Lamin A/C mutations with lipodystrophy, cardiac abnormalities, and muscular dystrophy

Kooi, Anneke J. van der; Bonne, Gisèle; Eymard, B.; Duboc, Denis; Talim, Beril; Valk, Marc van der; Reiss, Paul D.; Richard, Pascale; Demay, Laurence; Merlini, Luciano; Schwartz, Ketty; Busch, H. F. M.; Visser, Marjolein

doi:10.1212/wnl.59.4.620

Cited by 127 publications

(79 citation statements)

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“…Premature death occurred by 2-3 weeks of age. However, in this study, age matched heterozygous mice were indistinguishable from wild-type mice [24]. Only 1 study reported Lmna +/-mice with 50% of normal cardiac lamin A/C levels and displaying cardiac abnormalities [25].…”

Section: Introductioncontrasting

confidence: 57%

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Lamin A/C mutations in dilated cardiomyopathy

et al. 2014

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Section: Introductioncontrasting

confidence: 57%

“…A Lmna null mouse based on genetrap technology has been developed [24]. The mouse is characterized by postnatal maturation defects of cardiac, muscle, and adipose tissues.…”

Section: Introductionmentioning

confidence: 99%

Lamin A/C mutations in dilated cardiomyopathy

et al. 2014

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“…Other LMNA mutations cause syndromes with overlapping phenotypes, such as the syndrome lipodystrophy, insulin-resistant diabetes, disseminated leukomelanodermic papules, liver steatosis, and cardiomyopathy (MIM 608056) 20 and an overlap syndrome characterized by lipodystrophy, muscular dystrophy, and cardiac conduction anomalies. 21,22 However, again, there is no clear association between atherosclerosis and these particular laminopathies.…”

Section: Atherosclerosis In Laminopathies With a Lipodystrophy Componentmentioning

confidence: 99%

Laminopathies and Atherosclerosis

Alshali

Hegele

2004

ATVB

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Abstract-Laminopathies are genetic diseases that encompass a wide spectrum of phenotypes with diverse tissue pathologies and result mainly from mutations in the LMNA gene encoding nuclear lamin A/C. Some laminopathies affect the cardiovascular system, and a few (namely, Dunnigan-type familial partial lipodystrophy [FPLD2] and HutchinsonGilford progeria syndrome [HGPS]) feature atherosclerosis as a key component. The premature atherosclerosis of FPLD2 is probably related to characteristic proatherogenic metabolic disturbances such as dyslipidemia, hyperinsulinemia, hypertension, and diabetes. In contrast, the premature atherosclerosis of HGPS occurs with less exposure to metabolic proatherogenic traits and probably reflects the generalized process of accelerated aging in HGPS. Although some common polymorphisms of LMNA have been associated with traits related to atherosclerosis, the monogenic diseases Key Words: nuclear envelope Ⅲ insulin resistance Ⅲ aging Ⅲ vascular disease Ⅲ progeria T he nuclear lamina is a 20-nm filamentous meshwork that underlies the inner nuclear membrane and plays a central role in defining interphase nuclear architecture, DNA replication, and chromatin organization. 1 Nuclear lamins are type V intermediate filaments that are the major components of the nuclear lamina.

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“…For example, the permanent loss of lamin proteins causes muscular dystrophy and cardiomyopathy, and overaccumulation of lamin mutants at the nuclear membrane causes the rapid aging disorder Hutchinson-Gilford progeria syndrome (HGPS). [9][10][11] What is remarkable is that all the various types of nuclear lamina naturally feature structural imperfections, defects, and heterogeneities including those induced by nuclear pores. 1,[12][13][14] Defects in the lamina can also be caused by localized forces from cytoskeletal structures or by atomic-scale defects due to the imperfect assembly of the meshwork, leading to void formation in the meshwork.…”

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confidence: 99%

Flaw Tolerance of Nuclear Intermediate Filament Lamina under Extreme Mechanical Deformation

Qin

Buehler²

2011

ACS Nano

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The nuclear lamina, composed of intermediate filaments, is a structural protein meshwork at the nuclear membrane that protects genetic material and regulates gene expression.Here we uncover the physical basis of the material design of nuclear lamina that enables it to withstand extreme mechanical deformation of >100% strain despite the presence of structural defects. Through a simple in silico model we demonstrate that this is due to nanoscale mechanisms including protein unfolding, alpha-to-beta transition, and sliding, resulting in a characteristic nonlinear force-extension curve. At the larger microscale this leads to an extreme delocalization of mechanical energy dissipation, preventing catastrophic crack propagation. Yet, when catastrophic failure occurs under extreme loading, individual protein filaments are sacrificed rather than the entire meshwork. This mechanism is theoretically explained by a characteristic change of the tangent stress-strain hardening exponent under increasing strain. Our results elucidate the large extensibility of the nuclear lamina within muscle or skin tissue and potentially many other protein materials that are exposed to extreme mechanical conditions, and provide a new paradigm toward the de novo design of protein materials by engineering the nonlinear stress-strain response to facilitate flaw-tolerant behavior.

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Lamin A/C mutations with lipodystrophy, cardiac abnormalities, and muscular dystrophy

Cited by 127 publications

References 10 publications

Lamin A/C mutations in dilated cardiomyopathy

Lamin A/C mutations in dilated cardiomyopathy

Laminopathies and Atherosclerosis

Flaw Tolerance of Nuclear Intermediate Filament Lamina under Extreme Mechanical Deformation

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