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研究生:楊孟樺
研究生(外文):Meng-Hua Yang
論文名稱:脊髓小腦萎縮症第二十二型致病基因之研究
論文名稱(外文):Screening of Spinocerebellar Ataxia 22 Candidate Genes
指導教授:鍾明怡鍾明怡引用關係
指導教授(外文):Ming-Yi Chung
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:遺傳學研究所
學門:生命科學學門
學類:生物訊息學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:中文
中文關鍵詞:脊髓小腦萎縮症
外文關鍵詞:Spinocerebellar Ataxia
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顯性小腦共濟失調是一種神經退化的遺傳疾病,現在多以脊髓小腦共濟失調(或運動失調)來命名。
24型的體染色體顯性的運動失調-包括SCA 1-8,10-19,21-23及25,齒狀紅核蒼白球肌萎縮症(Dentatorubral-Pallidoluysian Atrophy, DRPLA)和FGF14 (fibroblast growth factor 14)突變所造成的運動失調。其中12種的致病基因及突變位置已知。6種SCAs(SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17) 和DRPLA是由於其相對應基因內的CAG repeats異常擴張所造成。這種異常擴張會轉譯出多重麩胺酸長鏈,與亨丁頓舞蹈症相同;所以這類又被稱做polyglutamine expansion disorders。
除了可譯區內的CAG repeats異常擴張之外,SCA12為PPP2R2B的5’UTR內CAG repeats重複超過66次所造成。SCA10則是該基因的intron 9中的五重核苷酸過度擴張所造成。而SCA8,目前對於是否為CTG repeats不穩定且擴張所造成,仍然有爭議。
本研究重點為已經map在第一對染色體(chromosome 1q)的Spinocerebellar ataxia type 22 (SCA22)。候選範圍為D1S2721至D1S2878之間。利用生化所楊永正老師及其實驗室所研發之SCAdb,將這個範圍內的Short Tandem Repeats (STRs)作為候選基因。一共篩檢了81個STR Markers,其中52個Markers不具多型性,其餘29個Markers在人群中具多型性。
這29個具多型性的Markers中,有23個Markers因為在SCA22 Family的已發病家族成員中,至少有一個成員為heterozygote,所以可以被排除在致病基因之外。
仍有6個Markers依STR genotyping方法無法被排除,所以利用dHPLC用以偵測是否在STRs鄰近的序列或STRs內有其他變異點。依dHPLC的結果可再排除掉1個Markers。
除了STRs篩檢之外,還定序了3個與細胞膜離子通道相關的基因:KCNN3、KCNJ9以及KCNJ10。SCA22 Family已發病的的Ⅳ-1及Ⅳ-4,在這3個基因的exon及exon-intron junctions並沒有發現突變點。
另外,與SCA22位於同一區域中Familial Hemiplegic Migraine type 2(FHM2),其致病基因ATP1A2已被發表,在人類的小腦也有表現。
Autosomal dominant cerebellar ataxias are hereditary neurodegenerative disorders that are known as spinocerebellar ataxias (SCA) in genetic nomenclature.
24 autosomal dominant ataxias—SCA 1–8, 10–19, 21–23, and 25, dentatorubral-pallidoluysian atrophy (DRPLA), and ataxia caused by mutations in the gene that encodes fibroblast growth factor 14 (FGF14)—have been identified. In 12 of these disorders the genes involved and the underlying mutations are known. Six SCA subtypes (SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17) and DRPLA are caused by CAG trinucleotide repeat expansions in the respective genes. These expansions encode polyglutamine repeats, as in Huntington’s disease (HD); and these diseases are also known as polyglutamine expansion disorders.
Besides CAG repeats in the coding regions, a CAG repeat expansion of more than 66 repeats has been found in the 5’region of the PPP2R2B gene in families with SCA12. In SCA10, the functional implication of a pentanucleotide-repeat expansion in intron 9 of a gene of unknown function has not been defined in detail. For SCA8, whether an unstable and expanded CTG repeat is indeed causal or only associated with the disease is still debated.
Spinocerebellar ataxia type 22 (SCA22) had been mapped to chromosome 1q. The candidate region was defined by flanking markers D1S2721 and D1S2878. We use SCAdb which was provided by Dr. Yang to find out all the short tandem repeats in this region as the candidate genes. 81 STR Markers were screened, 52 of them are nonpolymorphic, and the other 29 of them are polymorphic in our population.
In 29 polymorphic STR markers, 23 of them can be excluded because at least one affected member in SCA22 Family can be identified as heterozygote.
The remaining 6 markers which can’t be excluded will be detected by dHPLC, to see if there are other variations in the flanking sequences or in the STRs. According to the data of dHPLC, 1 markers can be excluded because of the formation of heteroduplexes.
Besides STRs screening, the exons and exon-intron junctions of three channel-related genes were sequenced: KCNN3, KCNJ9, and KCNJ10. No mutation was found in SCA22 Family affected members Ⅳ-1and Ⅳ-4.
The Familial Hemiplegic Migraine type 2 (FHM2) disease genes, ATP1A2 was reported. And this gene is located in SCA22 region and expressed in human cerebellum.
Alonso I, Barros J, Tuna A, Coelho J, Sequeiros J, Silveira I, Coutinho P. (2003) Phenotypes of Spinocerebellar Ataxia Type 6 and Familial Hemiplegic Migraine Caused by a Unique CACNA1A Missense Mutation in Patients From a Large Family. Arch Neurol. 60: 610-614.
Andres AM, Lao O, Soldevila M, Calafell F, Bertranpetit J. (2002) Dynamics of CAG Repeat Loci Revealed by the Analysis of Their Variability. Human Mutation 21: 61-70.
Baloh RW, Yue Q, Furman JM, Nelson SF. (1997) Familial episodic ataxia: clinical heterogeneity in four families linked to chromosome 19p. Ann Neurol. 41: 8-16.
Benzow KA, Koob MD. (2002) The KLHL1-antisense transcript (KLHL1AS) is evolutionarily conserved. Mamm. Genome 13: 134-141.
Brkanac Z, Bylenok L, Fernandez M, Matsushita M, Lipe H, Wolff, J, Nochlin D, Raskind WH, Bird TD. (2000) A new dominant spinocerebellar ataxia linked to chromosome 19q13.4-qter. Arch Neurol. 59: 1291–1295.
Brook JD, McCurrach ME, Harley HG, Buckler AJ, Church D, Aburatani H, Hunter K, Stanton VP, Thirion JP, Hudson T, et al. (1992) Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3' end of a transcript encoding a protein kinase family member. Cell 68: 799–808.
Campuzano V., Montermini L., Lutz Y., et al.,Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes. (1997) Hum Mol Genet. 6: 1771–1780.
Chen DH, Brkanac Z, Verlinde CL, Tan XJ, Bylenok L, Nochlin D, Matsushita M, Lipe H, Wolff J, Fernandez M, Cimino PJ, Bird TD, Raskind WH. (2003) Missense Mutations in the regulatory domain of PKCγ: A New Mechanism for dominant nonepisodic Cerebellar Ataxia. Am. J. Hum. Genet. 72: 839–849.
Chung MY, Lu YC, Cheng NC, Soong BW. (2003) A novel autosomal dominant spinocerebellar ataxia (SCA22) linked to chromosome 1p21-q23. Brain 126; 1293-1299.
Corrine O’Sullivan Smith, Robin L. Bennett, Thomas D. Bird. (1999) Spinocerebellar Ataxia: Making an Informed Choice about Genetic Testing. http://depts.washington.edu/neurogen/
De Fusco M, Marconi R, Silvestri L, Atorino L, Rampoldi L, Morgante L, Ballabio A, Aridon P, Casari G. (2003) Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump α2 subunit associated with familial hemiplegic migraine type 2. Nature Genet. 33: 192-196.
Ducros A, Joutel A, Vahedi K, Cecillon M, Ferreira A, Bernard E, Verier A, Echenne B, Lopez de Munain A, Bousser MG, Tournier-Lasserve E. (1997) Mapping of a second locus for familial hemiplegic migraine to 1q21-q23 and evidence of further heterogeneity. Ann. Neurol. 42: 885-890.
Flanigan K, Gardner K, Alderson K, Galster B, Otterud B, Leppert MF, Kaplan C, Ptacek LJ. (1996) Autosomal dominant spinocerebellar ataxia with sensory axonal neuropathy (SCA4): clinical description and genetic localization to chromosome 16q22.1. Am J Hum Genet. 59: 392-399.
Harding AE. (1982) The clinical features and classification of the late onset autosomal dominant cerebellar ataxias. Brain 105: 1-28.
Hohoff C, Brinkmann B. (1999) Human Identity Testing with PCR-based Systems. Molecular Biotech. 13: 123-136.
Holmes SE, O'Hearn EE, McInnis MG, Gorelick-Feldman DA, Kleiderlein JJ, Callahan C, Kwak NG, Ingersoll-Ashworth RG, et al. (1999) Expansion of a novel CAG trinucleotide repeat in the 5´ region of PPP2R2B is associated with SCA12. Nature Genet. 23: 391-392.
Imbert G, Saudou F, Yvert G, Devys D, Trottier Y, Garnier JM, Weber C, Mandel JL, Cancel G, Abbas N, Durr A, Didierjean O, Stevanin G, Agid Y, Brice A. (1996) Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats. Nat Genet. 14: 285-291.
Ishikawa K, Fujigasaki H, Saegusa H, et al. (1999) Abundant expression and cytoplasmic aggregations ofα1A voltage-dependent calcium channel protein associated with neurodegeneration in spinocerebellar ataxia type 6. Hum. Mol. Genet. 8: 1185–1193.
Izumi Y, Maruyama H, Oda M, Morino H, Okada T, Ito H, Sasaki I, Tanaka H, Komure O, Udaka F, Nakamura S, Kawakami H. (2003) SCA8 Repeat Expansion: Large CTA/CTG Repeat Alleles Are More Common in Ataxic Patients, Including Those with SCA6. Am. J. Hum. Genet. 72: 704–709.
Kawaguchi Y, Okamoto T, Taniwaki M, et al. (1994) CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nature Genet. 8: 221-228.
Kiehl TR, Shibata H, Vo T, Huynh DP, Pulst SM. (2001) Identification and expression of a mouse ortholog of A2BP1. Mamm. Genome 12: 595-601.
Koob MD, Moseley ML, Schut LJ, Benzow KA, Bird TD, Day JW, Ranum LP. (1999) An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8). Nature Genet. 21: 379-384.
Kremer EJ, Pritchard M, Lynch M, Yu S, Holman K, Baker E, Warren ST, Schlessinger D, Sutherland GR, Richards RI (1991) Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n. Science 252: 1711-4
Kunst CB, Zerylnick C, Karickhoff L, Eichler E, Bullard J, Chalifoux M, Holden JJ, Torroni A, Nelson DL, Warren ST. (1996) FMR1 in global populations. Am J Hum Genet. 58: 513-22.
La Spada AR, Taylor JP. ( 2003) Polyglutamines Placed into Context. Neuron 38: 681-684
Leeflang EP, Tavare S, Marjoram P, Neal CO, Srinidhi J, MacFarlane H, MacDonald ME, Gusella JF, de Young M, Wexler NS, Arnheim N. (1999) Analysis of germline mutation spectra at the Huntington's disease locus supports a mitotic mutation mechanism. Hum. Mol. Genet. 8: 173-183.
Mahadevan M, Tsilfidis C, Sabourin L, Shutler G, Amemiya C, Jansen G, Neville C, Narang M, Barcelo J, O'Hoy K, et al. (1992) Myotonic dystrophy mutation: an unstable CTG repeat in the 3' untranslated region of the gene. Science 255: 1253-1255.
Marconi R, De Fusco M, Aridon P, Plewnia K, Rossi M, Carapelli S, Ballabio A, Morgante L, Musolino R, Epifanio A, Micieli G, De Michele G, Casari G.(2003) Familial hemiplegic migraine type 2 Is linked to 0.9Mb region on chromosome 1q23. Ann Neurol. 53: 376–381.
Matilla A, Koshy BT, Cummings CJ, Isobe T, Orr HT, Zoghbi HY. (1997) The cerebellar leucine-rich acidic nuclear protein interacts with ataxin-1. Nature 389: 974-978.
Matsuura T, Yamagata T, Burgess DL, Rasmussen A, Grewal RP, Watase K, Khajavi M, McCall AE, Davis CF, Zu L, Achari M, Pulst SM, et al. (2000) Large expansion of the ATTCT pentanucleotide repeat in spinocerebellar ataxia type 10. Nature Genet. 26: 192-194.
Mohmood S, Sherwani A, Khan F, Khan RH, Azfer A. (2003) DNA trinucleotide repeat expansion in neuropsychiatric patients. Med Sci Monit. 9: RA237-245.
Moseley ML, Schut LJ, Bird TD, Koob MD, Day JW, Ranum LP. (2000) SCA8 CTG repeat: en masse contrations in sperm and intergenerational sequence changes may play a role in reduced penetrance. Human Molecular Genetics 9: 2125-2130.
Nakamura K, Jeong SY, Uchihara T, Anno M, Nagashima K, Nagashima T, Ikeda S, Tsuji S, Kanazawa I. (2001) SCA17, a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA-binding protein. Hum. Mol. Genet. 10: 1441-1448.
Nolin SL, Brown WT, Glicksman A, Houck GE Jr, Gargano AD, Sullivan A, Biancalana V, Brondum-Nielsen K, Hjalgrim H, Holinski-Feder E, Kooy F,et al (2003) Expansion of the Fragile X CGG Repeat in Females with Premutation or Intermediate Alleles. Am. J. Hum. Genet. 72: 454–464.
Orr HT, Chung MY, Banfi S, Kwiatkowski TJ Jr, Servadio A, Beaudet AL, McCall AE, Duvick LA, Ranum LP, Zoghbi HY. (1993) Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat Genet. 4: 221-226.
Page KJ, Potter L, Aronni S, Everitt BJ, Dunnett SB. (1998) The expression of Huntingtin-associated protein (HAP1) mRNA in developing, adult and ageing rat CNS: implications for Huntington's disease neuropathology. Eur J Neurosci. 10: 1835-45.
Pan H, Lin HM, Ku WY, Li TC, Li SY, Lin CC, Hsiao KM.(2001) Haplotype analysis of the myotonic dystrophy type 1(DM1) locus in Taiwan: implications for low prevalence and founder mutations of Taiwanese myotonic dystrophy type 1. Eur J Hum Genet. 9: 638-641.
Pandolfo M. (1999) Molecular pathogenesis of Friedreich ataxia. Arch. Neurol. 56: 1201-1208.
Pulst SM, Nechiporuk A, Nechiporuk T, Gispert S, Chen XN, Lopes-Cendes I, Pearlman S, Starkman S, Orozco-Diaz G, Lunkes A, DeJong P, Rouleau GA, Auburger G, Korenberg JR, Figueroa C, Sahba S. (1996) Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2.Nat Genet. 14: 269-276.
Ranum LP, Day JW. (2002) Dominantly inherited, non-coding microsatellite expansion disorders. Current Opinion in Genetics & Development 12: 266-271.
Sanpei K, Takano H, Igarashi S, Sato T, Oyake M, Sasaki H, Wakisaka A, Tashiro K, Ishida Y, Ikeuchi T, Koide R, Saito M, Sato A, Tanaka T. et al. (1996) Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT. Nat Genet. 14: 277-284.
Schlötterer C. (2000) Evolutionary dynamics of microsatellite DNA. Chromosoma 109: 365–371.
Schöls L, Bauer I, Zuhlke C, Schulte T, Kolmel C, Burk K, Topka H, Bauer P, Przuntek H, Riess O. (2003) Do CTG expansions at the SCA8 locus cause ataxia? Ann Neurol. 54: 110–115.
Schöls L. (2003) Autosomal dominant spinocerebellar ataxias. Orphanet Encyclopedia, August 2003. (http://www.orpha.net/data/patho/GB/uk-SCA.pdf)
Shibata H, Huynh DP, Pulst SM. (2000) A novel protein with RNA-binding motifs interacts with ataxin-2. Hum Mol Genet. 22: 1303-1313.
Siyanova E Y, Mirkin S M. (2001) Expansion of Trinucleotide Repeats. Molecular Biology 35: 168-182.
Soong B W, Lu Y C, Choo K B, Lee H Y. (2001) Frequency analysis of autosomal dominant cerebellar ataxias in Taiwanese patients and clinical and molecular characterization of spinocerebellar ataxia type 6. Arch Neurol. 58: 1105-1109.
Stevanin G, Bouslam N, Thobois S, Azzedine H, Ravaux L, Boland A, Schalling M, Broussolle E, Durr A, Brice A. (2004) Spinocerebellar Ataxia with Sensory Neuropathy (SCA25) Maps to Chromosome 2p. Ann. Neurol. 55: 97-104.
Stevanin G, Trottier Y, Cancel G, Durr A, David G, Didierjean O, Burk K, Imbert G, Saudou F, Abada-Bendib M, Gourfinkel-An I, Benomar A, Abbas N, Klockgether T, Grid D, Agid Y, Mandel JL, Brice A. (1996) Screening for proteins with polyglutamine expansions in autosomal dominant cerebellar ataxias. Human Molecular Genetics 5: 1887-1892.
Urquhart A, Kimpton CP, Downes TJ, Gill P. (1994) Variation in short tandem repeat sequences - a survey of twelve microsatellite loci for use as forensic identification markers. Int. J. Legal Med. 107: 13-20.
van Swieten JC, Brusse E, de Graaf BM, Krieger E, van de Graaf R, de Koning I, Maat-Kievit A, Leegwater P, Dooijes D, Oostra BA, Heutink P. (2003) A mutation in the fibroblast growth factor 14 gene is associated with autosomal dominant cerebellar ataxia [corrected]. Am. J. Hum. Genet. 72: 191-199.
Verbeek DS, Schelhaas JH, Ippel EF, Beemer FA, Pearson PL, Sinke RJ. (2002) Identification of a novel SCA locus ( SCA19) in a Dutch autosomal dominant cerebellar ataxia family on chromosome region 1p21-q21. Hum Genet. 111: 388–393.
Verkerk AJ, Pieretti M, Sutcliffe JS, Fu YH, Kuhl DP, Pizzuti A, Reiner O, Richards S, Victoria MF, Zhang FP, et al (1991) Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65: 905-14
Wierdl M, Dominska M, Petes TD. (1997) Microsatellite Instability in Yeast: Dependence on the Length of the Microsatellite. Genetics 146: 769-779.
Worth PF, Giunti P, Gardner-Thorpe C, Dixon PH, Davis MB, Wood NW. (1999) Autosomal Dominant Cerebellar Ataxia Type III: Linkage in a Large British Family to a 7.6-cM Region on Chromosome 15q14-21.3 Am. J. Hum. Genet. 65: 420-426.
Yabe I, Sasaki H, Chen DH, Raskind WH, Bird TD, Yamashita I, Tsuji S, Kikuchi S, Tashiro K. (2003) Spinocerebellar ataxia type 14 caused by a mutation in protein kinase C gamma.Arch Neurol. 60: 1749-1751.
Yamashita I, Sasaki H, Yabe I, Fukazawa T, Nogoshi S, Komeichi K, et al. (2000) A novel locus for dominant cerebellar ataxia (SCA14) maps to a 10.2-cM interval Fanked by D19S206 and D19S605 on chromosome 19q13.4-qter. Ann Neurol. 48: 156-163.
Yue Q, Jen JC, Nelson SF, Baloh RW. (1997) Progressive ataxia due to a missense mutation in a calcium-channel gene. Am J Hum Genet. 61: 1078-1087.
Zhuchenko O, Bailey J, Bonnen P, Ashizawa T, Stockton DW, Amos C, Dobyns WB, Subramony SH, Zoghbi HY, Lee CC. (1997) Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the α 1A-voltage-dependent calcium channel. Nat Genet. 15: 62-69.
Zu L, Figueroa KP, Grewal R, Pulst SM. (1999) Mapping of a New Autosomal dominant spinocerebellar ataxia to chromosome 22. Am. J. Hum. Genet. 64:594-599.
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