Diseases That Result from Expansion of Trinucleotide Repeats

1. Diseases That Result from Expansion of Trinucleotide Repeats TypeⅡ trinucleotide repeat diseases xuyan

2. TypeⅡ diseases differ from the TypeⅠdisease

3. The best studied TypeⅡdiseases is fragile X syndrome(X染色体脆性综合征) ,so named because the mutant X chromosome is especially susceptible(易受影响的） to damage.

4. The fragile X syndrome is the most common form of inherited mental retardation(智力迟钝) and accounts for approximately 40% of cases with X-linked mental retardation. 

5. Other characteristics of the fragile X syndrome include a wide range of cognitive(认知的), behavioral(行动的), and physical features such as variable IQ (profound to mild mental retardation), autistic-like(像孤独症一样) features, hyperactivity(过度活跃), increased testicular (睾丸)volume, macrocephaly(巨头症), and large ears.  .

6. The fragile X mental retardation-1 (FMR1) gene codes for the mRNA-binding fragile X mental retardation protein (FMRP). • FMRP is normally made in many tissues, especially in the brain and testes(睾丸).

7. Where is the FMR1 gene located? • The FMR1 gene is located on the long (q) arm of the X chromosome at position 27.3. • Cytogenetic Location: Xq27.3

8. Almost all cases of fragile X syndrome are caused by expansion of the CGG trinucleotide repeat in the FMR1 gene. In these cases, CGG is abnormally repeated from 200 to more than 1,000 times, which makes this region of the gene unstable.

9. A normal allele of FMR1 gene contains anywhere that is repeated in a part of the gene that corresponds to the 5’ noncoding portion of the messenger RNA (Figure 1).

10. Figure 1

11. The CGG repeat in FMR1 that can be categorized into three classes based on the size of the repeat: normal (5-55 repeats), premutation (60-200 repeats), and full mutation (200-2000 repeats). The full mutation is the disorder-causing form of the repeat, and the premutation is the carrier form of the repeat.

13. Full mutations result in hypermethylation of the DNA in and around the CGG tract, curtailed gene expression and no FMRP being produced.

14. Without adequate FMRP, severe learning problems or mental retardation and the other features of fragile X syndrome can developed.

15. Smaller expansions of the CGG repeat, or ‘premutations’, do not cause Fragile X syndrome but may show expansion into full mutations over one or more generations.

16. Unlike an abnormal HD allele, FMR1 allele causes disease as the result of a gain of function , an abnormal FMR1 allele causes disease as the result of a loss of function .

17. Conclusion • The fragile X syndrome is the best studied TypeⅡdiseases ,which is a X-linked disease .The most characteristic of the fragile X syndrome is mental retardation. Almost all cases of fragile X syndrome are caused by expansion of the CGG repeat in the FMR1 gene. In these cases, CGG is abnormally repeated from 200 to more than 1,000 times

18. Although there is no effective treatment for any of the disease caused by trinucleotide expansion, the risk of transmitting or possessing a mutant allele can be assessed through genetic screening.

19. Thank you!