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50 Cards in this Set

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Triple Repeat Disorders
cause
unstable dynamic mutations in a gene
increase in # of 3 nucleotide repeats
In a trinucleotide repeat, when does a disease occur?
occurs when the trinucleotide repeat goes beyond the threshold.
below the threshold it is stable in both meiosis and mitosis
above the threshold it is unable in both mitosis and meiosis
Anticipation
earlier onset in subsequent generations, as it progresses down generation, it becomes more severe
Myotonic Dystrophy
Repeat:
Location of Repeat:
Threshold
Inheritance Pattern
CTG
3' UTR
> 50
Maternal / AD
MD
Mild Stage
Threshold:
Symptoms
50-150 CTG repeats
Cataracts & Myopia
Classic stage of MD
100-1000 CTG repeat
myotonia cataract
arrthymia
sustained muscle contraction
Congenital MD
inherited form
> 2000 repeats
hypotonia
general weakness at birth with respiratory distress mental retardation
*** always from mother ****
Fragile X
Repeat Sequence
Location
Inheritance Pattern
CGG / GCC
5' promoter region
X Link Recessive
Maternal
Leading cause of inherited mental retardation.
Fragile X affects males or females more than the other?
Males are more prone to have mental retardation than females.
if inherited from the mother
onset of Fragile X
symptoms
early childhood
bad behavior
hyperactivity, hand flapping
biting
autistic features
Before / After Puberty
Large head
long face
large ears
prominent jaw
Big Testis
What gene's trinucleotides are being repeated that leads to Fragile X syndrome?
FRM 1 mutations are b/c of expanding CGG or GCC on the 5' end
Normal Alleles of FMR1
6 to 50 CGG = no risk for offspring
Premutation Allele FMR1
59 - 200 CGG repeats
males & females are with normal intellect
Full Mutation of FMR1
> 200 CGG repeats
hypermethylation of the promoter region
How does a pre-mutation lead to a full mutation?
Full mutation occurs from pre-mutation alleles with maternal transmission. The mother has a greater chance of going from premuation to full mutation as compared to father.
When father is affected, will its transmission lead to full mutation from a premutation?
NO! it decreases the risk of inheritance. Loss of function
Female carriers of pre-mutations risk
20% are at risk for developing Premature Ovarian Failure
Male Premutation carriers are at risk
20% risk for developing FXTAS
Inheritance risk of Fragile X
higher for males
lower for females
Huntington Disease
Repeat
Location
Inheritance
gain of function or loss
CAG
Exon
Paternal
AD
gain of function
HD Symptoms
loss of involuntary and voluntary muscle movement
Chorea (jerky dance movements)
Behavioral disturbances
Psychiatric Help
Age onset of HD
Mean age of onset
25% patients develop disease after age 50
* 35-44**
survival rate is 15-18 years after onset
HD Normal Range
Mutable Range
HD with reduced penetrance
HD allele
< 26
27-35
36-39
> 40
Patients age
inversely proportionately related to the onset of the disease. Greater the expansion of the repeats leads to earlier onset of HD
Freiderich Ataxia
A/R
trinucleotide repeat in the intron region
SCA
due to CAG repeat except for SCA 8 due to CTG
paternal transmission
CTG repeats can expand to several hundreds of repeat units in MD.
True
CTG repeat expansion located at 3' end in MD leads to methylation?
false
Methylation on occurs in Fragile X syndrome at the 5' end
Trinucleotide expansion to full mutation in Fragile X has been shown to lead to tremor and ataxia in females?
False
HD is a late onset disease, prenatal testing should be considered in childhood for individuals at risk ?
False, b/c its onset is at age 50
Fragile X is linked to point mutation b/c
it is paternally inherited
Who is at a higher high affected rate for Fragile X syndrome?
Males are at a higher risk for disease if it is transferred from mother
Dosage Compensation
inactivation of 1 x c'some in females. to keep a balanced ratio between the males and females.
Inactivation Occurs
in embryogenesis
random inactivation occurs (paternal or maternal)
irreversible process
X- inactivation
occurs
XIC center at Xq13
starts from long arm to short arm
Where does X-inactivation occur?
occurs at the XIC where the XIST gene is methylated.
DMD
X- linked
inherited form of muscle disease due to a mutation w/in the DMD gene called dystrophin.
DMD affects
pectoral and trunk muscles
upper and lower limb muscles ( diffculty standing, walking)
enlarged calf muscles
affects heart & respiratory system
Since dystrophin is associated with large complex of the sarcolemma, what other diseases can result?
Laminin mutations = CMD
Sacroglycan mutations = Limb Girdle MD (LGMD)
60% of the mutations in DMD
due to large deletions during oogenesis
most de novo nucleotide changes
occurs during spermatogenesis
BMD
allelic mutation
frame-shift mutation leading to a smaller dystrophin protein
DMD
age 5
Gowers maneuvers
hypertrophy of calf
Age 12 DMD
wheelchair bound
scoliosis
DMD;
pulmonary function is impaired
pneumonia death by 18yoa
standard IQ
1/3 develop mental retardation
DMD and females
if the female is carrying the mutant DMD allele then will develop sign of DMD.
females will develop cardiac myopathy
DMD X link recessive
50% of all males will be affected with DMD
50% of females will inherit the mutant DMD allele.
A mother has an affected son, what does this tell about his mother?
1/3 of all mother who have an affected son will not be carriers of DMD but rather is a new mutation
Testing for DMD
Creatine phosphokinase b/c because Dystrophin is present in cardiac, skeletal and smooth muscle