The Experts below are selected from a list of 8994 Experts worldwide ranked by ideXlab platform
Stephen G. Young - One of the best experts on this subject based on the ideXlab platform.
-
lmna missense mutations Causing familial partial lipodystrophy do not lead to an aCCumulation of preLamin a
Nucleus, 2016Co-Authors: Sofia Sancheziglesias, Loren G. Fong, David Araujovilar, Stephen G. YoungAbstract:ABSTRACTA variety of missense mutations in LMNA (the gene for Lamin C and preLamin A) Cause familial partial lipodystrophy (FPLD), a disease assoCiated with reduCed adipose tissue, partiCularly in the limbs. Several studies have reported that fibroblasts from FPLD subjeCts have an aCCumulation of preLamin A. Those findings were intriguing but also perplexing beCause many of the LMNA missense mutations assoCiated with lipodystrophy are loCated in sequenCes distant from the sequenCes required for the farnesylation of preLamin A and ZMPSTE24-mediated Conversion of preLamin A to mature Lamin A. Here, we revisited the issue of preLamin A aCCumulation in the setting of FPLD mutations. We used western blots with Lamin A/C antibodies and preLamin A–speCifiC monoClonal antibodies to assess preLamin A levels in wild-type fibroblasts and fibroblasts Carrying LMNA mutations assoCiated with lipodystrophy (R482W, I299V, C591F, T528M). None of the mutant fibroblasts exhibited an aCCumulation of preLamin A. Also, the amo...
-
modulation of lmna spliCing as a strategy to treat preLamin a diseases
Journal of Clinical Investigation, 2016Co-Authors: John M Lee, Shao H. Yang, Stephen G. Young, Hea-jin Jung, Timothy A. Vickers, Chika Nobumori, Catherine Choi, Frank Rigo, Frank C Bennett, Loren G. FongAbstract:The alternatively spliCed produCts of LMNA, Lamin C and preLamin A (the preCursor to Lamin A), are produCed in similar amounts in most tissues and have largely redundant funCtions. This redundanCy suggests that diseases, suCh as HutChinson-Gilford progeria syndrome (HGPS), that are Caused by preLamin A-speCifiC mutations Could be treated by shifting the output of LMNA more toward Lamin C. Here, we investigated meChanisms that regulate LMNA mRNA alternative spliCing and assessed the feasibility of reduCing preLamin A expression in vivo. We identified an exon 11 antisense oligonuCleotide (ASO) that inCreased Lamin C produCtion at the expense of preLamin A when transfeCted into mouse and human fibroblasts. The same ASO also reduCed the expression of progerin, the mutant preLamin A protein in HGPS, in fibroblasts derived from patients with HGPS. MeChanistiC studies revealed that the exon 11 sequenCes Contain binding sites for serine/arginine-riCh spliCing faCtor 2 (SRSF2), and SRSF2 knoCkdown lowered Lamin A produCtion in Cells and in murine tissues. Moreover, administration of the exon 11 ASO reduCed Lamin A expression in wild-type miCe and progerin expression in an HGPS mouse model. Together, these studies identify ASO-mediated reduCtion of preLamin A as a potential strategy to treat preLamin A-speCifiC diseases.
-
NuClear Lamins and neurobiology.
Molecular and Cellular Biology, 2014Co-Authors: Stephen G. Young, Hea-jin Jung, John M Lee, Loren G. FongAbstract:MuCh of the work on nuClear Lamins during the past 15 years has foCused on mutations in LMNA (the gene for preLamin A and Lamin C) that Cause partiCular musCular dystrophy, Cardiomyopathy, partial lipodystrophy, and progeroid syndromes. These disorders, often Called “Laminopathies,” mainly affeCt mesenChymal tissues (e.g., striated musCle, bone, and fibrous tissue). ReCently, however, a series of papers have identified important roles for nuClear Lamins in the Central nervous system. Studies of knoCkout miCe unCovered a key role for B-type Lamins (Lamins B1 and B2) in neuronal migration in the developing brain. Also, dupliCations of LMNB1 (the gene for Lamin B1) have been shown to Cause autosome-dominant leukodystrophy. Finally, reCent studies have unCovered a peCuliar pattern of nuClear Lamin expression in the brain. Lamin C transCripts are present at high levels in the brain, but preLamin A expression levels are very low—due to regulation of preLamin A transCripts by miCroRNA 9. This form of preLamin A regulation likely explains why “preLamin A diseases” suCh as HutChinson-Gilford progeria syndrome spare the Central nervous system. In this review, we summarize reCent progress in eluCidating links between nuClear Lamins and neurobiology.
-
Investigating the purpose of preLamin A proCessing.
Nucleus, 2011Co-Authors: Brandon S. J. Davies, Shao H. Yang, Stephen G. Young, Hea-jin Jung, Catherine Coffinier, Richard H. Barnes, Loren G. FongAbstract:Lmna yields two major protein produCts in somatiC Cells, Lamin C and preLamin A. Mature Lamin A is produCed from preLamin A by four posttranslational proCessing steps-farnesylation of a Carboxyl-terminal Cysteine, release of the last three amino aCids of the protein, methylation of the farnesylCysteine, and the endoproteolytiC release of the Carboxyl-terminal 15 amino aCids of the protein (inCluding the farnesylCysteine methyl ester). Although the posttranslational proCessing of preLamin A has been Conserved in vertebrate evolution, its physiologiC signifiCanCe remains unClear. Here we review reCent studies in whiCh we investigated preLamin A proCessing with Lmna knoCk-in miCe that produCe exClusively preLamin A (Lmna(PLAO)), mature Lamin A (Lmna(LAO)) or nonfarnesylated preLamin A (Lmna(nPLAO)). We found that the synthesis of Lamin C is dispensable in laboratory miCe, that the direCt produCtion of mature Lamin A (Completely bypassing all preLamin A proCessing) Causes no disCernable pathology in miCe, and that exClusive produCtion of nonfarnesylated preLamin A leads to Cardiomyopathy.
-
An aCCumulation of non-farnesylated preLamin A Causes Cardiomyopathy but not progeria
Human Molecular Genetics, 2010Co-Authors: Brandon S. J. Davies, Stephen G. Young, Richard H. Barnes, Jan Lammerding, Shuxun Ren, Douglas A. Andres, H. Peter Spielmann, Yibin Wang, Loren G. FongAbstract:Lamin A is formed from preLamin A by four post-translational proCessing steps—farnesylation, release of the last three amino aCids of the protein, methylation of the farnesylCysteine and the endoproteolytiC release of the C-terminal 15 amino aCids (inCluding the farnesylCysteine methyl ester). When the final proCessing step does not oCCur, a farnesylated and methylated preLamin A aCCumulates in Cells, Causing a severe progeroid disease, restriCtive dermopathy (RD). Whether RD is Caused by the retention of farnesyl lipid on preLamin A, or by the retention of the last 15 amino aCids of the protein, is unknown. To address this issue, we Created knoCk-in miCe harboring a mutant Lmna allele (LmnanPLAO) that yields exClusively non-farnesylated preLamin A (and no Lamin C). These miCe had no evidenCe of progeria but suCCumbed to Cardiomyopathy. We suspeCted that the non-farnesylated preLamin A in the tissues of these miCe would be strikingly misloCalized to the nuCleoplasm, but this was not the Case; most was at the nuClear rim (indistinguishable from the Lamin A in wild-type miCe). The Cardiomyopathy Could not be asCribed to an absenCe of Lamin C beCause miCe expressing an otherwise identiCal knoCk-in allele yielding only wild-type preLamin A appeared normal. We ConClude that Lamin C synthesis is dispensable in miCe and that the failure to Convert preLamin A to mature Lamin A Causes Cardiomyopathy (at least in the absenCe of Lamin C). The latter finding is potentially relevant to the long-term use of protein farnesyltransferase inhibitors, whiCh lead to an aCCumulation of non-farnesylated preLamin A.
Loren G. Fong - One of the best experts on this subject based on the ideXlab platform.
-
lmna missense mutations Causing familial partial lipodystrophy do not lead to an aCCumulation of preLamin a
Nucleus, 2016Co-Authors: Sofia Sancheziglesias, Loren G. Fong, David Araujovilar, Stephen G. YoungAbstract:ABSTRACTA variety of missense mutations in LMNA (the gene for Lamin C and preLamin A) Cause familial partial lipodystrophy (FPLD), a disease assoCiated with reduCed adipose tissue, partiCularly in the limbs. Several studies have reported that fibroblasts from FPLD subjeCts have an aCCumulation of preLamin A. Those findings were intriguing but also perplexing beCause many of the LMNA missense mutations assoCiated with lipodystrophy are loCated in sequenCes distant from the sequenCes required for the farnesylation of preLamin A and ZMPSTE24-mediated Conversion of preLamin A to mature Lamin A. Here, we revisited the issue of preLamin A aCCumulation in the setting of FPLD mutations. We used western blots with Lamin A/C antibodies and preLamin A–speCifiC monoClonal antibodies to assess preLamin A levels in wild-type fibroblasts and fibroblasts Carrying LMNA mutations assoCiated with lipodystrophy (R482W, I299V, C591F, T528M). None of the mutant fibroblasts exhibited an aCCumulation of preLamin A. Also, the amo...
-
modulation of lmna spliCing as a strategy to treat preLamin a diseases
Journal of Clinical Investigation, 2016Co-Authors: John M Lee, Shao H. Yang, Stephen G. Young, Hea-jin Jung, Timothy A. Vickers, Chika Nobumori, Catherine Choi, Frank Rigo, Frank C Bennett, Loren G. FongAbstract:The alternatively spliCed produCts of LMNA, Lamin C and preLamin A (the preCursor to Lamin A), are produCed in similar amounts in most tissues and have largely redundant funCtions. This redundanCy suggests that diseases, suCh as HutChinson-Gilford progeria syndrome (HGPS), that are Caused by preLamin A-speCifiC mutations Could be treated by shifting the output of LMNA more toward Lamin C. Here, we investigated meChanisms that regulate LMNA mRNA alternative spliCing and assessed the feasibility of reduCing preLamin A expression in vivo. We identified an exon 11 antisense oligonuCleotide (ASO) that inCreased Lamin C produCtion at the expense of preLamin A when transfeCted into mouse and human fibroblasts. The same ASO also reduCed the expression of progerin, the mutant preLamin A protein in HGPS, in fibroblasts derived from patients with HGPS. MeChanistiC studies revealed that the exon 11 sequenCes Contain binding sites for serine/arginine-riCh spliCing faCtor 2 (SRSF2), and SRSF2 knoCkdown lowered Lamin A produCtion in Cells and in murine tissues. Moreover, administration of the exon 11 ASO reduCed Lamin A expression in wild-type miCe and progerin expression in an HGPS mouse model. Together, these studies identify ASO-mediated reduCtion of preLamin A as a potential strategy to treat preLamin A-speCifiC diseases.
-
NuClear Lamins and neurobiology.
Molecular and Cellular Biology, 2014Co-Authors: Stephen G. Young, Hea-jin Jung, John M Lee, Loren G. FongAbstract:MuCh of the work on nuClear Lamins during the past 15 years has foCused on mutations in LMNA (the gene for preLamin A and Lamin C) that Cause partiCular musCular dystrophy, Cardiomyopathy, partial lipodystrophy, and progeroid syndromes. These disorders, often Called “Laminopathies,” mainly affeCt mesenChymal tissues (e.g., striated musCle, bone, and fibrous tissue). ReCently, however, a series of papers have identified important roles for nuClear Lamins in the Central nervous system. Studies of knoCkout miCe unCovered a key role for B-type Lamins (Lamins B1 and B2) in neuronal migration in the developing brain. Also, dupliCations of LMNB1 (the gene for Lamin B1) have been shown to Cause autosome-dominant leukodystrophy. Finally, reCent studies have unCovered a peCuliar pattern of nuClear Lamin expression in the brain. Lamin C transCripts are present at high levels in the brain, but preLamin A expression levels are very low—due to regulation of preLamin A transCripts by miCroRNA 9. This form of preLamin A regulation likely explains why “preLamin A diseases” suCh as HutChinson-Gilford progeria syndrome spare the Central nervous system. In this review, we summarize reCent progress in eluCidating links between nuClear Lamins and neurobiology.
-
Investigating the purpose of preLamin A proCessing.
Nucleus, 2011Co-Authors: Brandon S. J. Davies, Shao H. Yang, Stephen G. Young, Hea-jin Jung, Catherine Coffinier, Richard H. Barnes, Loren G. FongAbstract:Lmna yields two major protein produCts in somatiC Cells, Lamin C and preLamin A. Mature Lamin A is produCed from preLamin A by four posttranslational proCessing steps-farnesylation of a Carboxyl-terminal Cysteine, release of the last three amino aCids of the protein, methylation of the farnesylCysteine, and the endoproteolytiC release of the Carboxyl-terminal 15 amino aCids of the protein (inCluding the farnesylCysteine methyl ester). Although the posttranslational proCessing of preLamin A has been Conserved in vertebrate evolution, its physiologiC signifiCanCe remains unClear. Here we review reCent studies in whiCh we investigated preLamin A proCessing with Lmna knoCk-in miCe that produCe exClusively preLamin A (Lmna(PLAO)), mature Lamin A (Lmna(LAO)) or nonfarnesylated preLamin A (Lmna(nPLAO)). We found that the synthesis of Lamin C is dispensable in laboratory miCe, that the direCt produCtion of mature Lamin A (Completely bypassing all preLamin A proCessing) Causes no disCernable pathology in miCe, and that exClusive produCtion of nonfarnesylated preLamin A leads to Cardiomyopathy.
-
An aCCumulation of non-farnesylated preLamin A Causes Cardiomyopathy but not progeria
Human Molecular Genetics, 2010Co-Authors: Brandon S. J. Davies, Stephen G. Young, Richard H. Barnes, Jan Lammerding, Shuxun Ren, Douglas A. Andres, H. Peter Spielmann, Yibin Wang, Loren G. FongAbstract:Lamin A is formed from preLamin A by four post-translational proCessing steps—farnesylation, release of the last three amino aCids of the protein, methylation of the farnesylCysteine and the endoproteolytiC release of the C-terminal 15 amino aCids (inCluding the farnesylCysteine methyl ester). When the final proCessing step does not oCCur, a farnesylated and methylated preLamin A aCCumulates in Cells, Causing a severe progeroid disease, restriCtive dermopathy (RD). Whether RD is Caused by the retention of farnesyl lipid on preLamin A, or by the retention of the last 15 amino aCids of the protein, is unknown. To address this issue, we Created knoCk-in miCe harboring a mutant Lmna allele (LmnanPLAO) that yields exClusively non-farnesylated preLamin A (and no Lamin C). These miCe had no evidenCe of progeria but suCCumbed to Cardiomyopathy. We suspeCted that the non-farnesylated preLamin A in the tissues of these miCe would be strikingly misloCalized to the nuCleoplasm, but this was not the Case; most was at the nuClear rim (indistinguishable from the Lamin A in wild-type miCe). The Cardiomyopathy Could not be asCribed to an absenCe of Lamin C beCause miCe expressing an otherwise identiCal knoCk-in allele yielding only wild-type preLamin A appeared normal. We ConClude that Lamin C synthesis is dispensable in miCe and that the failure to Convert preLamin A to mature Lamin A Causes Cardiomyopathy (at least in the absenCe of Lamin C). The latter finding is potentially relevant to the long-term use of protein farnesyltransferase inhibitors, whiCh lead to an aCCumulation of non-farnesylated preLamin A.
Shao H. Yang - One of the best experts on this subject based on the ideXlab platform.
-
modulation of lmna spliCing as a strategy to treat preLamin a diseases
Journal of Clinical Investigation, 2016Co-Authors: John M Lee, Shao H. Yang, Stephen G. Young, Hea-jin Jung, Timothy A. Vickers, Chika Nobumori, Catherine Choi, Frank Rigo, Frank C Bennett, Loren G. FongAbstract:The alternatively spliCed produCts of LMNA, Lamin C and preLamin A (the preCursor to Lamin A), are produCed in similar amounts in most tissues and have largely redundant funCtions. This redundanCy suggests that diseases, suCh as HutChinson-Gilford progeria syndrome (HGPS), that are Caused by preLamin A-speCifiC mutations Could be treated by shifting the output of LMNA more toward Lamin C. Here, we investigated meChanisms that regulate LMNA mRNA alternative spliCing and assessed the feasibility of reduCing preLamin A expression in vivo. We identified an exon 11 antisense oligonuCleotide (ASO) that inCreased Lamin C produCtion at the expense of preLamin A when transfeCted into mouse and human fibroblasts. The same ASO also reduCed the expression of progerin, the mutant preLamin A protein in HGPS, in fibroblasts derived from patients with HGPS. MeChanistiC studies revealed that the exon 11 sequenCes Contain binding sites for serine/arginine-riCh spliCing faCtor 2 (SRSF2), and SRSF2 knoCkdown lowered Lamin A produCtion in Cells and in murine tissues. Moreover, administration of the exon 11 ASO reduCed Lamin A expression in wild-type miCe and progerin expression in an HGPS mouse model. Together, these studies identify ASO-mediated reduCtion of preLamin A as a potential strategy to treat preLamin A-speCifiC diseases.
-
Regulation of preLamin A but not Lamin C by miR-9, a brain-speCifiC miCroRNA
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Hea-jin Jung, Shao H. Yang, Catherine Coffinier, Youngshik Choe, Anne P. Beigneux, Brandon S. J. Davies, Richard H. Barnes, Janet Hong, Tao Sun, Samuel J. PleasureAbstract:Lamins A and C, alternatively spliCed produCts of the LMNA gene, are key Components of the nuClear Lamina. The two isoforms are found in similar amounts in most tissues, but we observed an unexpeCted pattern of expression in the brain. Western blot and immunohistoChemistry studies showed that Lamin C is abundant in the mouse brain, whereas Lamin A and its preCursor preLamin A are restriCted to endothelial Cells and meningeal Cells and are absent in neurons and glia. PreLamin A transCript levels were low in the brain, but this finding Could not be explained by alternative spliCing. In Lamin A-only knoCkin miCe, where alternative spliCing is absent and all the output of the gene is Channeled into preLamin A transCripts, large amounts of Lamin A were found in peripheral tissues, but there was very little Lamin A in the brain. Also, in knoCkin miCe expressing exClusively progerin (a toxiC form of preLamin A found in HutChinson–Gilford progeria syndrome), the levels of progerin in the brain were extremely low. Further studies showed that preLamin A expression, but not Lamin C expression, is down-regulated by a brain-speCifiC miCroRNA, miR-9. Expression of miR-9 in Cultured Cells reduCed Lamin A expression, and this effeCt was abolished when the miR-9–binding site in the preLamin A 3′ UTR was mutated. The down-regulation of preLamin A expression in the brain Could explain why mouse models of HutChinson–Gilford progeria syndrome are free of Central nervous system pathology.
-
Investigating the purpose of preLamin A proCessing.
Nucleus, 2011Co-Authors: Brandon S. J. Davies, Shao H. Yang, Stephen G. Young, Hea-jin Jung, Catherine Coffinier, Richard H. Barnes, Loren G. FongAbstract:Lmna yields two major protein produCts in somatiC Cells, Lamin C and preLamin A. Mature Lamin A is produCed from preLamin A by four posttranslational proCessing steps-farnesylation of a Carboxyl-terminal Cysteine, release of the last three amino aCids of the protein, methylation of the farnesylCysteine, and the endoproteolytiC release of the Carboxyl-terminal 15 amino aCids of the protein (inCluding the farnesylCysteine methyl ester). Although the posttranslational proCessing of preLamin A has been Conserved in vertebrate evolution, its physiologiC signifiCanCe remains unClear. Here we review reCent studies in whiCh we investigated preLamin A proCessing with Lmna knoCk-in miCe that produCe exClusively preLamin A (Lmna(PLAO)), mature Lamin A (Lmna(LAO)) or nonfarnesylated preLamin A (Lmna(nPLAO)). We found that the synthesis of Lamin C is dispensable in laboratory miCe, that the direCt produCtion of mature Lamin A (Completely bypassing all preLamin A proCessing) Causes no disCernable pathology in miCe, and that exClusive produCtion of nonfarnesylated preLamin A leads to Cardiomyopathy.
-
Eliminating the Synthesis of Mature Lamin A ReduCes Disease Phenotypes in MiCe Carrying a HutChinson-Gilford Progeria Syndrome Allele
Journal of Biological Chemistry, 2008Co-Authors: Shao H. Yang, Xin Qiao, Emily Farber, Sandy Y. Chang, Loren G. Fong, Stephen G. YoungAbstract:HutChinson-Gilford progeria syndrome is Caused by the synthesis of a mutant form of preLamin A, whiCh is generally Called progerin. Progerin is targeted to the nuClear rim, where it interferes with the integrity of the nuClear Lamina, Causes misshapen Cell nuClei, and leads to multiple aging-like disease phenotypes. We Created a gene-targeted allele yielding exClusively progerin (Lmna HG) and found that heterozygous miCe (Lmna HG/+) exhibit many phenotypes of progeria. In this study, we tested the hypothesis that the phenotypes eliCited by the Lmna HG allele might be modulated by Compositional Changes in the nuClear Lamina. To explore this hypothesis, we bred miCe harboring one Lmna HG allele and one Lmna LCO allele (a mutant allele that produCes Lamin C but no Lamin A). We then Compared the phenotypes of Lmna HG/LCO miCe (whiCh produCe progerin and Lamin C) with littermate Lmna HG/+ miCe (whiCh produCe Lamin A, Lamin C, and progerin). Lmna HG/LCO miCe exhibited improved HG/LCO fibroblasts had fewer misshapen nuClei than Lmna HG/+ fibroblasts (p < 0.0001). A likely explanation for these differenCes was unCovered; the amount of progerin in Lmna HG/LCO fibroblasts and tissues was lower than in Lmna HG/+ fibroblasts and tissues. These studies suggest that Compositional Changes in the nuClear Lamina Can influenCe both the steady-state levels of progerin and the severity of progeria-like disease phenotypes.
-
Eliminating the Synthesis of Mature Lamin A ReduCes Disease Phenotypes in MiCe Carrying a HutChinson-Gilford
2008Co-Authors: Shao H. Yang, Xin Qiao, Emily Farber, Sandy Y. Chang, Loren G. Fong, Stephen G. Young, Fromthedepartmentsof ‡ MedicineandAbstract:HutChinson-Gilford progeria syndrome is Caused by the synthesis of a mutant form of preLamin A, whiCh is generally Called progerin. Progerin is targeted to the nuClear rim, where it interferes with the integrity of the nuClear Lamina, Causes misshapen Cell nuClei, and leads to multiple aging-like disease phenotypes. We Created a gene-targeted allele yielding exClusively progerin (Lmna HG ) and found that heterozygous miCe (Lmna HG/ ) exhibit many phenotypes of progeria. In this study, we tested the hypothesis that the phenotypes eliCited by the Lmna HG allele might be modulated by Compositional Changes in the nuClear Lamina. To explore this hypothesis, we bred miCe harboring one Lmna HG allele and one Lmna LCO allele (a mutant allele that produCes Lamin C but no Lamin A). We then Compared the phenotypes of Lmna HG/LCO miCe (whiCh produCe progerin and Lamin C) with littermate Lmna HG/ miCe (whiCh produCe Lamin A, Lamin C, and progerin). Lmna HG/LCO miCe exhibited improved body weight Curves (p< 0.0001), reduCed numbers of spontaneous rib fraCtures (p < 0.0001), and improved survival (p < 0.0001). In addition, Lmna HG/LCO fibroblasts had fewer misshapen nuClei than Lmna HG/ fibroblasts (p < 0.0001). A likely
Howard J. Worman - One of the best experts on this subject based on the ideXlab platform.
-
BloCking farnesylation of the preLamin A variant in HutChinson-Gilford progeria syndrome alters the distribution of A-type Lamins
Nucleus, 2012Co-Authors: Yuexia Wang, Cecilia Ӧstlund, Jason C. Choi, Theresa C. Swayne, Gregg G. Gundersen, Howard J. WormanAbstract:Mutations in the Lamin A/C gene that Cause HutChinson-Gilford progeria syndrome lead to expression of a trunCated, permanently farnesylated preLamin A variant Called progerin. BloCking farnesylation leads to an improvement in the abnormal nuClear morphology observed in Cells expressing progerin, whiCh is assoCiated with a re-loCalization of the variant protein from the nuClear envelope to the nuClear interior. We now show that a progerin ConstruCt that Cannot be farnesylated is loCalized primarily in intranuClear foCi and that its diffusional mobility is signifiCantly greater than that of farnesylated progerin loCalized predominantly at the nuClear envelope. Expression of non-farnesylated progerin in transfeCted Cells leads to a redistribution of Lamin A and Lamin C away from the nuClear envelope into intranuClear foCi but does not signifiCantly affeCt the loCalization of endogenous Lamin B1 at nuClear envelope. There is a similar redistribution of Lamin A and Lamin C into intranuClear foCi in transfeCted Cells expressing progerin in whiCh protein farnesylation is bloCked by treatment with a protein farnesyltransferase inhibitor. BloCking farnesylation of progerin Can lead to a redistribution of normal A-type Lamins away from the inner nuClear envelope. This may have impliCations for using drugs that bloCk protein prenylation to treat Children with HutChinson-Gilford progeria syndrome. These findings also provide additional evidenCe that A-type and B-type Lamins Can form separate miCrodomains within the nuCleus.
-
Loss of a DNA binding site within the tail of preLamin A Contributes to altered heteroChromatin anChorage by progerin
FEBS Letters, 2010Co-Authors: Francine Bruston, Howard J. Worman, Erwan Delbarre, Cecilia Östlund, Brigitte Buendia, Isabelle Duband-gouletAbstract:Mutations in the Lamin A/C (LMNA) gene that Cause HutChinson-Gilford progeria syndrome (HGPS) lead to expression of a protein Called progerin with 50 amino aCids deleted from the tail of preLamin A. In Cells from patients with HGPS, both the amount and distribution of heteroChromatin are altered. We designed in vitro assays to ask whether suCh alterations might refleCt Changes in Chromatin, DNA and/or histone binding properties of progerin Compared to wild-type Lamin C-terminal tails. We show that progerin tail has a reduCed DNA/Chromatin binding CapaCity and modified trimethylated H3K27 binding pattern, offering a moleCular meChanism for heteroChromatin alterations related to HGPS.
-
both Lamin a and Lamin C mutations Cause Lamina instability as well as loss of internal nuClear Lamin organization
Experimental Cell Research, 2005Co-Authors: Jlv Jos Broers, Howard J. Worman, Cecilia Östlund, Hjh Kuijpers, J Endert, Fcs Frans RamaekersAbstract:We have applied the fluoresCenCe loss of intensity after photobleaChing (FLIP) teChnique to study the moleCular dynamiCs and organization of nuClear Lamin proteins in Cell lines stably transfeCted with green fluoresCent protein (GFP)-tagged A-type Lamin CDNA. Normal Lamin A and C proteins show abundant deCoration of the inner layer of the nuClear membrane, the nuClear Lamina, and a generally diffuse loCalization in the nuClear interior. BleaChing studies revealed that, while the GFP-tagged Lamins in the Lamina were virtually immobile, the intranuClear fraCtion of these moleCules was partially mobile. IntranuClear Lamin C was signifiCantly more mobile than intranuClear Lamina A. In searCh of a struCtural Cause for the variety of inherited diseases Caused by A-type Lamin mutations, we have studied the moleCular organization of GFP-tagged Lamin A and Lamin C mutants R453W and R386K, found in Emery-Dreifuss musCular dystrophy (EDMD), and Lamin A and Lamin C mutant R482W, found in patients with Dunnigan-type familial partial lipodystrophy (FPLD). In all mutants, a prominent inCrease in Lamin mobility was observed, indiCating loss of struCtural stability of Lamin polymers, both at the perinuClear Lamina and in the intranuClear Lamin organization. While the Lamin rod domain mutant showed overall inCreased mobility, the tail domain mutants showed mainly intranuClear destabilization, possibly as a result of loss of interaCtion with Chromatin. DeCreased stability of Lamin mutant polymers was Confirmed by flow CytometriC analyses and immunoblotting of nuClear extraCts. Our findings suggest a loss of funCtion of A-type Lamin mutant proteins in the organization of intranuClear Chromatin and prediCt the loss of gene regulatory funCtion in Laminopathies.
-
The nuClear Lamina and inherited disease
Trends in Cell Biology, 2002Co-Authors: Howard J. Worman, Jean-claude CourvalinAbstract:AbstraCt Inherited disorders of the nuClear Lamina present some of the most intriguing puzzles in Cell biology. Mutations in Lamin A and Lamin C – nuClear intermediate filament proteins that are expressed in nearly all somatiC Cells – Cause tissue-speCifiC diseases that affeCt striated musCle, adipose tissue and peripheral nerve or skeletal development. ReCent studies provide Clues about how different mutations in these proteins Cause either musCle disease or partial lipodystrophy. Although the preCise pathogeniC meChanisms are Currently unknown, the involvement of Lamins in several different disorders shows that researCh on the nuClear Lamina will shed light on Common human pathologies.
-
Protein-protein interaCtions between human nuClear Lamins expressed in yeast.
Experimental Cell Research, 1995Co-Authors: Howard J. WormanAbstract:Protein-protein interaCtions between the nuClear Lamins are responsible for the assembly of the nuClear Lamina, a meshwork of intermediate filaments assoCiated with the nuClear envelope inner membrane. We have used the yeast two-hybrid system to examine the interaCtions between the predominant human nuClear Lamins expressed as GAL4 fusion proteins in SaCCharomyCes Cerevisiae. Lamin A, preLamin A, Lamin B1, and Lamin C were able to form homodimers as well as heterodimers. Analysis of the different struCtural domains of Lamin B1 demonstrated that the seCond half of Coil 2 of the rod domain was neCessary for the formation of the most stable homodimers. The results show that the yeast two-hybrid system Can be used to study the interaCtions between struCtural proteins and their domains.
Fowzan S Alkuraya - One of the best experts on this subject based on the ideXlab platform.
-
distal aCroosteolysis poikiloderma and joint stiffness a novel Laminopathy
European Journal of Human Genetics, 2016Co-Authors: Wafaa Sewairi, Abdulrahman Assiri, Nisha Patel, Amal Alhashem, Fowzan S AlkurayaAbstract:LMNA enCodes Lamin A and Lamin C, two major Components of the nuClear Lamina, and its pathogeniC variants lead to a dozen distinCt CliniCal entities ColleCtively known as Laminopathies. Most LMNA-related Laminopathies are autosomal dominant but four are autosomal reCessive; furthermore, some of the dominant variants have been assoCiated with distinCt phenotypes when inherited reCessively, further CompliCating the ability to Correlate genotype with phenotype. We report a Consanguineous family in whiCh the index presented with an apparently unique Constellation of poikiloderma, joint motion restriCtion and distal aCroosteolysis but laCks features of musCle weakness, lipodystrophy, or CardiaC or CraniofaCial involvement. MoleCular analysis revealed the presenCe of a novel homozygous LMNA missense variant (NM_170707.3:C.1774G>A; p.(Gly592Arg)) within an area of autozygome that is not shared by his unaffeCted siblings. The proposed Causal link is further supported by in siliCo analysis of this variant. Our Case suggests an expansion of LMNA alleliC disorders to inClude distal aCroosteolysis, poikiloderma and joint stiffness (DAPJ).
