is inhibited. Progeria-associated LMNA mutations inhibit the recruitment affected A-type lamin to nuclear ruptures, due to either permanent farnesylation or inhibition of BAF binding. A progeria-associated BAF mutant targets to nuclear ruptures but is unable to recruit A-type lamins. Together, these data reveal the mechanisms that determine how lamins respond to nuclear ruptures and how progeric mutations of LMNA and BANF1 impair recruitment of A-type lamins to nuclear ruptures.

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“…FRAP studies on transfected cells have shown that some lamin A mutants that cause disease are more mobile in the nuclear envelope than wild-type lamin A ( , ). Emerin is also partly mislocalized to the ER in some cells transfected with plasmids encoding certain lamin A and C mutants ( − ). However, emerin appears to be exclusively localized to the nuclear envelope in cells from human subjects heterozygous for dominant A-type lamin mutations examined by immunofluorescence microscopy ( − ).…”

Section: Discussionmentioning

confidence: 99%

Dependence of Diffusional Mobility of Integral Inner Nuclear Membrane Proteins on A-Type Lamins

et al. 2006

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Integral proteins of the nuclear envelope inner membrane have been proposed to reach their sites by diffusion after their co-translational insertion in the rough endoplasmic reticulum. They are then retained in the inner nuclear membrane by binding to nuclear structures. One such structure is the nuclear lamina, an intermediate filament meshwork composed of A-type and B-type lamin proteins. Emerin, MAN1, and LBR are three integral inner nuclear membrane proteins. We expressed these proteins fused to green fluorescent protein in embryonic fibroblasts from wild-type mice and Lmna -/- mice, which lack A-type lamins. We then studied the diffusional mobilities of emerin, MAN1, and LBR using fluorescence recovery after photobleaching. We show that emerin and MAN1, but not LBR, are more mobile in the inner nuclear membrane of cells from Lmna -/- mice than in cells from wild-type mice. In cells from Lmna -/- mice expressing exogenous lamin A, the protein mobilities were similar to those in cells from wild-type mice. This supports a model where emerin and MAN1 are at least partly retained in the inner nuclear membrane by binding to A-type lamins, while LBR depends on other binding partners for its retention.

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Nuclear envelope defects associated withLMNAmutations cause dilated cardiomyopathy and Emery-Dreifuss muscular dystrophy

Cited by 206 publications

References 48 publications

Structural Alterations of Lamin A Protein in Dilated Cardiomyopathy

Structural Alterations of Lamin A Protein in Dilated Cardiomyopathy

Mechanisms of A-Type Lamin Targeting to Nuclear Ruptures Are Disrupted in LMNA- and BANF1-Associated Progerias

Dependence of Diffusional Mobility of Integral Inner Nuclear Membrane Proteins on A-Type Lamins

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