Lethal neonatal Hutchinson-Gilford progeria syndrome

Rodrı́guez, José Ignacio; Pérez‐Alonso, Pablo; Funes, Rosa; Pérez‐Rodríguez, Jesús

doi:10.1002/(sici)1096-8628(19990129)82:3<242::aid-ajmg9>3.0.co;2-e

Cited by 41 publications

(21 citation statements)

References 17 publications

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“…This would be consistent with the recent observation that exclusive expression of farnesylatable progerin elicited a relatively more severe progeroid phenotypes than those of its non-farnesylated form in knock-in mice [37]. On the other hand, exclusively expressed non-farnesylated prelamin A still induced prominent cardiomyopathy but not progeria in knock-in mice, whereas the survival of such mice which exclusively produce farnesylatable prelamin A was very similar to that of wild-type mice [38], which is quite possibly due to the lower amount of farnesylated prelamin A. Embryonic senescence and further unforeseen developmental abnormalities may also be occurring in human (or mice) progeria given that severe neonatal lethality has been reported [15] [77] [78].…”

Section: Discussionmentioning

confidence: 98%

Embryonic Senescence and Laminopathies in a Progeroid Zebrafish Model

Koshimizu

Imamura

et al. 2011

PLoS ONE

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BackgroundMutations that disrupt the conversion of prelamin A to mature lamin A cause the rare genetic disorder Hutchinson-Gilford progeria syndrome and a group of laminopathies. Our understanding of how A-type lamins function in vivo during early vertebrate development through aging remains limited, and would benefit from a suitable experimental model. The zebrafish has proven to be a tractable model organism for studying both development and aging at the molecular genetic level. Zebrafish show an array of senescence symptoms resembling those in humans, which can be targeted to specific aging pathways conserved in vertebrates. However, no zebrafish models bearing human premature senescence currently exist.Principal FindingsWe describe the induction of embryonic senescence and laminopathies in zebrafish harboring disturbed expressions of the lamin A gene (LMNA). Impairments in these fish arise in the skin, muscle and adipose tissue, and sometimes in the cartilage. Reduced function of lamin A/C by translational blocking of the LMNA gene induced apoptosis, cell-cycle arrest, and craniofacial abnormalities/cartilage defects. By contrast, induced cryptic splicing of LMNA, which generates the deletion of 8 amino acid residues lamin A (zlamin A-Δ8), showed embryonic senescence and S-phase accumulation/arrest. Interestingly, the abnormal muscle and lipodystrophic phenotypes were common in both cases. Hence, both decrease-of-function of lamin A/C and gain-of-function of aberrant lamin A protein induced laminopathies that are associated with mesenchymal cell lineages during zebrafish early development. Visualization of individual cells expressing zebrafish progerin (zProgerin/zlamin A-Δ37) fused to green fluorescent protein further revealed misshapen nuclear membrane. A farnesyltransferase inhibitor reduced these nuclear abnormalities and significantly prevented embryonic senescence and muscle fiber damage induced by zProgerin. Importantly, the adult Progerin fish survived and remained fertile with relatively mild phenotypes only, but had shortened lifespan with obvious distortion of body shape.ConclusionWe generated new zebrafish models for a human premature aging disorder, and further demonstrated the utility for studying laminopathies. Premature aging could also be modeled in zebrafish embryos. This genetic model may thus provide a new platform for future drug screening as well as genetic analyses aimed at identifying modifier genes that influence not only progeria and laminopathies but also other age-associated human diseases common in vertebrates.

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Section: Discussionmentioning

confidence: 98%

Embryonic Senescence and Laminopathies in a Progeroid Zebrafish Model

Koshimizu

Imamura

et al. 2011

PLoS ONE

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“…Affected children appear normal at birth but then manifest a number of disease phenotypes, including failure-to-thrive, dental abnormalities, micrognathia, stiff joints, alopecia, sclerodermatous skin, loss of subcutaneous fat, osteoporosis, and osteolytic lesions in bones (3, 31, 36, 37, 40, 57, 82). Death generally occurs by the teenage years, generally from occlusions of the coronary or cerebral arteries.…”

Section: Lmna Mutations and Human Diseasementioning

confidence: 99%

The Posttranslational Processing of Prelamin A and Disease

Davies

Fong

Yang

et al. 2009

Annu. Rev. Genom. Hum. Genet.

128

115

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Human geneticists have shown that some progeroid syndromes are caused by mutations that interfere with the conversion of farnesyl-prelamin A to mature lamin A. For example, Hutchinson-Gilford progeria syndrome is caused by LMNA mutations that lead to the accumulation of a farnesylated version of prelamin A. In this review, we discuss the posttranslational modifications of prelamin A and their relevance to the pathogenesis and treatment of progeroid syndromes.

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“…Lamin A has also recently emerged as a key player vulnerable to epigenetic changes that contribute to aging [69-72]. Embryonic senescence and further unforeseen developmental abnormalities may also be occurring in human (or mice) progeria in either de novo genetic and/or epigenetic manners, given that severe neonatal lethality has been reported [73-75]. Thus, aging research should therefore extend to the study of early developmental process at least within the context of reproduction and regeneration.…”

Section: Evolutionary Developmental Origins Of Aging and Diseasementioning

confidence: 99%

Using zebrafish models to explore genetic and epigenetic impacts on evolutionary developmental origins of aging

Kishi

2014

Translational Research

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Can we reset, reprogram, rejuvenate or reverse the organismal aging process? Certain genetic manipulations could at least reset and reprogram epigenetic dynamics beyond phenotypic plasticity and elasticity in cells, which can be further manipulated into organisms. However, in a whole complex aging organism, how can we rejuvenate intrinsic resources and infrastructures in an intact/noninvasive manner? The incidence of diseases increases exponentially with age, accompanied by progressive deteriorations of physiological functions in organisms. Aging-associated diseases are sporadic but essentially inevitable complications arising from senescence. Senescence is often considered the antithesis of early development, but yet there may be factors and mechanisms in common between these two phenomena to rejuvenate over the dynamic process of aging. The association between early development and late-onset disease with advancing age is thought to come from a consequence of developmental plasticity, the phenomenon by which one genotype can give rise to a range of physiologically and/or morphologically adaptive states based on diverse epigenotypes, in response to intrinsic or extrinsic environmental cues and genetic perturbations. We hypothesized that the future aging process can be predictive based on adaptivity during the early developmental period. Modulating the thresholds and windows of plasticity and its robustness by molecular genetic and chemical epigenetic approaches, we have successfully conducted experiments to isolate zebrafish mutants expressing apparently altered senescence phenotypes during their embryonic and/or larval stages (“embryonic/larval senescence”). Subsequently, at least some of these mutant animals were found to show shortened lifespan, while some others would be expected to live longer in adulthoods. We anticipate that previously uncharacterized developmental genes may mediate the aging process and play a pivotal role in senescence. On the other hand, unexpected senescence-related genes might also be involved in the early developmental process and its regulation. The ease of manipulation using the zebrafish system allows us to conduct an exhaustive exploration of novel genes/genotypes and epigenotype that can be linked to the senescence phenotype, and thereby facilitates searching for the evolutionary and developmental origins of aging in vertebrates.

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Lethal neonatal Hutchinson-Gilford progeria syndrome

Cited by 41 publications

References 17 publications

Embryonic Senescence and Laminopathies in a Progeroid Zebrafish Model

Embryonic Senescence and Laminopathies in a Progeroid Zebrafish Model

The Posttranslational Processing of Prelamin A and Disease

Using zebrafish models to explore genetic and epigenetic impacts on evolutionary developmental origins of aging

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