Transcript Diseases That Result from Expansion of Trinucleotide Repeats

Diseases That Result
from Expansion of
Trinucleotide Repeats
TypeⅡ trinucleotide repeat
diseases
xuyan
TypeⅡ diseases differ from the
TypeⅠdisease
TypeⅠdisease
CAG
Repeating
trinucleotide unit
Encode amino
Yes (Glu)
acids
Quantity of
Exceed 35 Glu
trinucleotide
repeats
Affected part
Brain
TypeⅡdiseases
A variety of
trinucleotides,
No
Massive
repeats(>200)
Numerous of
body
• 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.
• 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.
• 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. .
• 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).
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
• 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.
• 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).
Figure 1
• 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.
• Full mutations result in
hypermethylation of the
DNA in and around the
CGG tract, curtailed gene
expression and no FMRP
being produced.
• Without adequate FMRP, severe
learning problems or mental
retardation and the other features of
fragile X syndrome can developed.
• 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.
• 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 .
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
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.