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Young Ho Koh - One of the best experts on this subject based on the ideXlab platform.
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The pAthogenic humAn Torsin A in DrosophilA ActivAtes the unfolded protein response And increAses susceptibility to oxidAtive stress.
BMC genomics, 2015Co-Authors: A-young Kim, Jong Bok Seo, Won-tae Kim, Hee Jeong Choi, Soo-young Kim, Genevieve Morrow, Robert M Tanguay, Hermann Steller, Young Ho KohAbstract:DystoniA1 (DYT1) dystoniA is cAused by A glutAmic Acid deletion (ΔE) mutAtion in the gene encoding Torsin A in humAns (HTorA). To investigAte the unknown moleculAr And cellulAr mechAnisms underlying DYT1 dystoniA, we performed An unbiAsed proteomic AnAlysis. We found thAt the Amount of proteins And trAnscripts of An EndoplAsmic reticulum (ER) resident chAperone HeAt shock protein cognAte 3 (HSC3) And A mitochondriA chAperone HeAt Shock Protein 22 (HSP22) were significAntly increAsed in the HTorAΔE– expressing brAins compAred to the normAl HTorA (HTorAWT) expressing brAins. The physiologicAl consequences included An increAsed susceptibility to oxidAtive And ER stress compAred to normAl HTorAWT flies. The AlterAtion of trAnscripts of Inositol-requiring enzyme-1 (IRE1)-dependent spliced X box binding protein 1(Xbp1), severAl ER chAperones, A nucleotide exchAnge fActor, AutophAgy relAted protein 8b (ATG8b) And components of the ER AssociAted degrAdAtion (ERAD) pAthwAy And increAsed expression of the Xbp1-enhAnced Green Fluorescence Protein (eGFP) in HTorAΔE brAins strongly indicAted the ActivAtion of the unfolded protein response (UPR). In Addition, perturbed expression of the UPR sensors And inducers in the HTorAΔE DrosophilA brAins resulted in A significAntly reduced life spAn of the flies. Furthermore, the types And quAntities of proteins present in the Anti-HSC3 positive microsomes in the HTorAΔE brAins were different from those of the HTorAWT brAins. TAken together, these dAtA show thAt HTorAΔE in DrosophilA brAins mAy ActivAte the UPR And increAse the expression of HSP22 to compensAte for the toxic effects cAused by HTorAΔE in the brAins.
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The pAthogenic humAn Torsin A in DrosophilA ActivAtes the unfolded protein response And increAses susceptibility to oxidAtive stress
BMC Genomics, 2015Co-Authors: A-young Kim, Jong Bok Seo, Won-tae Kim, Hee Jeong Choi, Soo-young Kim, Genevieve Morrow, Robert M Tanguay, Hermann Steller, Young Ho KohAbstract:BAckground DystoniA1 (DYT1) dystoniA is cAused by A glutAmic Acid deletion (ΔE) mutAtion in the gene encoding Torsin A in humAns (HTorA). To investigAte the unknown moleculAr And cellulAr mechAnisms underlying DYT1 dystoniA, we performed An unbiAsed proteomic AnAlysis. Results We found thAt the Amount of proteins And trAnscripts of An EndoplAsmic reticulum (ER) resident chAperone HeAt shock protein cognAte 3 (HSC3) And A mitochondriA chAperone HeAt Shock Protein 22 (HSP22) were significAntly increAsed in the HTorA^ΔE– expressing brAins compAred to the normAl HTorA (HTorA^WT) expressing brAins. The physiologicAl consequences included An increAsed susceptibility to oxidAtive And ER stress compAred to normAl HTorA^WT flies. The AlterAtion of trAnscripts of Inositol-requiring enzyme-1 (IRE1)-dependent spliced X box binding protein 1(Xbp1), severAl ER chAperones, A nucleotide exchAnge fActor, AutophAgy relAted protein 8b (ATG8b) And components of the ER AssociAted degrAdAtion (ERAD) pAthwAy And increAsed expression of the Xbp1-enhAnced Green Fluorescence Protein (eGFP) in HTorA^ΔE brAins strongly indicAted the ActivAtion of the unfolded protein response (UPR). In Addition, perturbed expression of the UPR sensors And inducers in the HTorA^ΔE DrosophilA brAins resulted in A significAntly reduced life spAn of the flies. Furthermore, the types And quAntities of proteins present in the Anti-HSC3 positive microsomes in the HTorA^ΔE brAins were different from those of the HTorA^WT brAins. Conclusion TAken together, these dAtA show thAt HTorA^ΔE in DrosophilA brAins mAy ActivAte the UPR And increAse the expression of HSP22 to compensAte for the toxic effects cAused by HTorA^ΔE in the brAins.
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DeltAFY mutAtion in humAn Torsin A [corrected] induces locomotor disAbility And AbberAnt synAptic structures in DrosophilA.
Molecules and cells, 2009Co-Authors: Dae-weon Lee, Jong Bok Seo, Barry Ganetzky, Young Ho KohAbstract:We investigAte the moleculAr And cellulAr etiologies thAt underlie the deletion of the six Amino Acid residues (DeltAF323-Y328; DeltAFY) in humAn Torsin A (HtorA). The most common And severe mutAtion involved with eArly-onset torsion dystoniA is A glutAmic Acid deletion (DeltAE 302/303; DeltAE) in HtorA which induces protein AggregAtes in neurons And cells. Even though DeltAFY HtorA forms no protein clusters, flies expressing DeltAFY HtorA in neurons or muscles mAnifested A similAr but delAyed onset of Adult locomotor disAbility compAred with flies expressing DeltAE in HtorA. In Addition, flies expressing DeltAFY HtorA hAd fewer AberrAnt ultrAstructures At synApses compAred with flies expressing DeltAE HtorA. TAken together, the DeltAFY mutAtion in HtorA mAy be responsible for behAviorAl And AnAtomicAl AberrAtions in gDrosophilA.
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ΔFY mutAtion in humAn TorsinA induces locomotor disAbility And AbberAnt synAptic structures in DrosophilA
Molecules and Cells, 2009Co-Authors: Dae-weon Lee, Jong Bok Seo, Barry Ganetzky, Young Ho KohAbstract:We investigAte the moleculAr And cellulAr etiologies thAt underlie the deletion of the six Amino Acid residues (ΔF323-Y328; ΔFY) in humAn Torsin A (HtorA). The most common And severe mutAtion involved with eArly-onset torsion dystoniA is A glutAmic Acid deletion (ΔE 302/303; ΔE) in HtorA which induces protein AggregAtes in neurons And cells. Even though ΔFY HtorA forms no protein clusters, flies expressing ΔFY HtorA in neurons or muscles mAnifested A similAr but delAyed onset of Adult locomotor disAbility compAred with flies expressing ΔE in HtorA. In Addition, flies expressing ΔFY HtorA hAd fewer AberrAnt ultrAstructures At synApses compAred with flies expressing ΔE HtorA. TAken together, the ΔFY mutAtion in HtorA mAy be responsible for behAviorAl And AnAtomicAl AberrAtions in gDrosophilA .
Jong Bok Seo - One of the best experts on this subject based on the ideXlab platform.
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The pAthogenic humAn Torsin A in DrosophilA ActivAtes the unfolded protein response And increAses susceptibility to oxidAtive stress.
BMC genomics, 2015Co-Authors: A-young Kim, Jong Bok Seo, Won-tae Kim, Hee Jeong Choi, Soo-young Kim, Genevieve Morrow, Robert M Tanguay, Hermann Steller, Young Ho KohAbstract:DystoniA1 (DYT1) dystoniA is cAused by A glutAmic Acid deletion (ΔE) mutAtion in the gene encoding Torsin A in humAns (HTorA). To investigAte the unknown moleculAr And cellulAr mechAnisms underlying DYT1 dystoniA, we performed An unbiAsed proteomic AnAlysis. We found thAt the Amount of proteins And trAnscripts of An EndoplAsmic reticulum (ER) resident chAperone HeAt shock protein cognAte 3 (HSC3) And A mitochondriA chAperone HeAt Shock Protein 22 (HSP22) were significAntly increAsed in the HTorAΔE– expressing brAins compAred to the normAl HTorA (HTorAWT) expressing brAins. The physiologicAl consequences included An increAsed susceptibility to oxidAtive And ER stress compAred to normAl HTorAWT flies. The AlterAtion of trAnscripts of Inositol-requiring enzyme-1 (IRE1)-dependent spliced X box binding protein 1(Xbp1), severAl ER chAperones, A nucleotide exchAnge fActor, AutophAgy relAted protein 8b (ATG8b) And components of the ER AssociAted degrAdAtion (ERAD) pAthwAy And increAsed expression of the Xbp1-enhAnced Green Fluorescence Protein (eGFP) in HTorAΔE brAins strongly indicAted the ActivAtion of the unfolded protein response (UPR). In Addition, perturbed expression of the UPR sensors And inducers in the HTorAΔE DrosophilA brAins resulted in A significAntly reduced life spAn of the flies. Furthermore, the types And quAntities of proteins present in the Anti-HSC3 positive microsomes in the HTorAΔE brAins were different from those of the HTorAWT brAins. TAken together, these dAtA show thAt HTorAΔE in DrosophilA brAins mAy ActivAte the UPR And increAse the expression of HSP22 to compensAte for the toxic effects cAused by HTorAΔE in the brAins.
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The pAthogenic humAn Torsin A in DrosophilA ActivAtes the unfolded protein response And increAses susceptibility to oxidAtive stress
BMC Genomics, 2015Co-Authors: A-young Kim, Jong Bok Seo, Won-tae Kim, Hee Jeong Choi, Soo-young Kim, Genevieve Morrow, Robert M Tanguay, Hermann Steller, Young Ho KohAbstract:BAckground DystoniA1 (DYT1) dystoniA is cAused by A glutAmic Acid deletion (ΔE) mutAtion in the gene encoding Torsin A in humAns (HTorA). To investigAte the unknown moleculAr And cellulAr mechAnisms underlying DYT1 dystoniA, we performed An unbiAsed proteomic AnAlysis. Results We found thAt the Amount of proteins And trAnscripts of An EndoplAsmic reticulum (ER) resident chAperone HeAt shock protein cognAte 3 (HSC3) And A mitochondriA chAperone HeAt Shock Protein 22 (HSP22) were significAntly increAsed in the HTorA^ΔE– expressing brAins compAred to the normAl HTorA (HTorA^WT) expressing brAins. The physiologicAl consequences included An increAsed susceptibility to oxidAtive And ER stress compAred to normAl HTorA^WT flies. The AlterAtion of trAnscripts of Inositol-requiring enzyme-1 (IRE1)-dependent spliced X box binding protein 1(Xbp1), severAl ER chAperones, A nucleotide exchAnge fActor, AutophAgy relAted protein 8b (ATG8b) And components of the ER AssociAted degrAdAtion (ERAD) pAthwAy And increAsed expression of the Xbp1-enhAnced Green Fluorescence Protein (eGFP) in HTorA^ΔE brAins strongly indicAted the ActivAtion of the unfolded protein response (UPR). In Addition, perturbed expression of the UPR sensors And inducers in the HTorA^ΔE DrosophilA brAins resulted in A significAntly reduced life spAn of the flies. Furthermore, the types And quAntities of proteins present in the Anti-HSC3 positive microsomes in the HTorA^ΔE brAins were different from those of the HTorA^WT brAins. Conclusion TAken together, these dAtA show thAt HTorA^ΔE in DrosophilA brAins mAy ActivAte the UPR And increAse the expression of HSP22 to compensAte for the toxic effects cAused by HTorA^ΔE in the brAins.
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DeltAFY mutAtion in humAn Torsin A [corrected] induces locomotor disAbility And AbberAnt synAptic structures in DrosophilA.
Molecules and cells, 2009Co-Authors: Dae-weon Lee, Jong Bok Seo, Barry Ganetzky, Young Ho KohAbstract:We investigAte the moleculAr And cellulAr etiologies thAt underlie the deletion of the six Amino Acid residues (DeltAF323-Y328; DeltAFY) in humAn Torsin A (HtorA). The most common And severe mutAtion involved with eArly-onset torsion dystoniA is A glutAmic Acid deletion (DeltAE 302/303; DeltAE) in HtorA which induces protein AggregAtes in neurons And cells. Even though DeltAFY HtorA forms no protein clusters, flies expressing DeltAFY HtorA in neurons or muscles mAnifested A similAr but delAyed onset of Adult locomotor disAbility compAred with flies expressing DeltAE in HtorA. In Addition, flies expressing DeltAFY HtorA hAd fewer AberrAnt ultrAstructures At synApses compAred with flies expressing DeltAE HtorA. TAken together, the DeltAFY mutAtion in HtorA mAy be responsible for behAviorAl And AnAtomicAl AberrAtions in gDrosophilA.
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ΔFY mutAtion in humAn TorsinA induces locomotor disAbility And AbberAnt synAptic structures in DrosophilA
Molecules and Cells, 2009Co-Authors: Dae-weon Lee, Jong Bok Seo, Barry Ganetzky, Young Ho KohAbstract:We investigAte the moleculAr And cellulAr etiologies thAt underlie the deletion of the six Amino Acid residues (ΔF323-Y328; ΔFY) in humAn Torsin A (HtorA). The most common And severe mutAtion involved with eArly-onset torsion dystoniA is A glutAmic Acid deletion (ΔE 302/303; ΔE) in HtorA which induces protein AggregAtes in neurons And cells. Even though ΔFY HtorA forms no protein clusters, flies expressing ΔFY HtorA in neurons or muscles mAnifested A similAr but delAyed onset of Adult locomotor disAbility compAred with flies expressing ΔE in HtorA. In Addition, flies expressing ΔFY HtorA hAd fewer AberrAnt ultrAstructures At synApses compAred with flies expressing ΔE HtorA. TAken together, the ΔFY mutAtion in HtorA mAy be responsible for behAviorAl And AnAtomicAl AberrAtions in gDrosophilA .
Yu Tang - One of the best experts on this subject based on the ideXlab platform.
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GenerAtion of pAtient-specific induced pluripotent stem cell line (CSUi002-A) from A pAtient with isolAted dystoniA cArrying TOR1A mutAtion.
Stem cell research, 2021Co-Authors: Jie Ren, Hui Luo, Xiaoxia Zuo, Yu TangAbstract:EArly onset isolAted dystoniA (DYT1) is A hereditAry neurologicAl movement diseAse cAused by A single Amino-Acid deletion in Torsin A (TOR1A), A gene encoding A membrAne-embedded ATPAse. In this study, we generAted An induced pluripotent stem cell (iPSC) line from fibroblAsts of A DYT1 pAtient by the retrovirAl trAnsduction of YAmAnAkA fActors. The iPSCs retAined the heterozygous TOR1A mutAtion (p.Glu303del), showed A normAl kAryotype, expressed pluripotency mArkers And exhibited the potentiAl to differentiAte into three germ lAyers both in vitro And in vivo. This DYT1 pAtient-specific iPSC will be used for modeling the dystoniA pAthophysiology And probAbly drug screening.
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DiseAse modeling with humAn neurons reveAls LMNB1 dysregulAtion underlying DYT1 dystoniA.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2021Co-Authors: Baojin Ding, Yu Tang, Masuma Akter, Meng Lu Liu, Tong Zang, Chun Li ZhangAbstract:DYT1 dystoniA is A hereditAry neurologic movement disorder chArActerized by uncontrollAble muscle contrActions. It is cAused by A heterozygous mutAtion in Torsin A (TOR1A), A gene encoding A membrAne-embedded ATPAse. While AnimAl models provide insights into diseAse mechAnisms, significAnt species-dependent differences exist since AnimAls with the identicAl heterozygous mutAtion fAil to show pAthology. Here, we model DYT1 by using humAn pAtient-specific cholinergic motor neurons (MNs) thAt Are generAted through either direct conversion of pAtients' skin fibroblAsts or differentiAtion of induced pluripotent stem cells (iPSCs). These humAn MNs with the heterozygous TOR1A mutAtion show reduced neurite length And brAnches, mArkedly thickened nucleAr lAminA, disrupted nucleAr morphology, And impAired nucleocytoplAsmic trAnsport (NCT) of mRNAs And proteins, whereAs they lAck the perinucleAr "blebs" thAt Are often observed in AnimAl models. Furthermore, we uncover thAt the nucleAr lAminA protein LMNB1 is upregulAted in DYT1 cells And exhibits AbnormAl subcellulAr distribution in A cholinergic MNs-specific mAnner. Such dysregulAtion of LMNB1 cAn be recApitulAted by either ectopic expression of the mutAnt TOR1A gene or shRNA-mediAted downregulAtion of endogenous TOR1A in heAlthy control MNs. Interestingly, downregulAtion of LMNB1 cAn lArgely AmeliorAte All the cellulAr defects in DYT1 MNs. These results reveAl the vAlue of diseAse modeling with humAn pAtient-specific neurons And indicAte thAt dysregulAtion of LMNB1, A cruciAl component of the nucleAr lAminA, mAy constitute A mAjor moleculAr mechAnism underlying DYT1 pAthology.SIGNIFICANCE STATEMENT InAccessibility to pAtient neurons greAtly impedes our understAnding of the pAthologic mechAnisms for dystoniA. In this study, we employ reprogrAmmed humAn pAtient-specific motor neurons (MNs) to model DYT1, the most severe hereditAry form of dystoniA. Our results reveAl diseAse-dependent deficits in nucleAr morphology And nucleocytoplAsmic trAnsport (NCT). Most importAntly, we further identify LMNB1 dysregulAtion As A mAjor contributor to these deficits, uncovering A new pAthologic mechAnism for DYT1 dystoniA.
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DiseAse modeling with humAn neurons reveAls LMNB1 dysregulAtion underlying DYT1 dystoniA
2020Co-Authors: Baojin Ding, Yu Tang, Masuma Akter, Meng Lu Liu, Tong Zang, Chun Li ZhangAbstract:AbstrAct DYT1 dystoniA is A hereditAry neurologicAl diseAse cAused by A heterozygous mutAtion in Torsin A (TOR1A). While AnimAl models provide insights into diseAse mechAnisms, significAnt species-dependent differences exist since mice with the identicAl heterozygous mutAtion fAil to show pAthology. Here, we model DYT1 by using humAn pAtient-derived motor neurons. These neurons with the heterozygous TOR1A mutAtion show mArkedly thickened nucleAr lAminA, disrupted nucleAr morphology, And impAired nucleocytoplAsmic trAnsport, whereAs they lAck the perinucleAr “blebs” thAt Are often observed in AnimAl models. ImportAntly, we further uncover thAt the nucleAr lAminA protein LMNB1 is specificAlly dysregulAted in expression And subcellulAr locAlizAtion. LMNB1 downregulAtion cAn lArgely AmeliorAte All the cellulAr defects in DYT1 motor neurons. These results reveAl the vAlue of diseAse modeling with humAn neurons And provide novel moleculAr mechAnisms underlying DYT1 dystoniA And potentiAlly other neurologicAl diseAses with impAired nucleocytoplAsmic trAnsport.
A-young Kim - One of the best experts on this subject based on the ideXlab platform.
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The pAthogenic humAn Torsin A in DrosophilA ActivAtes the unfolded protein response And increAses susceptibility to oxidAtive stress
BMC Genomics, 2015Co-Authors: A-young Kim, Jong Bok Seo, Won-tae Kim, Hee Jeong Choi, Soo-young Kim, Genevieve Morrow, Robert M Tanguay, Hermann Steller, Young Ho KohAbstract:BAckground DystoniA1 (DYT1) dystoniA is cAused by A glutAmic Acid deletion (ΔE) mutAtion in the gene encoding Torsin A in humAns (HTorA). To investigAte the unknown moleculAr And cellulAr mechAnisms underlying DYT1 dystoniA, we performed An unbiAsed proteomic AnAlysis. Results We found thAt the Amount of proteins And trAnscripts of An EndoplAsmic reticulum (ER) resident chAperone HeAt shock protein cognAte 3 (HSC3) And A mitochondriA chAperone HeAt Shock Protein 22 (HSP22) were significAntly increAsed in the HTorA^ΔE– expressing brAins compAred to the normAl HTorA (HTorA^WT) expressing brAins. The physiologicAl consequences included An increAsed susceptibility to oxidAtive And ER stress compAred to normAl HTorA^WT flies. The AlterAtion of trAnscripts of Inositol-requiring enzyme-1 (IRE1)-dependent spliced X box binding protein 1(Xbp1), severAl ER chAperones, A nucleotide exchAnge fActor, AutophAgy relAted protein 8b (ATG8b) And components of the ER AssociAted degrAdAtion (ERAD) pAthwAy And increAsed expression of the Xbp1-enhAnced Green Fluorescence Protein (eGFP) in HTorA^ΔE brAins strongly indicAted the ActivAtion of the unfolded protein response (UPR). In Addition, perturbed expression of the UPR sensors And inducers in the HTorA^ΔE DrosophilA brAins resulted in A significAntly reduced life spAn of the flies. Furthermore, the types And quAntities of proteins present in the Anti-HSC3 positive microsomes in the HTorA^ΔE brAins were different from those of the HTorA^WT brAins. Conclusion TAken together, these dAtA show thAt HTorA^ΔE in DrosophilA brAins mAy ActivAte the UPR And increAse the expression of HSP22 to compensAte for the toxic effects cAused by HTorA^ΔE in the brAins.
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The pAthogenic humAn Torsin A in DrosophilA ActivAtes the unfolded protein response And increAses susceptibility to oxidAtive stress.
BMC genomics, 2015Co-Authors: A-young Kim, Jong Bok Seo, Won-tae Kim, Hee Jeong Choi, Soo-young Kim, Genevieve Morrow, Robert M Tanguay, Hermann Steller, Young Ho KohAbstract:DystoniA1 (DYT1) dystoniA is cAused by A glutAmic Acid deletion (ΔE) mutAtion in the gene encoding Torsin A in humAns (HTorA). To investigAte the unknown moleculAr And cellulAr mechAnisms underlying DYT1 dystoniA, we performed An unbiAsed proteomic AnAlysis. We found thAt the Amount of proteins And trAnscripts of An EndoplAsmic reticulum (ER) resident chAperone HeAt shock protein cognAte 3 (HSC3) And A mitochondriA chAperone HeAt Shock Protein 22 (HSP22) were significAntly increAsed in the HTorAΔE– expressing brAins compAred to the normAl HTorA (HTorAWT) expressing brAins. The physiologicAl consequences included An increAsed susceptibility to oxidAtive And ER stress compAred to normAl HTorAWT flies. The AlterAtion of trAnscripts of Inositol-requiring enzyme-1 (IRE1)-dependent spliced X box binding protein 1(Xbp1), severAl ER chAperones, A nucleotide exchAnge fActor, AutophAgy relAted protein 8b (ATG8b) And components of the ER AssociAted degrAdAtion (ERAD) pAthwAy And increAsed expression of the Xbp1-enhAnced Green Fluorescence Protein (eGFP) in HTorAΔE brAins strongly indicAted the ActivAtion of the unfolded protein response (UPR). In Addition, perturbed expression of the UPR sensors And inducers in the HTorAΔE DrosophilA brAins resulted in A significAntly reduced life spAn of the flies. Furthermore, the types And quAntities of proteins present in the Anti-HSC3 positive microsomes in the HTorAΔE brAins were different from those of the HTorAWT brAins. TAken together, these dAtA show thAt HTorAΔE in DrosophilA brAins mAy ActivAte the UPR And increAse the expression of HSP22 to compensAte for the toxic effects cAused by HTorAΔE in the brAins.
Bertram Müller-myhsok - One of the best experts on this subject based on the ideXlab platform.
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MutAtions in the gene encoding ɛ-sArcoglycAn cAuse myoclonus–dystoniA syndrome
Nature Genetics, 2001Co-Authors: Alexander Zimprich, Friedrich Asmus, Monika Grabowski, Markus Naumann, Daniela Berg, M. Bertram, Karl Scheidtmann, Peter Kern, Juliane Winkelmann, Bertram Müller-myhsokAbstract:The dystoniAs Are A common clinicAlly And geneticAlly heterogeneous group of movement disorders. More thAn ten loci for inherited forms of dystoniA hAve been mApped, but only three mutAted genes hAve been identified so fAr. These Are DYT1 , encoding Torsin A^ 1 And mutAnt in the eArly-onset generAlized form, GCH1 (formerly known As DYT5 ), encoding GTP–cyclohydrolAse I And mutAnt in dominAnt dopA-responsive dystoniA^ 2 , And TH , encoding tyrosine hydroxylAse And mutAnt in the recessive form of the diseAse^ 3 . Myoclonus–dystoniA syndrome (MDS; DYT11 ) is An AutosomAl dominAnt disorder chArActerized by bilAterAl, Alcohol-sensitive myoclonic jerks involving mAinly the Arms And AxiAl muscles^ 4 , 5 . DystoniA, usuAlly torticollis And/or writer's crAmp, occurs in most but not All Affected pAtients And mAy occAsionAlly be the only symptom of the diseAse^ 6 , 7 . In Addition, pAtients often show prominent psychiAtric AbnormAlities, including pAnic AttAcks And obsessive–compulsive behAvior^ 8 , 9 , 10 . In most MDS fAmilies, the diseAse is linked to A locus on chromosome 7q21 (refs. 11 – 13 ). Using A positionAl cloning ApproAch, we hAve identified five different heterozygous loss-of-function mutAtions in the gene for ɛ-sArcoglycAn ( SGCE ), which we mApped to A refined criticAl region of About 3.2 Mb. SGCE is expressed in All brAin regions exAmined. Pedigree AnAlysis shows A mArked difference in penetrAnce depending on the pArentAl origin of the diseAse Allele. This is indicAtive of A mAternAl imprinting mechAnism, which hAs been demonstrAted in the mouse ɛ-sArcoglycAn gene^ 14 .
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MutAtions in the gene encoding ε-sArcoglycAn cAuse myoclonus-dystoniA syndrome
Nature genetics, 2001Co-Authors: Alexander Zimprich, Friedrich Asmus, Monika Grabowski, Markus Naumann, Daniela Berg, M. Bertram, Karl Scheidtmann, Peter Kern, Juliane Winkelmann, Bertram Müller-myhsokAbstract:The dystoniAs Are A common clinicAlly And geneticAlly heterogeneous group of movement disorders. More thAn ten loci for inherited forms of dystoniA hAve been mApped, but only three mutAted genes hAve been identified so fAr. These Are DYT1, encoding Torsin A And mutAnt in the eArly-onset generAlized form, GCH1 (formerly known As DYT5), encoding GTP-cyclohydrolAse I And mutAnt in dominAnt dopA-responsive dystoniA, And TH, encoding tyrosine hydroxylAse And mutAnt in the recessive form of the diseAse. Myoclonus-dystoniA syndrome (MDS; DYT11) is An AutosomAl dominAnt disorder chArActerized by bilAterAl, Alcohol-sensitive myoclonic jerks involving mAinly the Arms And AxiAl muscles. DystoniA, usuAlly torticollis And/or writer's crAmp, occurs in most but not All Affected pAtients And mAy occAsionAlly be the only symptom of the diseAse. In Addition, pAtients often show prominent psychiAtric AbnormAlities, including pAnic AttAcks And obsessive-compulsive behAvior. In most MDS fAmilies, the diseAse is linked to A locus on chromosome 7q21 (refs. 11-13). Using A positionAl cloning ApproAch, we hAve identified five different heterozygous loss-of-function mutAtions in the gene for epsilon-sArcoglycAn (SGCE), which we mApped to A refined criticAl region of About 3.2 Mb. SGCE is expressed in All brAin regions exAmined. Pedigree AnAlysis shows A mArked difference in penetrAnce depending on the pArentAl origin of the diseAse Allele. This is indicAtive of A mAternAl imprinting mechAnism, which hAs been demonstrAted in the mouse epsilon-sArcoglycAn gene.