1. Disease That Result from Expansion of Trinucleotide Repeats Tianyang Wang

2. Genes transmit from generation to generation Genes transmit from generation to generation Rarely changes Rarely changes Is it virtually this case?

3. Dynamic mutation, 1991 Small number, stable Large number, unstable Gene changes dramatictly Affect genes containing a repeating trinucleotide Critical number —— onset disorders

4. Huntington ’ s disease Huntington ’ s disease Fragile X syndrom Fragile X syndrom Myotonic dystrophy Myotonic dystrophy Diseases attributed to expansion of trinucleotide repeat

5. Genetic Ataxia Genetic Ataxia  Dominant –Spinocerebellar Ataxia (SCA) 1,2,3 …..  Recessive –Friedreich Ataxia –Ataxia With Vitamin E Deficiency (AVED) –Ataxia Telangiectasia –Ataxia With Retained Reflexes

6. SCA Atrophied cerebellum

7. Fragile X syndrome

8. Categories of Disease Type Ⅰ Type Ⅰ Type Ⅱ Type Ⅱ  Neurodegenerative disorders  Variety of trinucleotide repeats within noncoding portion  CAG repeats within coding portion or exon

9. Categories of Disease

10. Huntington ’ s Disease (HD) Type Ⅰ disease Type Ⅰ disease Affects about 1:10,000 Affects about 1:10,000

11. Huntington ’ s Disease (HD)  Involuntary, uncoordinated movements  Change in personality  Gradual intellectual decline Symptoms Symptoms

12. ventriculi lateralis

13. Expanded ventriculi lateralis and atrophied caput nuclei caudati

14. Huntington ’ s Disease (HD) Not losing a function, but acquiring an additional function Dominant genetic disorder Dominant genetic disorder Gain-of-function mutation

15. Huntington ’ s Disease (HD) Autosomal 4 CAG RepeatPolyglutamine tract (huntingtin) Normal huntingtin —— 6~35 repeats Abnormal huntingtin —— more than 35 repeats Gene Identified In 1993 Gene Identified In 1993

17. Huntington ’ s Disease (HD) Why dose only huntingtin containing more than 35 glutamine residues cause the HD?

18. Huntington ’ s Disease (HD)  Abnormal folding  Binds to other mutant huntingtin  Binds other protein Transcription factors, such as TBP & CBP

19. Never fiber tangle of Alzheimer ’ s victim

20. Huntington ’ s Disease (HD) Genetic anticipation Genetic anticipation Disease passed from generation to generation, its severity increases and/or it strikes at an increasingly early age.

22. Huntington ’ s Disease (HD) There is no efficient drug that can cure the HD by now. But people are trying their best to defeat it!!!

23. World Congress on Huntington's Disease: 11th – 13th September 2005 International Huntington Association Meeting: 13th – 14th September 2005

24. Reference Dr David Amor, Novel Mechanisms of genetic disease, Murdoch Children Research Institute Dr David Amor, Novel Mechanisms of genetic disease, Murdoch Children Research Institute 楊永正, 基因體計畫 ( 續 ), 陽明生物資訊所, Jan. 3, 2005 楊永正, 基因體計畫 ( 續 ), 陽明生物資訊所, Jan. 3, 2005 www.hda.org.uk,The Huntington ’ s Disease Association www.hda.org.uk,The Huntington ’ s Disease Association www.hda.org.uk