The Experts below are selected from a list of 921 Experts worldwide ranked by ideXlab platform
Junko Oshima - One of the best experts on this subject based on the ideXlab platform.
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novel lmna mutations in greek and myanmar patients with Progeroid features and cardiac manifestations
2020Co-Authors: Renuka Kandhayapillai, Fuki M Hisama, George M. Martin, Stephanie A Bucks, Soe Yarzar, Haroula Korovou, Junko OshimaAbstract:Segmental Progeroid Syndromes are groups of genetic disorders with multiple features resembling accelerated aging. The International Registry of Werner Syndrome (Seattle, WA) recruits pedigrees of Progeroid Syndromes from all over the world. We identified two novel LMNA mutations, p.Asp300Gly in a patient from Myanmar, and p.Asn466Lys, in a patient from Greece. Both were referred to our Registry for the genetic diagnosis because of the accelerated aged-appearance and cardiac complications. LMNA mutations are the second most common genetic cause of Progeroid Syndromes after WRN mutations in our Registry. As the next generation sequencing becomes readily available, we expect to identify more cases of rare genetic diseases in the developing countries. Keywords: Lamin A/C, atypical Werner syndrome, Progeroid syndrome, medical genetics, human
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recq helicase disease and related Progeroid Syndromes recq2018 meeting
2018Co-Authors: Junko Oshima, Hisaya Kato, Yoshiro Maezawa, Koutaro YokoteAbstract:Abstract Progeroid syndrome is a group of disorders characterized by the early onset of diseases that are associated with aging. Best known examples are Werner syndrome, which is adult onset and results from disease-causing DNA sequence variants in the RecQ helicase gene WRN, and Hutchison-Gilford progeria syndrome, which is childhood-onset and results from unique, recurrent disease-causing DNA sequence variants of the gene LMNA that encodes nuclear intermediate filaments. Related single gene RecQ disorders are Bloom syndrome and Rothmund-Thomson syndrome. The RecQ disorders Cockayne syndrome and xeroderma pigmentosum result from disease-causing DNA sequence variants in genes involved in the nucleotide excision repair pathway. RECQ2018: The International Meeting on RECQ Helicases and Related Diseases was held on February 16–18, 2018 in Chiba, Japan. The purpose of the meeting was to facilitate clinical and research collaborations for the goal of developing effective treatments for RECQ disorders and other Progeroid Syndromes.
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werner syndrome clinical features pathogenesis and potential therapeutic interventions
2017Co-Authors: Junko Oshima, Julia M Sidorova, Raymond J MonnatAbstract:Werner syndrome (WS) is a prototypical segmental Progeroid syndrome characterized by multiple features consistent with accelerated aging. It is caused by null mutations of the WRN gene, which encodes a member of the RECQ family of DNA helicases. A unique feature of the WRN helicase is the presence of an exonuclease domain in its N-terminal region. Biochemical and cell biological studies during the past decade have demonstrated involvements of the WRN protein in multiple DNA transactions, including DNA repair, recombination, replication and transcription. A role of the WRN protein in telomere maintenance could explain many of the WS phenotypes. Recent discoveries of new Progeroid loci found in atypical Werner cases continue to support the concept of genomic instability as a major mechanism of biological aging. Based on these biological insights, efforts are underway to develop therapeutic interventions for WS and related Progeroid Syndromes.
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how research on human Progeroid and antigeroid Syndromes can contribute to the longevity dividend initiative
2016Co-Authors: Fuki M Hisama, Junko Oshima, George M. MartinAbstract:Although translational applications derived from research on basic mechanisms of aging are likely to enhance health spans and life spans for most of us (the longevity dividend), there will remain subsets of individuals with special vulnerabilities. Medical genetics is a discipline that describes such "private" patterns of aging and can reveal underlying mechanisms, many of which support genomic instability as a major mechanism of aging. We review examples of three classes of informative disorders: "segmental Progeroid Syndromes" (those that appear to accelerate multiple features of aging), "unimodal Progeroid Syndromes" (those that impact on a single disorder of aging), and "unimodal antigeroid Syndromes," variants that provide enhanced protection against specific disorders of aging; we urge our colleagues to expand our meager research efforts on the latter, including ancillary somatic cell genetic approaches.
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search and insights into novel genetic alterations leading to classical and atypical werner syndrome
2014Co-Authors: Junko Oshima, Fuki M HisamaAbstract:Segmental Progeroid Syndromes are a group of disorders with multiple features resembling accelerated aging. Adultonset Werner syndrome (WS) and childhood-onset Hutchinson-Gilford progeria syndrome are the best known examples. The discovery of genes responsible for such Syndromes has facilitated our understanding of the basic mechanisms of aging as well as the pathogenesis of other common, agerelated diseases. Our International Registry of Werner Syndrome accesses Progeroid pedigrees from all over the world, including those for whom we have ruled out a mutation at the WRN locus. Cases without WRN mutations are operationally categorized as ‘atypical WS’ (AWS). In 2003, we identified LMNA mutations among a subset of AWS cases using a candidate gene approach. As of 2013, the Registry has 142 WS patients with WRN mutations, 11 AWS patients with LMNA mutations, and 49 AWS patients that have neither WRN nor LMNA mutations. Efforts are underway to identify the responsible genes for AWS with unknown genetic causes. While WS and AWS are rare disorders, the causative genes have been shown to have much wider implications for cancer, cardiovascular disease and the biology of aging. Re
Jeffrey H Miner - One of the best experts on this subject based on the ideXlab platform.
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increased progerin expression associated with unusual lmna mutations causes severe Progeroid Syndromes
2007Co-Authors: Casey L Moulson, Emily Farber, Loren G. Fong, Stephen G. Young, Jennifer M Gardner, A Passariello, Dorothy K Grange, Jeffrey H MinerAbstract:Hutchinson-Gilford progeria syndrome (HGPS) is a rare precocious aging syndrome caused by mutations in LMNA that lead to synthesis of a mutant form of prelamin A, generally called progerin, that cannot be processed to mature lamin A. Most HGPS patients have a recurrent heterozygous de novo mutation in exon 11 of LMNA, c.1824C>T/p.G608G; this synonymous mutation activates a nearby cryptic splice donor site, resulting in synthesis of the mutant prelamin A, progerin, which lacks 50 amino acids within the carboxyl-terminal domain. Abnormal splicing is incomplete, so the mutant allele produces some normally-spliced transcripts. Nevertheless, the synthesis of progerin is sufficient to cause misshapen nuclei in cultured cells and severe disease phenotypes in affected patients. Here we present two patients with extraordinarily severe forms of progeria caused by unusual mutations in LMNA. One had a splice site mutation (c.1968+1G>A; or IVS11+1G>A), and the other had a novel synonymous coding region mutation (c.1821G>A/p.V607V). Both mutations caused very frequent use of the same exon 11 splice donor site that is activated in typical HGPS patients. As a consequence, the ratios of progerin mRNA and protein to wild-type were higher than in typical HGPS patients. Fibroblasts from both patients exhibited nuclear shape abnormalities typical of HGPS, and cells treated with a protein farnesyltransferase inhibitor exhibited fewer misshapen nuclei. Thus, farnesyltransferase inhibitors may prove to be useful even when progerin expression levels are higher than those in typical HGPS patients. Hum Mutat 28(9), 882–889, 2007. Published 2007 Wiley-Liss, Inc.
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increased progerin expression associated with unusual lmna mutations causes severe Progeroid Syndromes
2007Co-Authors: Casey L Moulson, Emily Farber, Loren G. Fong, Stephen G. Young, Jennifer M Gardner, A Passariello, Dorothy K Grange, Jeffrey H MinerAbstract:Hutchinson-Gilford progeria syndrome (HGPS) is a rare precocious aging syndrome caused by mutations in LMNA that lead to synthesis of a mutant form of prelamin A, generally called progerin, that cannot be processed to mature lamin A. Most HGPS patients have a recurrent heterozygous de novo mutation in exon 11 of LMNA, c.1824C>T/p.G608G; this synonymous mutation activates a nearby cryptic splice donor site, resulting in synthesis of the mutant prelamin A, progerin, which lacks 50 amino acids within the carboxyl-terminal domain. Abnormal splicing is incomplete, so the mutant allele produces some normally-spliced transcripts. Nevertheless, the synthesis of progerin is sufficient to cause misshapen nuclei in cultured cells and severe disease phenotypes in affected patients. Here we present two patients with extraordinarily severe forms of progeria caused by unusual mutations in LMNA. One had a splice site mutation (c.1968+1G>A; or IVS11+1G>A), and the other had a novel synonymous coding region mutation (c.1821G>A/p.V607V). Both mutations caused very frequent use of the same exon 11 splice donor site that is activated in typical HGPS patients. As a consequence, the ratios of progerin mRNA and protein to wild-type were higher than in typical HGPS patients. Fibroblasts from both patients exhibited nuclear shape abnormalities typical of HGPS, and cells treated with a protein farnesyltransferase inhibitor exhibited fewer misshapen nuclei. Thus, farnesyltransferase inhibitors may prove to be useful even when progerin expression levels are higher than those in typical HGPS patients.
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blocking protein farnesyltransferase improves nuclear shape in fibroblasts from humans with Progeroid Syndromes
2005Co-Authors: Julia I Toth, Stephen G. Young, Casey L Moulson, Jeffrey H Miner, Shao H. Yang, Xin Qiao, Anne P Beigneux, Michael H Gelb, Loren G. FongAbstract:Defects in the biogenesis of lamin A from its farnesylated precursor, prelamin A, lead to the accumulation of prelamin A at the nuclear envelope, cause misshapen nuclei, and result in Progeroid Syndromes. A deficiency in ZMPSTE24, a protease involved in prelamin A processing, leads to prelamin A accumulation, an absence of mature lamin A, misshapen nuclei, and a lethal perinatal Progeroid syndrome: restrictive dermopathy (RD). Hutchinson-Gilford progeria syndrome (HGPS) is caused by a mutant prelamin A that cannot be processed to lamin A. The hallmark cellular abnormality in RD and HGPS is misshapen nuclei. We hypothesized that the farnesylation of prelamin A is important for its targeting to the nuclear envelope in RD and HGPS and that blocking farnesylation would ameliorate the nuclear shape abnormalities. Indeed, when RD fibroblasts were treated with a farnesyltransferase inhibitor (FTI), prelamin A was partially mislocalized away from the nuclear envelope, and the frequency of nuclear shape abnormalities was reduced (P < 0.0001). A FTI also mislocalized prelamin A and improved nuclear shape in Zmpste24-deficient mouse embryonic fibroblasts (P < 0.0001) and improved nuclear shape in human HGPS fibroblasts (P < 0.0001). Most remarkably, a FTI significantly improved nuclear shape in two fibroblast cell lines from atypical progeria patients with lamin A missense mutations in the absence of prelamin A accumulation (P = 0.0003 and P < 0.0001). These findings establish a paradigm for ameliorating the most obvious cellular pathology in lamin-related Progeroid Syndromes and suggest a potential strategy for treating these diseases.
Loren G. Fong - One of the best experts on this subject based on the ideXlab platform.
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laminopathies and the long strange trip from basic cell biology to therapy
2009Co-Authors: Howard J Worman, Loren G. Fong, Antoine Muchir, Stephen G. YoungAbstract:The main function of the nuclear lamina, an intermediate filament meshwork lying primarily beneath the inner nuclear membrane, is to provide structural scaffolding for the cell nucleus. However, the lamina also serves other functions, such as having a role in chromatin organization, connecting the nucleus to the cytoplasm, gene transcription, and mitosis. In somatic cells, the main protein constituents of the nuclear lamina are lamins A, C, B1, and B2. Interest in the nuclear lamins increased dramatically in recent years with the realization that mutations in LMNA, the gene encoding lamins A and C, cause a panoply of human diseases ("laminopathies"), including muscular dystrophy, cardiomyopathy, partial lipodystrophy, and Progeroid Syndromes. Here, we review the laminopathies and the long strange trip from basic cell biology to therapeutic approaches for these diseases.
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increased progerin expression associated with unusual lmna mutations causes severe Progeroid Syndromes
2007Co-Authors: Casey L Moulson, Emily Farber, Loren G. Fong, Stephen G. Young, Jennifer M Gardner, A Passariello, Dorothy K Grange, Jeffrey H MinerAbstract:Hutchinson-Gilford progeria syndrome (HGPS) is a rare precocious aging syndrome caused by mutations in LMNA that lead to synthesis of a mutant form of prelamin A, generally called progerin, that cannot be processed to mature lamin A. Most HGPS patients have a recurrent heterozygous de novo mutation in exon 11 of LMNA, c.1824C>T/p.G608G; this synonymous mutation activates a nearby cryptic splice donor site, resulting in synthesis of the mutant prelamin A, progerin, which lacks 50 amino acids within the carboxyl-terminal domain. Abnormal splicing is incomplete, so the mutant allele produces some normally-spliced transcripts. Nevertheless, the synthesis of progerin is sufficient to cause misshapen nuclei in cultured cells and severe disease phenotypes in affected patients. Here we present two patients with extraordinarily severe forms of progeria caused by unusual mutations in LMNA. One had a splice site mutation (c.1968+1G>A; or IVS11+1G>A), and the other had a novel synonymous coding region mutation (c.1821G>A/p.V607V). Both mutations caused very frequent use of the same exon 11 splice donor site that is activated in typical HGPS patients. As a consequence, the ratios of progerin mRNA and protein to wild-type were higher than in typical HGPS patients. Fibroblasts from both patients exhibited nuclear shape abnormalities typical of HGPS, and cells treated with a protein farnesyltransferase inhibitor exhibited fewer misshapen nuclei. Thus, farnesyltransferase inhibitors may prove to be useful even when progerin expression levels are higher than those in typical HGPS patients. Hum Mutat 28(9), 882–889, 2007. Published 2007 Wiley-Liss, Inc.
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increased progerin expression associated with unusual lmna mutations causes severe Progeroid Syndromes
2007Co-Authors: Casey L Moulson, Emily Farber, Loren G. Fong, Stephen G. Young, Jennifer M Gardner, A Passariello, Dorothy K Grange, Jeffrey H MinerAbstract:Hutchinson-Gilford progeria syndrome (HGPS) is a rare precocious aging syndrome caused by mutations in LMNA that lead to synthesis of a mutant form of prelamin A, generally called progerin, that cannot be processed to mature lamin A. Most HGPS patients have a recurrent heterozygous de novo mutation in exon 11 of LMNA, c.1824C>T/p.G608G; this synonymous mutation activates a nearby cryptic splice donor site, resulting in synthesis of the mutant prelamin A, progerin, which lacks 50 amino acids within the carboxyl-terminal domain. Abnormal splicing is incomplete, so the mutant allele produces some normally-spliced transcripts. Nevertheless, the synthesis of progerin is sufficient to cause misshapen nuclei in cultured cells and severe disease phenotypes in affected patients. Here we present two patients with extraordinarily severe forms of progeria caused by unusual mutations in LMNA. One had a splice site mutation (c.1968+1G>A; or IVS11+1G>A), and the other had a novel synonymous coding region mutation (c.1821G>A/p.V607V). Both mutations caused very frequent use of the same exon 11 splice donor site that is activated in typical HGPS patients. As a consequence, the ratios of progerin mRNA and protein to wild-type were higher than in typical HGPS patients. Fibroblasts from both patients exhibited nuclear shape abnormalities typical of HGPS, and cells treated with a protein farnesyltransferase inhibitor exhibited fewer misshapen nuclei. Thus, farnesyltransferase inhibitors may prove to be useful even when progerin expression levels are higher than those in typical HGPS patients.
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prelamin a zmpste24 misshapen cell nuclei and progeria new evidence suggesting that protein farnesylation could be important for disease pathogenesis
2005Co-Authors: Stephen G. Young, Loren G. Fong, Susan MichaelisAbstract:Prelamin A undergoes multistep processing to yield lamin A, a structural protein of the nuclear lamina. Prelamin A terminates with a CAAX motif, which triggers farnesylation of a C-terminal cysteine (the C of the CAAX motif), endoproteolytic release of the last three amino acids (the AAX), and methylation of the newly exposed farnesyl- cysteine residue. In addition, prelamin A is cleaved a sec- ond time, releasing 15 more residues from the C terminus (including the farnesylcysteine methyl ester), generating ma- ture lamin A. This second cleavage step is carried out by an endoplasmic reticulum membrane protease, ZMPSTE24. In- terest in the posttranslational processing of prelamin A has increased with the recognition that certain Progeroid syn- dromes can be caused by mutations that lead to an accumu- lation of farnesyl-prelamin A. Recently, we showed that a key cellular phenotype of these Progeroid disorders, misshapen cell nuclei, can be ameliorated by inhibitors of protein far- nesylation, suggesting a potential strategy for treating these diseases. In this article, we review the posttranslational pro- cessing of prelamin A, describe several mouse models for Progeroid Syndromes, explain the mutations underlying sev- eral human Progeroid Syndromes, and summarize recent data showing that misshapen nuclei can be ameliorated by treat- ing cells with protein farnesyltransferase inhibitors. —Young, S. G., L. G. Fong, and S. Michaelis. Prelamin A, Zmpste24, misshapen cell nuclei, and progeria—new evidence suggest- ing that protein farnesylation could be important for dis- ease pathogenesis. J. Lipid Res. 2005. 46: 2531-2558.
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blocking protein farnesyltransferase improves nuclear shape in fibroblasts from humans with Progeroid Syndromes
2005Co-Authors: Julia I Toth, Stephen G. Young, Casey L Moulson, Jeffrey H Miner, Shao H. Yang, Xin Qiao, Anne P Beigneux, Michael H Gelb, Loren G. FongAbstract:Defects in the biogenesis of lamin A from its farnesylated precursor, prelamin A, lead to the accumulation of prelamin A at the nuclear envelope, cause misshapen nuclei, and result in Progeroid Syndromes. A deficiency in ZMPSTE24, a protease involved in prelamin A processing, leads to prelamin A accumulation, an absence of mature lamin A, misshapen nuclei, and a lethal perinatal Progeroid syndrome: restrictive dermopathy (RD). Hutchinson-Gilford progeria syndrome (HGPS) is caused by a mutant prelamin A that cannot be processed to lamin A. The hallmark cellular abnormality in RD and HGPS is misshapen nuclei. We hypothesized that the farnesylation of prelamin A is important for its targeting to the nuclear envelope in RD and HGPS and that blocking farnesylation would ameliorate the nuclear shape abnormalities. Indeed, when RD fibroblasts were treated with a farnesyltransferase inhibitor (FTI), prelamin A was partially mislocalized away from the nuclear envelope, and the frequency of nuclear shape abnormalities was reduced (P < 0.0001). A FTI also mislocalized prelamin A and improved nuclear shape in Zmpste24-deficient mouse embryonic fibroblasts (P < 0.0001) and improved nuclear shape in human HGPS fibroblasts (P < 0.0001). Most remarkably, a FTI significantly improved nuclear shape in two fibroblast cell lines from atypical progeria patients with lamin A missense mutations in the absence of prelamin A accumulation (P = 0.0003 and P < 0.0001). These findings establish a paradigm for ameliorating the most obvious cellular pathology in lamin-related Progeroid Syndromes and suggest a potential strategy for treating these diseases.
Stephen G. Young - One of the best experts on this subject based on the ideXlab platform.
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laminopathies and the long strange trip from basic cell biology to therapy
2009Co-Authors: Howard J Worman, Loren G. Fong, Antoine Muchir, Stephen G. YoungAbstract:The main function of the nuclear lamina, an intermediate filament meshwork lying primarily beneath the inner nuclear membrane, is to provide structural scaffolding for the cell nucleus. However, the lamina also serves other functions, such as having a role in chromatin organization, connecting the nucleus to the cytoplasm, gene transcription, and mitosis. In somatic cells, the main protein constituents of the nuclear lamina are lamins A, C, B1, and B2. Interest in the nuclear lamins increased dramatically in recent years with the realization that mutations in LMNA, the gene encoding lamins A and C, cause a panoply of human diseases ("laminopathies"), including muscular dystrophy, cardiomyopathy, partial lipodystrophy, and Progeroid Syndromes. Here, we review the laminopathies and the long strange trip from basic cell biology to therapeutic approaches for these diseases.
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increased progerin expression associated with unusual lmna mutations causes severe Progeroid Syndromes
2007Co-Authors: Casey L Moulson, Emily Farber, Loren G. Fong, Stephen G. Young, Jennifer M Gardner, A Passariello, Dorothy K Grange, Jeffrey H MinerAbstract:Hutchinson-Gilford progeria syndrome (HGPS) is a rare precocious aging syndrome caused by mutations in LMNA that lead to synthesis of a mutant form of prelamin A, generally called progerin, that cannot be processed to mature lamin A. Most HGPS patients have a recurrent heterozygous de novo mutation in exon 11 of LMNA, c.1824C>T/p.G608G; this synonymous mutation activates a nearby cryptic splice donor site, resulting in synthesis of the mutant prelamin A, progerin, which lacks 50 amino acids within the carboxyl-terminal domain. Abnormal splicing is incomplete, so the mutant allele produces some normally-spliced transcripts. Nevertheless, the synthesis of progerin is sufficient to cause misshapen nuclei in cultured cells and severe disease phenotypes in affected patients. Here we present two patients with extraordinarily severe forms of progeria caused by unusual mutations in LMNA. One had a splice site mutation (c.1968+1G>A; or IVS11+1G>A), and the other had a novel synonymous coding region mutation (c.1821G>A/p.V607V). Both mutations caused very frequent use of the same exon 11 splice donor site that is activated in typical HGPS patients. As a consequence, the ratios of progerin mRNA and protein to wild-type were higher than in typical HGPS patients. Fibroblasts from both patients exhibited nuclear shape abnormalities typical of HGPS, and cells treated with a protein farnesyltransferase inhibitor exhibited fewer misshapen nuclei. Thus, farnesyltransferase inhibitors may prove to be useful even when progerin expression levels are higher than those in typical HGPS patients. Hum Mutat 28(9), 882–889, 2007. Published 2007 Wiley-Liss, Inc.
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increased progerin expression associated with unusual lmna mutations causes severe Progeroid Syndromes
2007Co-Authors: Casey L Moulson, Emily Farber, Loren G. Fong, Stephen G. Young, Jennifer M Gardner, A Passariello, Dorothy K Grange, Jeffrey H MinerAbstract:Hutchinson-Gilford progeria syndrome (HGPS) is a rare precocious aging syndrome caused by mutations in LMNA that lead to synthesis of a mutant form of prelamin A, generally called progerin, that cannot be processed to mature lamin A. Most HGPS patients have a recurrent heterozygous de novo mutation in exon 11 of LMNA, c.1824C>T/p.G608G; this synonymous mutation activates a nearby cryptic splice donor site, resulting in synthesis of the mutant prelamin A, progerin, which lacks 50 amino acids within the carboxyl-terminal domain. Abnormal splicing is incomplete, so the mutant allele produces some normally-spliced transcripts. Nevertheless, the synthesis of progerin is sufficient to cause misshapen nuclei in cultured cells and severe disease phenotypes in affected patients. Here we present two patients with extraordinarily severe forms of progeria caused by unusual mutations in LMNA. One had a splice site mutation (c.1968+1G>A; or IVS11+1G>A), and the other had a novel synonymous coding region mutation (c.1821G>A/p.V607V). Both mutations caused very frequent use of the same exon 11 splice donor site that is activated in typical HGPS patients. As a consequence, the ratios of progerin mRNA and protein to wild-type were higher than in typical HGPS patients. Fibroblasts from both patients exhibited nuclear shape abnormalities typical of HGPS, and cells treated with a protein farnesyltransferase inhibitor exhibited fewer misshapen nuclei. Thus, farnesyltransferase inhibitors may prove to be useful even when progerin expression levels are higher than those in typical HGPS patients.
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Prelamin A farnesylation and Progeroid Syndromes.
2006Co-Authors: Stephen G. Young, Margarita Meta, Shao H. Yang, Loren G. FongAbstract:Hutchinson-Gilford progeria syndrome (HGPS) is caused by a LMNA mutation that leads to the synthesis of a mutant prelamin A that is farnesylated but cannot be further processed to mature lamin A. A more severe Progeroid disorder, restrictive dermopathy (RD), is caused by the loss of the prelamin A-processing enzyme, ZMPSTE24. The absence of ZMPSTE24 prevents the endoproteolytic processing of farnesyl-prelamin A to mature lamin A and leads to the accumulation of farnesyl-prelamin A. In both HGPS and RD, the farnesyl-prelamin A is targeted to the nuclear envelope, where it interferes with the integrity of the nuclear envelope and causes misshapen cell nuclei. Recent studies have shown that the frequency of misshapen nuclei can be reduced by treating cells with a farnesyltransferase inhibitor (FTI). Also, administering an FTI to mouse models of HGPS and RD ameliorates the phenotypes of progeria. These studies have prompted interest in testing the efficacy of FTIs in children with HGPS.
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prelamin a zmpste24 misshapen cell nuclei and progeria new evidence suggesting that protein farnesylation could be important for disease pathogenesis
2005Co-Authors: Stephen G. Young, Loren G. Fong, Susan MichaelisAbstract:Prelamin A undergoes multistep processing to yield lamin A, a structural protein of the nuclear lamina. Prelamin A terminates with a CAAX motif, which triggers farnesylation of a C-terminal cysteine (the C of the CAAX motif), endoproteolytic release of the last three amino acids (the AAX), and methylation of the newly exposed farnesyl- cysteine residue. In addition, prelamin A is cleaved a sec- ond time, releasing 15 more residues from the C terminus (including the farnesylcysteine methyl ester), generating ma- ture lamin A. This second cleavage step is carried out by an endoplasmic reticulum membrane protease, ZMPSTE24. In- terest in the posttranslational processing of prelamin A has increased with the recognition that certain Progeroid syn- dromes can be caused by mutations that lead to an accumu- lation of farnesyl-prelamin A. Recently, we showed that a key cellular phenotype of these Progeroid disorders, misshapen cell nuclei, can be ameliorated by inhibitors of protein far- nesylation, suggesting a potential strategy for treating these diseases. In this article, we review the posttranslational pro- cessing of prelamin A, describe several mouse models for Progeroid Syndromes, explain the mutations underlying sev- eral human Progeroid Syndromes, and summarize recent data showing that misshapen nuclei can be ameliorated by treat- ing cells with protein farnesyltransferase inhibitors. —Young, S. G., L. G. Fong, and S. Michaelis. Prelamin A, Zmpste24, misshapen cell nuclei, and progeria—new evidence suggest- ing that protein farnesylation could be important for dis- ease pathogenesis. J. Lipid Res. 2005. 46: 2531-2558.
George M. Martin - One of the best experts on this subject based on the ideXlab platform.
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novel lmna mutations in greek and myanmar patients with Progeroid features and cardiac manifestations
2020Co-Authors: Renuka Kandhayapillai, Fuki M Hisama, George M. Martin, Stephanie A Bucks, Soe Yarzar, Haroula Korovou, Junko OshimaAbstract:Segmental Progeroid Syndromes are groups of genetic disorders with multiple features resembling accelerated aging. The International Registry of Werner Syndrome (Seattle, WA) recruits pedigrees of Progeroid Syndromes from all over the world. We identified two novel LMNA mutations, p.Asp300Gly in a patient from Myanmar, and p.Asn466Lys, in a patient from Greece. Both were referred to our Registry for the genetic diagnosis because of the accelerated aged-appearance and cardiac complications. LMNA mutations are the second most common genetic cause of Progeroid Syndromes after WRN mutations in our Registry. As the next generation sequencing becomes readily available, we expect to identify more cases of rare genetic diseases in the developing countries. Keywords: Lamin A/C, atypical Werner syndrome, Progeroid syndrome, medical genetics, human
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how research on human Progeroid and antigeroid Syndromes can contribute to the longevity dividend initiative
2016Co-Authors: Fuki M Hisama, Junko Oshima, George M. MartinAbstract:Although translational applications derived from research on basic mechanisms of aging are likely to enhance health spans and life spans for most of us (the longevity dividend), there will remain subsets of individuals with special vulnerabilities. Medical genetics is a discipline that describes such "private" patterns of aging and can reveal underlying mechanisms, many of which support genomic instability as a major mechanism of aging. We review examples of three classes of informative disorders: "segmental Progeroid Syndromes" (those that appear to accelerate multiple features of aging), "unimodal Progeroid Syndromes" (those that impact on a single disorder of aging), and "unimodal antigeroid Syndromes," variants that provide enhanced protection against specific disorders of aging; we urge our colleagues to expand our meager research efforts on the latter, including ancillary somatic cell genetic approaches.
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dna damage accumulation and trf2 degradation in atypical werner syndrome fibroblasts with lmna mutations
2013Co-Authors: Bhaskar Saha, George M. Martin, Galynn Zitnik, Simon C Johnson, Quyen T N Nguyen, Rosa Ana Risques, Junko OshimaAbstract:Segmental Progeroid Syndromes are groups of disorders with multiple features suggestive of accelerated aging. One subset of adult-onset Progeroid Syndromes, referred to as atypical Werner syndrome (AWS), is caused by mutations in the LMNA gene, which encodes a class of nuclear intermediate filaments, lamin A/C. We previously described rapid telomere attrition and accelerated replicative senescence in cultured fibroblasts overexpressing mutant lamin A. In this study, we investigated the cellular phenotypes associated with accelerated telomere shortening in LMNA mutant primary fibroblasts. In early passage primary fibroblasts with R133L or L140R LMNA mutations, shelterin protein components were already reduced while cells still retained telomere lengths comparable to those of controls. There was a significant inverse correlation between the degree of abnormal nuclear morphology and the level of TRF2, a shelterin subunit, suggesting a potential causal relationship. Stabilization of the telomeres via the introduction of the catalytic subunit of human telomerase, hTERT, did not prevent degradation of shelterin components, indicating that reduced TRF2 in LMNA mutants is not mediated by short telomeres. Interestingly, -H2AX foci (reflecting double strand DNA damage) in early passage LMNA mutant primary fibroblasts and LMNA mutant hTERT fibroblasts were markedly increased in non-telomeric regions of DNA. Our results raise the possibility that mutant lamin A/C causes global genomic instability with accumulation of non-telomeric DNA damage as an early event, followed by TRF2 degradation and telomere shortening.
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Review Genetic Determinants of Human Health Span and Life Span: Progress and New Opportunities
2013Co-Authors: George M. Martin, Aviv Bergman, Nir BarzilaiAbstract:We review three approaches to the genetic analysis of the biology and pathobiology of human aging. The first and so far the best-developed is the search for the biochemical genetic basis of varying susceptibilities to major geriatric disorders. These include a range of Progeroid Syndromes. Collectively, they tell us much about the genetics of health span. Given that the major risk factor for virtually all geriatric disorders is biological aging, they may also serve as markers for the study of intrinsic biological aging. The second approach seeks to identify allelic contributions to exceptionally long life spans. While linkage to a locus on Chromosome 4 has not been confirmed, association studies have revealed a number of significant polymorphisms that impact upon late-life diseases and life span. The third approach remains theoretical. It would require longitudinal studies of large numbers of middle-aged sib-pairs who are extremely discordant or concordant for their rates of decline in various physiological functions. We can conclude that there are great opportunities for research on the genetics of human aging, particularly given the huge fund of information on human biology and pathobiology, and the rapidly developing knowledge of the human genome
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Molecular Genetics & Genomic Medicine
2013Co-Authors: Bidisha Saha, Fuki M Hisama, Davor Lessel, George M. Martin, Sheela Nampoothiri, Anuradha S. Rao, Dincy Peter, Chris Bennett, Christian Kubisch, Junko OshimaAbstract:segmental Progeroid Syndromes, Werner syndrome, WRN
