Human laminopathies: nuclei gone genetically awry.
TL;DR: The study of LMNA, its products and the phenotypes that result from its mutation have provided important insights into subjects ranging from transcriptional regulation, the cell biology of the nuclear lamina and mechanisms of ageing.
Abstract: Few genes have generated as much recent interest as LMNA, LMNB1 and LMNB2, which encode the components of the nuclear lamina. Over 180 mutations in these genes are associated with at least 13 known diseases--the laminopathies. In particular, the study of LMNA, its products and the phenotypes that result from its mutation have provided important insights into subjects ranging from transcriptional regulation, the cell biology of the nuclear lamina and mechanisms of ageing. Recent studies have begun the difficult task of correlating the genotypes of laminopathies with their phenotypes, and potential therapeutic strategies using existing drugs, modified oligonucleotides and RNAi are showing real promise for the treatment of these diseases.
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TL;DR: It is demonstrated that mTORC1 regulates SREBP by controlling the nuclear entry of lipin 1, a phosphatidic acid phosphatase, which is a key component of the m TORC1-SREBP pathway.
999 citations
Cites background from "Human laminopathies: nuclei gone ge..."
..., 2002); (2) lamin A mutations in humans commonly result in a lipodystrophy, a condition characterized by abnormal adipose tissue that is also seen in adipocyte-specific SREBP-1-overexpressing mice (Capell and Collins, 2006; Shimomura et al., 1999)....
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TL;DR: This article considers the growing recognition of precision medicine by clinicians, patients, the pharmaceutical industry, and policymakers and summarizes how this rapidly accelerating field will leave a major imprint on the practice of medicine.
Abstract: This article considers the growing recognition of precision medicine by clinicians, patients, the pharmaceutical industry, and policymakers and summarizes how this rapidly accelerating field will leave a major imprint on the practice of medicine.
868 citations
TL;DR: The putative pathogenetic roles and common biochemical pathways of some of the most genetically and biologically compelling of these potential AD risk factors are discussed.
Abstract: The genetic underpinnings of Alzheimer's disease (AD) remain largely elusive despite early successes in identifying three genes that cause early-onset familial AD (those that encode amyloid precursor protein (APP) and the presenilins (PSEN1 and PSEN2)), and one genetic risk factor for late-onset AD (the gene that encodes apolipoprotein E (APOE)) A large number of studies that aimed to help uncover the remaining disease-related loci have been published in recent decades, collectively proposing or refuting the involvement of over 500 different gene candidates Systematic meta-analyses of these studies currently highlight more than 20 loci that have modest but significant effects on AD risk This Review discusses the putative pathogenetic roles and common biochemical pathways of some of the most genetically and biologically compelling of these potential AD risk factors
722 citations
TL;DR: The analysis of these various diseases suggests that IFs also have an important role in cell-type-specific physiological functions, and the nanomechanical properties of cell- type-specific IFs are central to the pathogenesis of diseases as diverse as muscular dystrophy and premature ageing.
Abstract: Intermediate filaments (IFs) constitute a major structural element of animal cells They build two distinct systems, one in the nucleus and one in the cytoplasm In both cases, their major function is assumed to be that of a mechanical stress absorber and an integrating device for the entire cytoskeleton In line with this, recent disease mutations in human IF proteins indicate that the nanomechanical properties of cell-type-specific IFs are central to the pathogenesis of diseases as diverse as muscular dystrophy and premature ageing However, the analysis of these various diseases suggests that IFs also have an important role in cell-type-specific physiological functions
654 citations
TL;DR: The basic principles of particle-tracking microrheology are established, describing the advantages of this approach over more conventional approaches to cell mechanics, and basic concepts of molecular mechanics and polymer physics relevant to themicrorheological response of cells are presented.
Abstract: A multitude of cellular and subcellular processes depend critically on the mechanical deformability of the cytoplasm. We have recently introduced the method of particle-tracking microrheology, which measures the viscoelastic properties of the cytoplasm locally and with high spatiotemporal resolution. Here we establish the basic principles of particle-tracking microrheology, describing the advantages of this approach over more conventional approaches to cell mechanics. We present basic concepts of molecular mechanics and polymer physics relevant to the microrheological response of cells. Particle-tracking microrheology can probe the mechanical properties of live cells in experimentally difficult, yet more physiological, environments, including cells embedded inside a 3D matrix, adherent cells subjected to shear flows, and cells inside a developing embryo. Particle-tracking microrheology can readily reveal the lost ability of diseased cells to resist shear forces.
585 citations
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TL;DR: Evidence of mutations in lamin A (LMNA) as the cause of Hutchinson–Gilford progeria syndrome is presented, and the discovery of the molecular basis of this disease may shed light on the general phenomenon of human ageing.
Abstract: Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by features reminiscent of marked premature ageing. Here, we present evidence of mutations in lamin A (LMNA) as the cause of this disorder. The HGPS gene was initially localized to chromosome 1q by observing two cases of uniparental isodisomy of 1q-the inheritance of both copies of this material from one parent-and one case with a 6-megabase paternal interstitial deletion. Sequencing of LMNA, located in this interval and previously implicated in several other heritable disorders, revealed that 18 out of 20 classical cases of HGPS harboured an identical de novo (that is, newly arisen and not inherited) single-base substitution, G608G(GGC > GGT), within exon 11. One additional case was identified with a different substitution within the same codon. Both of these mutations result in activation of a cryptic splice site within exon 11, resulting in production of a protein product that deletes 50 amino acids near the carboxy terminus. Immunofluorescence of HGPS fibroblasts with antibodies directed against lamin A revealed that many cells show visible abnormalities of the nuclear membrane. The discovery of the molecular basis of this disease may shed light on the general phenomenon of human ageing.
1,963 citations
TL;DR: The identification of a mutated putative helicase as the gene product of the WS gene suggests that defective DNA metabolism is involved in the complex process of aging in WS patients.
Abstract: Werner9s syndrome (WS) is an inherited disease with clinical symptoms resembling premature aging. Early susceptibility to a number of major age-related diseases is a key feature of this disorder. The gene responsible for WS (known as WRN ) was identified by positional cloning. The predicted protein is 1432 amino acids in length and shows significant similarity to DNA helicases. Four mutations in WS patients were identified. Two of the mutations are splice-junction mutations, with the predicted result being the exclusion of exons from the final messenger RNA. One of these mutations, which results in a frameshift and a predicted truncated protein, was found in the homozygous state in 60 percent of Japanese WS patients examined. The other two mutations are nonsense mutations. The identification of a mutated putative helicase as the gene product of the WS gene suggests that defective DNA metabolism is involved in the complex process of aging in WS patients.
1,673 citations
TL;DR: It is shown that siRNAs, when delivered systemically in a liposomal formulation, can silence the disease target apolipoprotein B in non-human primates, supporting RNAi therapeutics as a potential new class of drugs.
Abstract: The opportunity to harness the RNA interference (RNAi) pathway to silence disease-causing genes holds great promise for the development of therapeutics directed against targets that are otherwise not addressable with current medicines. Although there are numerous examples of in vivo silencing of target genes after local delivery of small interfering RNAs (siRNAs), there remain only a few reports of RNAi-mediated silencing in response to systemic delivery of siRNA, and there are no reports of systemic efficacy in non-rodent species. Here we show that siRNAs, when delivered systemically in a liposomal formulation, can silence the disease target apolipoprotein B (ApoB) in non-human primates. APOB-specific siRNAs were encapsulated in stable nucleic acid lipid particles (SNALP) and administered by intravenous injection to cynomolgus monkeys at doses of 1 or 2.5 mg kg(-1). A single siRNA injection resulted in dose-dependent silencing of APOB messenger RNA expression in the liver 48 h after administration, with maximal silencing of >90%. This silencing effect occurred as a result of APOB mRNA cleavage at precisely the site predicted for the RNAi mechanism. Significant reductions in ApoB protein, serum cholesterol and low-density lipoprotein levels were observed as early as 24 h after treatment and lasted for 11 days at the highest siRNA dose, thus demonstrating an immediate, potent and lasting biological effect of siRNA treatment. Our findings show clinically relevant RNAi-mediated gene silencing in non-human primates, supporting RNAi therapeutics as a potential new class of drugs.
1,417 citations
TL;DR: HGPS is an exceedingly rare but typical progeria, clinically characterized by postnatal growth retardation, midface hypoplasia, micrognathia, premature atherosclerosis, absence of subcutaneous fat, and others.
Abstract: Little is known about the pathophysiology of human senescence. Hutchinson-Gilford progeria syndrome (HGPS) is an exceedingly rare but typical progeria, clinically characterized by postnatal growth retardation, midface hypoplasia, micrognathia, premature atherosclerosis, absence of subcutaneous fat,
1,325 citations
TL;DR: This work has mapped the locus for EDMD-AD to an 8-cM interval on chromosome 1q11-q23 in a large French pedigree, and found that the EMD phenotype in four other small families was potentially linked to this locus, and identified four mutations in LMNA that co-segregate with the disease phenotype in the five families.
Abstract: Emery-Dreifuss muscular dystrophy (EDMD) is characterized by early contractures of elbows and Achilles tendons, slowly progressive muscle wasting and weakness, and a cardiomyopathy with conduction blocks which is life-threatening1. Two modes of inheritance exist, X-linked (OMIM 310300) and autosomal dominant (EDMD-AD; OMIM 181350). EDMD-AD is clinically identical to the X-linked forms of the disease2,3,4. Mutations in EMD, the gene encoding emerin, are responsible for the X-linked form5,6. We have mapped the locus for EDMD-AD to an 8-cM interval on chromosome 1q11-q23 in a large French pedigree, and found that the EMD phenotype in four other small families was potentially linked to this locus. This region contains the lamin A/C gene (LMNA), a candidate gene encoding two proteins of the nuclear lamina, lamins A and C, produced by alternative splicing7,8. We identified four mutations in LMNA that co-segregate with the disease phenotype in the five families: one nonsense mutation and three missense mutations. These results are the first identification of mutations in a component of the nuclear lamina as a cause of inherited muscle disorder. Together with mutations in EMD (Refs 5,6), they underscore the potential importance of the nuclear envelope components in the pathogenesis of neuromuscular disorders.
1,264 citations