HGPS and related premature aging disorders: From genomic identification to the first therapeutic approaches

Pereira, Sandrine; Bourgeois, P.; Navarro, Claire; Esteves-Vieira, Vera; Cau, Pierre; Sandre-Giovannoli, Annachiara De; Lévy, Nicolas

doi:10.1016/j.mad.2008.04.003

Cited by 70 publications

(58 citation statements)

References 141 publications

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“…During the past 25 years, more than 400 mutations within the LMNA gene have been identified that cause at least 12 distinct diseases, collectively termed laminopathies (Worman, 2012). Laminopathies include muscular dystrophies, as well as the premature aging disease Hutchison Gilford progeria syndrome (Bertrand et al, 2011;Pereira et al, 2008;Worman, 2012). Currently, the lack of tools for altering the binding and biochemical properties of lamins, and consequently the lamina, present a limiting step in deciphering the precise functional and structural aspects of these important cellular elements.…”

Section: Discussionmentioning

confidence: 99%

Altering lamina assembly identifies lamina-dependent and -independent functions for A-type lamins

Zwerger

Roschitzki-Voser

Zbinden

et al. 2015

Journal of Cell Science

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Lamins are intermediate filament proteins that form a fibrous meshwork, called the nuclear lamina, between the inner nuclear membrane and peripheral heterochromatin of metazoan cells. The assembly and incorporation of lamin A/C into the lamina, as well as their various functions, are still not well understood. Here, we employed designed ankyrin repeat proteins (DARPins) as new experimental tools for lamin research. We screened for DARPins that specifically bound to lamin A/C, and interfered with lamin assembly in vitro and with incorporation of lamin A/C into the native lamina in living cells. The selected DARPins inhibited lamin assembly and delocalized A-type lamins to the nucleoplasm without modifying lamin expression levels or the amino acid sequence. Using these lamin binders, we demonstrate the importance of proper integration of lamin A/C into the lamina for nuclear mechanical properties and nuclear envelope integrity. Finally, our study provides evidence for cell-type-specific differences in lamin functions.

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Section: Discussionmentioning

confidence: 99%

Altering lamina assembly identifies lamina-dependent and -independent functions for A-type lamins

Zwerger

Roschitzki-Voser

Zbinden

et al. 2015

Journal of Cell Science

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“…42,43 However, the safety of long-term administration in such patients remains unknown. FTIs, alone or combined with a statin and aminobisphosphonate, have been shown to cause donut-shaped nuclei attributable to a centrosome separation defect in mitotic to wild type A-type lamins.…”

Section: -21mentioning

confidence: 99%

Blocking farnesylation of the prelamin A variant in Hutchinson-Gilford progeria syndrome alters the distribution of A-type lamins

Wang

Östlund

Choi

et al. 2012

Nucleus

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“…The vast majority of progeroid syndromes are a consequence of inefficient DNA repair mechanisms or defective nuclear envelope assembly, which ultimately lead to DNA damage accumulation and chromosome instability (3). Thus, mutations in the gene encoding lamin A (an essential component of the nuclear envelope) or in Zmpste24 (encoding a metalloproteinase involved in the maturation of lamin A) are responsible for several devastating human progeroid syndromes, including Hutchinson-Gilford progeria, atypical Werner syndrome, restrictive dermopathy, and mandibuloacral dysplasia (3)(4)(5)(6)(7). The elucidation of the molecular mechanisms underlying these diseases has been facilitated by the generation and analysis of Lmna-and Zmpste24-deficient mice, which exhibit profound nuclear architecture abnormalities and multiple histopathological defects that phenocopy human progeroid syndromes (8)(9)(10)(11)(12).…”

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confidence: 99%

Insulin-like growth factor 1 treatment extends longevity in a mouse model of human premature aging by restoring somatotroph axis function

Mariño¹,

Ugalde²,

Fernández³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

126

138

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Zmpste24 (also called FACE-1) is a metalloproteinase involved in the maturation of lamin A, an essential component of the nuclear envelope. Zmpste24-deficient mice exhibit multiple defects that phenocopy human accelerated aging processes such as HutchinsonGilford progeria syndrome. In this work, we report that progeroid Zmpste24 -/− mice present profound transcriptional alterations in genes that regulate the somatotroph axis, together with extremely high circulating levels of growth hormone (GH) and a drastic reduction in plasma insulin-like growth factor 1 (IGF-1). We also show that recombinant IGF-1 treatment restores the proper balance between IGF-1 and GH in Zmpste24 -/− mice, delays the onset of many progeroid features, and significantly extends the lifespan of these progeroid animals. Our findings highlight the importance of IGF/GH balance in longevity and may be of therapeutic interest for devastating human progeroid syndromes associated with nuclear envelope abnormalities.

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HGPS and related premature aging disorders: From genomic identification to the first therapeutic approaches

Cited by 70 publications

References 141 publications

Altering lamina assembly identifies lamina-dependent and -independent functions for A-type lamins

Altering lamina assembly identifies lamina-dependent and -independent functions for A-type lamins

Blocking farnesylation of the prelamin A variant in Hutchinson-Gilford progeria syndrome alters the distribution of A-type lamins

Insulin-like growth factor 1 treatment extends longevity in a mouse model of human premature aging by restoring somatotroph axis function

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