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Disease That Result from ExpansiDisease That Result from Expansion of Trinucleotide Repeatson of Trinucleotide RepeatsTianyang WangTianyang Wang
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•Genes transmit from Genes transmit from generation to generationgeneration to generation
•Rarely changesRarely changes
Is it virtually this Is it virtually this case?case?
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Dynamic mutation, 1991Dynamic mutation, 1991
Small number, stableLarge number, unstable
Gene changes dramatictlyGene changes dramatictlyAffect genes containing a repeating trinAffect genes containing a repeating trinucleotideucleotide
Critical number——onset disorders
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• Huntington’s diseaseHuntington’s disease• Fragile X syndromFragile X syndrom• Myotonic dystrophyMyotonic dystrophy
Diseases attributed to expansion of trinucleotide repeat
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• Genetic AtaxiaGenetic Ataxia
DominantDominant– Spinocerebellar Ataxia (SCA) 1,2,3…..Spinocerebellar Ataxia (SCA) 1,2,3…..
RecessiveRecessive– Friedreich AtaxiaFriedreich Ataxia– Ataxia With Vitamin E Deficiency (AVED)Ataxia With Vitamin E Deficiency (AVED)– Ataxia TelangiectasiaAtaxia Telangiectasia– Ataxia With Retained ReflexesAtaxia With Retained Reflexes
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SCASCA
Atrophied cerebellum
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Fragile X syndromeFragile X syndrome
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Categories of DiseaseCategories of Disease• Type ⅠType Ⅰ
• Type ⅡType Ⅱ
Neurodegenerative disordersNeurodegenerative disorders
Variety of trinucleotide repeats within Variety of trinucleotide repeats within noncoding portionnoncoding portion
CAG repeats within coding portion or exonCAG repeats within coding portion or exon
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Categories of DiseaseCategories of Disease
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Huntington’s Disease (HD)Huntington’s Disease (HD)
•Type Ⅰ diseaseType Ⅰ disease•Affects about 1:10,000Affects about 1:10,000
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Huntington’s Disease (HD)Huntington’s Disease (HD)
Involuntary, uncoordinated Involuntary, uncoordinated movementsmovements
Change in personalityChange in personalityGradual intellectual declineGradual intellectual decline
•SymptomsSymptoms
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ventriculi lateralis
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Expanded ventriculi lateralis and atrophied caput nuclei caudati
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Huntington’s Disease (HD)Huntington’s Disease (HD)
Not losing a function, but acquiring an additional function
•DominantDominant genetic disorder genetic disorder
Gain-of-function mutation
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Huntington’s Disease (HD)Huntington’s Disease (HD)
Autosomal 4CAG Repeat
Polyglutamine tract(huntingtin)Normal huntingtin —— 6~35 repeatsAbnormal huntingtin —— more than 35 repeats
•Gene Identified In 1993Gene Identified In 1993
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Huntington’s Disease (HD)Huntington’s Disease (HD)
Why dose only huntingtin Why dose only huntingtin containing more than 35 containing more than 35 glutamine residues causglutamine residues cause the HD?e the HD?
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Huntington’s Disease (HD)Huntington’s Disease (HD)Abnormal foldingAbnormal folding
Binds to other mutant huntingtinBinds other proteinTranscription factors, such
as TBP & CBP
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Never fiber tangle of Alzheimer’s victim
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Huntington’s Disease (HD)Huntington’s Disease (HD)
•Genetic anticipationGenetic anticipation
Disease passed from generation to generation, its severity increases and/or it strikes at an increasingly early age.
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Huntington’s Disease (HD)Huntington’s Disease (HD)
There is no efficient drug that There is no efficient drug that can cure the HD by now.can cure the HD by now.
But people are trying their best to defeat it!!!
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World Congress on Huntington's Disease: 11th–13th September 2005International Huntington Association Meeting: 13th–14th September 2005
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ReferenceReference• Dr David Amor, Novel Mechanisms of Dr David Amor, Novel Mechanisms of
genetic disease, genetic disease, Murdoch Children Research Murdoch Children Research InstituteInstitute• 楊永正楊永正 ,, 基因體計畫基因體計畫 (( 續續 )) ,, 陽明生物資訊所陽明生物資訊所 , , Jan. Jan.
3, 20053, 2005• www.hda.org.ukwww.hda.org.uk ,The Huntington’s Dis ,The Huntington’s Dis
ease Associationease Association