메뉴 건너뛰기




Volumn 3, Issue C, 1999, Pages 81-92

Chapter 3 The Genetic Basis and Molecular Pathogenesis of Huntington's Disease

Author keywords

[No Author keywords available]

Indexed keywords


EID: 0004876014     PISSN: 15663124     EISSN: None     Source Type: Book Series    
DOI: 10.1016/S1566-3124(08)60023-1     Document Type: Article
Times cited : (1)

References (73)
  • 1
    • 0030444263 scopus 로고    scopus 로고
    • Molecular detection of new mutations, resolution of ambiguous results and complex genetic counseling issues in Huntington disease
    • Alford R.L., Ashizawa T., Jankovic J., Caskey C.T., and Richards C.S. Molecular detection of new mutations, resolution of ambiguous results and complex genetic counseling issues in Huntington disease. Am. J. Med. Genet. 66 (1996) 281-286
    • (1996) Am. J. Med. Genet. , vol.66 , pp. 281-286
    • Alford, R.L.1    Ashizawa, T.2    Jankovic, J.3    Caskey, C.T.4    Richards, C.S.5
  • 2
    • 0028785593 scopus 로고
    • Origins and evolution of Huntington disease chromosomes
    • Andrew S.E., and Hayden M.R. Origins and evolution of Huntington disease chromosomes. Neurodegeneration 4 (1995) 239-244
    • (1995) Neurodegeneration , vol.4 , pp. 239-244
    • Andrew, S.E.1    Hayden, M.R.2
  • 4
    • 0026584524 scopus 로고
    • Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illnesses? Ann
    • Beal M.F. Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illnesses? Ann. Neurol. 31 (1992) 119-130
    • (1992) Neurol. , vol.31 , pp. 119-130
    • Beal, M.F.1
  • 5
    • 0028214436 scopus 로고
    • Huntington's disease, energy, and excitotoxicity
    • Beal M.F. Huntington's disease, energy, and excitotoxicity. Neurobiol. Aging 15 (1994) 275-276
    • (1994) Neurobiol. Aging , vol.15 , pp. 275-276
    • Beal, M.F.1
  • 6
    • 0025161567 scopus 로고
    • Kynurenine pathway measurements in Huntington's disease striatum: evidence for reduced formation of kynurenic acid
    • Beal M.F., Matson W.R., Swartz K.J., Gamache P.H., and Bird E.D. Kynurenine pathway measurements in Huntington's disease striatum: evidence for reduced formation of kynurenic acid. J. Neurochem. 55 (1990) 1327-1339
    • (1990) J. Neurochem. , vol.55 , pp. 1327-1339
    • Beal, M.F.1    Matson, W.R.2    Swartz, K.J.3    Gamache, P.H.4    Bird, E.D.5
  • 7
    • 0026043565 scopus 로고
    • Chronic quinolinic acid lesions in rats closely resemble Huntington's disease
    • Beal M.F., Swartz K.J., Ferrante R.J., and Kowall N.W. Chronic quinolinic acid lesions in rats closely resemble Huntington's disease. J. Neurosci. 11 (1991) 1649-1659
    • (1991) J. Neurosci. , vol.11 , pp. 1649-1659
    • Beal, M.F.1    Swartz, K.J.2    Ferrante, R.J.3    Kowall, N.W.4
  • 8
    • 0026554440 scopus 로고
    • Kynurenic acid concentrations are reduced in Huntington's disease cerebral cortex [see comments]
    • Beal M.F., Matson W.R., Storey E., Milbury P., Ryan E.A., Ogawa T., and Bird E.D. Kynurenic acid concentrations are reduced in Huntington's disease cerebral cortex [see comments]. Neurol. Sci. 108 (1992) 80-87
    • (1992) Neurol. Sci. , vol.108 , pp. 80-87
    • Beal, M.F.1    Matson, W.R.2    Storey, E.3    Milbury, P.4    Ryan, E.A.5    Ogawa, T.6    Bird, E.D.7
  • 9
    • 0032540437 scopus 로고    scopus 로고
    • HAP1-huntingtin interactions do not contribute to the molecular pathology in Huntington's disease transgenic mice
    • Bertaux F., Sharp A.H., Ross C.A., Lehrach H., Bates G.P., and Wanker E. HAP1-huntingtin interactions do not contribute to the molecular pathology in Huntington's disease transgenic mice. FEBS Lett. 426 (1998) 229-232
    • (1998) FEBS Lett. , vol.426 , pp. 229-232
    • Bertaux, F.1    Sharp, A.H.2    Ross, C.A.3    Lehrach, H.4    Bates, G.P.5    Wanker, E.6
  • 10
    • 0023792365 scopus 로고
    • Energy metabolism in disorders of the nervous system [review]
    • Blass J.P., Sheu R.K., and Cedarbaum J.M. Energy metabolism in disorders of the nervous system [review]. Rev. Neurol. 144 (1988) 543-563
    • (1988) Rev. Neurol. , vol.144 , pp. 543-563
    • Blass, J.P.1    Sheu, R.K.2    Cedarbaum, J.M.3
  • 13
    • 0021883670 scopus 로고
    • Regional mitochondrial respiratory activity in Huntington's disease brain
    • Brennan W.A.J., Bird E.D., and Aprille J.R. Regional mitochondrial respiratory activity in Huntington's disease brain. J. Neurochem. 44 (1985) 1948-1950
    • (1985) J. Neurochem. , vol.44 , pp. 1948-1950
    • Brennan, W.A.J.1    Bird, E.D.2    Aprille, J.R.3
  • 14
    • 0029129227 scopus 로고
    • Spinal and bulbar muscular atrophy: a trinucleotide-repeat expansion neurodegenerative disease
    • Brooks B.P., and Fischbeck K.H. Spinal and bulbar muscular atrophy: a trinucleotide-repeat expansion neurodegenerative disease. Trends Neurosci. 18 (1995) 459-461
    • (1995) Trends Neurosci. , vol.18 , pp. 459-461
    • Brooks, B.P.1    Fischbeck, K.H.2
  • 15
    • 0028045985 scopus 로고
    • Systemic or local administration of azide produces striatal lesions by an energy impairment-induced excitotoxic mechanism
    • Brouillet E., Hyman B.T., Jenkins B.G., Henshaw D.R., Schulz J.B., Sodhi P., Rosen B.R., and Beal M.F. Systemic or local administration of azide produces striatal lesions by an energy impairment-induced excitotoxic mechanism. Exp. Neurol. 129 (1994) 175-182
    • (1994) Exp. Neurol. , vol.129 , pp. 175-182
    • Brouillet, E.1    Hyman, B.T.2    Jenkins, B.G.3    Henshaw, D.R.4    Schulz, J.B.5    Sodhi, P.6    Rosen, B.R.7    Beal, M.F.8
  • 16
  • 17
    • 0032925851 scopus 로고    scopus 로고
    • Food restriction reduces brain damage and improves behavioral outcome following excitotoxic and metabolic insults
    • Bruce-Keller A.J., Umberger G., McFall R., and Mattson M.P. Food restriction reduces brain damage and improves behavioral outcome following excitotoxic and metabolic insults. Ann. Neurol. 45 (1999) 8-15
    • (1999) Ann. Neurol. , vol.45 , pp. 8-15
    • Bruce-Keller, A.J.1    Umberger, G.2    McFall, R.3    Mattson, M.P.4
  • 18
    • 0025190080 scopus 로고
    • The quinolinic acid hypothesis in Huntington's chorea
    • Bruyn R.P., and Stoof J.C. The quinolinic acid hypothesis in Huntington's chorea. J. Neurol. Sci. 95 (1990) 29-38
    • (1990) J. Neurol. Sci. , vol.95 , pp. 29-38
    • Bruyn, R.P.1    Stoof, J.C.2
  • 21
    • 0017167057 scopus 로고
    • Lesions of striatal neurons with kainic acid provides an animal model for Huntington's chorea
    • Coyle J.T., and Schwarcz R. Lesions of striatal neurons with kainic acid provides an animal model for Huntington's chorea. Nature 263 (1976) 244-246
    • (1976) Nature , vol.263 , pp. 244-246
    • Coyle, J.T.1    Schwarcz, R.2
  • 23
    • 0032501740 scopus 로고    scopus 로고
    • Are neuronal intranuclear inclusions the common neuropathology of triplet-repeat disorders with polyglutamine-repeat expansions?
    • Davies S.W., Beardsall K., Turmaine M., DiFiglia M., Aronin N., and Bates G.P. Are neuronal intranuclear inclusions the common neuropathology of triplet-repeat disorders with polyglutamine-repeat expansions?. Lancet 351 (1998) 131-133
    • (1998) Lancet , vol.351 , pp. 131-133
    • Davies, S.W.1    Beardsall, K.2    Turmaine, M.3    DiFiglia, M.4    Aronin, N.5    Bates, G.P.6
  • 25
    • 0030752709 scopus 로고    scopus 로고
    • Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain
    • DiFiglia M., Sapp E., Chase K.O., Davies S.W., Bates G.P., Vonsattel J.P., and Aronin N. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277 (1997) 1990-1993
    • (1997) Science , vol.277 , pp. 1990-1993
    • DiFiglia, M.1    Sapp, E.2    Chase, K.O.3    Davies, S.W.4    Bates, G.P.5    Vonsattel, J.P.6    Aronin, N.7
  • 26
    • 2642646258 scopus 로고    scopus 로고
    • Mouse mutant embryos lacking huntingtin are rescued from lethality by wild-type extraembryonic tissues
    • Dragatsis I., and Zeitlin A. Mouse mutant embryos lacking huntingtin are rescued from lethality by wild-type extraembryonic tissues. Development 125 (1998) 1529-1539
    • (1998) Development , vol.125 , pp. 1529-1539
    • Dragatsis, I.1    Zeitlin, A.2
  • 28
    • 77956864777 scopus 로고
    • Patch-matrix distribution of cholecystokinin and cytochrome oxidase activity in normal and Huntington's disease striatum
    • Ferrante R.J., Kowall N.W., and Richardson E.P. Patch-matrix distribution of cholecystokinin and cytochrome oxidase activity in normal and Huntington's disease striatum. Soc. Neurosci. Abs. 14 (1988) 1046
    • (1988) Soc. Neurosci. Abs. , vol.14 , pp. 1046
    • Ferrante, R.J.1    Kowall, N.W.2    Richardson, E.P.3
  • 29
    • 0027396021 scopus 로고
    • Excitotoxin lesions in primates as a model for Huntington's disease: histopathologic and neurochemical characterization
    • Ferrante R.J., Kowall N.W., Cipolloni P.B., Storey E., and Beal M.F. Excitotoxin lesions in primates as a model for Huntington's disease: histopathologic and neurochemical characterization. Exp. Neurol. 119 (1993) 46-71
    • (1993) Exp. Neurol. , vol.119 , pp. 46-71
    • Ferrante, R.J.1    Kowall, N.W.2    Cipolloni, P.B.3    Storey, E.4    Beal, M.F.5
  • 31
    • 0031005815 scopus 로고    scopus 로고
    • Systemic administration of rotenone produces selective damage in the striatum and globus pallidus, but not the substsantia nigra
    • Ferrante R.J., Shulz J.B., Kowall N.W., and Beal M.F. Systemic administration of rotenone produces selective damage in the striatum and globus pallidus, but not the substsantia nigra. Brain Res. 753 (1997) 157-162
    • (1997) Brain Res. , vol.753 , pp. 157-162
    • Ferrante, R.J.1    Shulz, J.B.2    Kowall, N.W.3    Beal, M.F.4
  • 33
    • 0032522165 scopus 로고    scopus 로고
    • Tissue transglutaminase-catalyzed formation of high-molecular-weight aggregates in vitro is favored with long polyglutamine domains: a possible mechanism contributing to CAG-triplet diseases
    • Gentile V., Sepe C., Calvani M., Melone M.A., Cotrufo R., Cooper A.J., Blass J.P., and Peluso G. Tissue transglutaminase-catalyzed formation of high-molecular-weight aggregates in vitro is favored with long polyglutamine domains: a possible mechanism contributing to CAG-triplet diseases. Arch. Biochem. Biophys. 352 (1998) 314-321
    • (1998) Arch. Biochem. Biophys. , vol.352 , pp. 314-321
    • Gentile, V.1    Sepe, C.2    Calvani, M.3    Melone, M.A.4    Cotrufo, R.5    Cooper, A.J.6    Blass, J.P.7    Peluso, G.8
  • 36
    • 0029245405 scopus 로고
    • Huntington's disease [review], Sem
    • Gusella J.F., and MacDonald M.E. Huntington's disease [review], Sem. Cell Biol. 6 (1995) 21-28
    • (1995) Cell Biol. , vol.6 , pp. 21-28
    • Gusella, J.F.1    MacDonald, M.E.2
  • 39
    • 0021891869 scopus 로고
    • The mitochondrial electron transport and oxidative phosphorylation system
    • Hatefi Y. The mitochondrial electron transport and oxidative phosphorylation system. Annu. Rev. Biochem. 54 (1985) 1015-1069
    • (1985) Annu. Rev. Biochem. , vol.54 , pp. 1015-1069
    • Hatefi, Y.1
  • 41
    • 0028069665 scopus 로고
    • Muscle tone in Huntington's disease
    • Homberg V., and Huttunen J. Muscle tone in Huntington's disease. J. Neurol. Sci. 121 (1994) 147-154
    • (1994) J. Neurol. Sci. , vol.121 , pp. 147-154
    • Homberg, V.1    Huttunen, J.2
  • 43
    • 0027480960 scopus 로고
    • A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes
    • Huntington's Disease Collaborative Research Group.
    • Huntington's Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 72 (1993) 971-983
    • (1993) Cell , vol.72 , pp. 971-983
  • 44
    • 0027741301 scopus 로고
    • Evidence for impairment of energy metabolism in vivo in Huntington's disease using localized 1H NMR spectroscopy
    • Jenkins B.G., Koroshetz W.J., Beal M.F., and Rosen B.R. Evidence for impairment of energy metabolism in vivo in Huntington's disease using localized 1H NMR spectroscopy. Neurology 43 (1993) 2689-2695
    • (1993) Neurology , vol.43 , pp. 2689-2695
    • Jenkins, B.G.1    Koroshetz, W.J.2    Beal, M.F.3    Rosen, B.R.4
  • 46
    • 0028807448 scopus 로고
    • Pausing of DNA synthesis in vitro at specific loci in CTG and CGG triplet repeats from human hereditary disease genes
    • Kang S., Ohshima K., Shimizu M., Amirhaeri S., and Wells R.D. Pausing of DNA synthesis in vitro at specific loci in CTG and CGG triplet repeats from human hereditary disease genes. J. Biol. Chem. 270 (1995) 27014-27021
    • (1995) J. Biol. Chem. , vol.270 , pp. 27014-27021
    • Kang, S.1    Ohshima, K.2    Shimizu, M.3    Amirhaeri, S.4    Wells, R.D.5
  • 48
    • 0023082843 scopus 로고
    • Patterns of cell loss in Huntington's disease
    • Kowall N.W., Ferrante R.J., and Martin J.B. Patterns of cell loss in Huntington's disease. TINS 10 (1987) 24-29
    • (1987) TINS , vol.10 , pp. 24-29
    • Kowall, N.W.1    Ferrante, R.J.2    Martin, J.B.3
  • 49
    • 0028080406 scopus 로고
    • Trinucleotide repeat expansion in neurological disease
    • La Spada A.R., Paulson H.L., and Fischbeck K.H. Trinucleotide repeat expansion in neurological disease. Ann. Neurol. 36 (1994) 814-822
    • (1994) Ann. Neurol. , vol.36 , pp. 814-822
    • La Spada, A.R.1    Paulson, H.L.2    Fischbeck, K.H.3
  • 50
    • 0025936841 scopus 로고
    • Leber's hereditary optic neuropathy and Complex I deficiency in muscle
    • Larsson N.-G., Andersen O., Home E., Oldfors A., and Wahlstrom J. Leber's hereditary optic neuropathy and Complex I deficiency in muscle. Ann. Neurol 30 (1991) 701-708
    • (1991) Ann. Neurol , vol.30 , pp. 701-708
    • Larsson, N.-G.1    Andersen, O.2    Home, E.3    Oldfors, A.4    Wahlstrom, J.5
  • 51
    • 0032524312 scopus 로고    scopus 로고
    • Distinct nuclear localization and activity of tissue transglutaminase
    • Lesort M., Attanavanich K., Zhang J., and Johnson G.V. Distinct nuclear localization and activity of tissue transglutaminase. J. Biol. Chem. 273 (1998) 11991-11994
    • (1998) J. Biol. Chem. , vol.273 , pp. 11991-11994
    • Lesort, M.1    Attanavanich, K.2    Zhang, J.3    Johnson, G.V.4
  • 53
    • 0024541837 scopus 로고
    • Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases
    • Linnane A.W., Marzuki S., Ozawa T., and Tanaka M. Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases. Lancet 1 (1989) 642-645
    • (1989) Lancet , vol.1 , pp. 642-645
    • Linnane, A.W.1    Marzuki, S.2    Ozawa, T.3    Tanaka, M.4
  • 56
    • 0017090806 scopus 로고
    • Duplication of biochemical changes of Huntington's chorea by intrastriatal injections of glutamic and kainic acid
    • McGeer E.G., and McGeer P.L. Duplication of biochemical changes of Huntington's chorea by intrastriatal injections of glutamic and kainic acid. Nature 263 (1976) 517-519
    • (1976) Nature , vol.263 , pp. 517-519
    • McGeer, E.G.1    McGeer, P.L.2
  • 57
    • 0032522281 scopus 로고    scopus 로고
    • Mismatched nucleotides may facilitate expansion of trinucleotide repeats in genetic diseases
    • Nakayabu M., Miwa S., Suzuki M., Izuta S., Sobue G., and Yoshida S. Mismatched nucleotides may facilitate expansion of trinucleotide repeats in genetic diseases. Nucleic Acids Res. 26 (1998) 1980-1984
    • (1998) Nucleic Acids Res. , vol.26 , pp. 1980-1984
    • Nakayabu, M.1    Miwa, S.2    Suzuki, M.3    Izuta, S.4    Sobue, G.5    Yoshida, S.6
  • 58
    • 0025087726 scopus 로고
    • Evidence for a defect in NADH: ubiquinone oxidoreductase (complex I) in Huntington's diseases
    • Parker W.D.J., Boyson S.J., Luder A.S., and Parks J.K. Evidence for a defect in NADH: ubiquinone oxidoreductase (complex I) in Huntington's diseases. Neurology 40 (1990) 1231-1234
    • (1990) Neurology , vol.40 , pp. 1231-1234
    • Parker, W.D.J.1    Boyson, S.J.2    Luder, A.S.3    Parks, J.K.4
  • 59
    • 0026783169 scopus 로고
    • Increased brain concentrations of a neurotoxin, 3-hydroxykynurenine, in Huntington's disease
    • Pearson S.J., and Reynolds G.P. Increased brain concentrations of a neurotoxin, 3-hydroxykynurenine, in Huntington's disease. Neurosci. Lett. 144 (1992) 199-201
    • (1992) Neurosci. Lett. , vol.144 , pp. 199-201
    • Pearson, S.J.1    Reynolds, G.P.2
  • 60
    • 0028309533 scopus 로고
    • Genes with triplet repeats: a new class of mutations causing neurological diseases
    • Plassart E., and Fontaine B. Genes with triplet repeats: a new class of mutations causing neurological diseases. Biomed. Pharmacother. 48 (1994) 191-197
    • (1994) Biomed. Pharmacother. , vol.48 , pp. 191-197
    • Plassart, E.1    Fontaine, B.2
  • 61
    • 0031446233 scopus 로고    scopus 로고
    • Intranuclear neuronal inclusions: a common pathogenic mechanism for glutamine-repeat neurodegenerative diseases?
    • Ross C.A. Intranuclear neuronal inclusions: a common pathogenic mechanism for glutamine-repeat neurodegenerative diseases?. Neuron 19 (1997) 1147-1150
    • (1997) Neuron , vol.19 , pp. 1147-1150
    • Ross, C.A.1
  • 64
    • 0032052003 scopus 로고    scopus 로고
    • Huntingtin protein colocalizes with lesions of neurodegenerative diseases: an investigation in Huntington's, Alzheimer's, and Pick's diseases
    • Singhrao S.K., Thomas P., Wood J.D., MacMillan J.C., Neal J.W., Harper P.S., and Jones A.L. Huntingtin protein colocalizes with lesions of neurodegenerative diseases: an investigation in Huntington's, Alzheimer's, and Pick's diseases. Exp. Neurol. 150 (1998) 213-222
    • (1998) Exp. Neurol. , vol.150 , pp. 213-222
    • Singhrao, S.K.1    Thomas, P.2    Wood, J.D.3    MacMillan, J.C.4    Neal, J.W.5    Harper, P.S.6    Jones, A.L.7
  • 65
    • 0029066045 scopus 로고
    • Effects of striatal excitotoxicity on huntingtin-like immunoreactivity
    • Tatter S.B., Galpern W.R., Hoogeveen A.T., and Isacson O. Effects of striatal excitotoxicity on huntingtin-like immunoreactivity. Neuroreport 6 (1995) 1125-1129
    • (1995) Neuroreport , vol.6 , pp. 1125-1129
    • Tatter, S.B.1    Galpern, W.R.2    Hoogeveen, A.T.3    Isacson, O.4
  • 66
    • 0000864725 scopus 로고
    • Ultrastructural and histochemical study of cerebral biopsies in Huntington's chorea
    • Tellez-Nagel I., Johnson A.B., and Terry R.D. Ultrastructural and histochemical study of cerebral biopsies in Huntington's chorea. Adv. Neurol. 1 (1973) 387-398
    • (1973) Adv. Neurol. , vol.1 , pp. 387-398
    • Tellez-Nagel, I.1    Johnson, A.B.2    Terry, R.D.3
  • 67
    • 0023880409 scopus 로고
    • The coexistence of bradykinesia and chorea in Huntington's disease and its implications for theories of basal ganglia control of movement
    • Thompson P.D., Berardelli A., Rothwell J.C., Day B.L., Dick J.P., Benecke R., and Marsden C.D. The coexistence of bradykinesia and chorea in Huntington's disease and its implications for theories of basal ganglia control of movement. Brain 111 (1988) 223-244
    • (1988) Brain , vol.111 , pp. 223-244
    • Thompson, P.D.1    Berardelli, A.2    Rothwell, J.C.3    Day, B.L.4    Dick, J.P.5    Benecke, R.6    Marsden, C.D.7
  • 69
    • 0024580556 scopus 로고
    • Decline in skeletal muscle mitochondrial respiratory chain function: possible factor in ageing
    • Trounce I., Byrne E., and Marzuki S. Decline in skeletal muscle mitochondrial respiratory chain function: possible factor in ageing. Lancet 1 8639 (1989) 637-639
    • (1989) Lancet , vol.1 , Issue.8639 , pp. 637-639
    • Trounce, I.1    Byrne, E.2    Marzuki, S.3
  • 70
    • 0031451262 scopus 로고    scopus 로고
    • Huntington's disease gene product, huntingtin, associates with microtubules in vitro
    • Tukamoto T., Nukina N., Ide K., and Kanazawa I. Huntington's disease gene product, huntingtin, associates with microtubules in vitro. Arch. Med. Res. 28 (1997) 513-516
    • (1997) Arch. Med. Res. , vol.28 , pp. 513-516
    • Tukamoto, T.1    Nukina, N.2    Ide, K.3    Kanazawa, I.4
  • 73
    • 84993912315 scopus 로고
    • Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington's disease gene homologue
    • Zeitlin S., Liu J.P., Chapman D.L., Papaioannou V.E., and Efstratiadis A. Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington's disease gene homologue. Nat. Genet. 11 (1995) 155-163
    • (1995) Nat. Genet. , vol.11 , pp. 155-163
    • Zeitlin, S.1    Liu, J.P.2    Chapman, D.L.3    Papaioannou, V.E.4    Efstratiadis, A.5


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.