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37 Cards in this Set
- Front
- Back
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What is fragile X synd?
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most common hereditary form of mental retardation. Can also cause other learning/behav. probs w/o mental retardation.
in 1/4000 males; 1/200 female Carriers --> some carriers show intellectual impairment. (Due to phenotype variability). Phenotype: large ears, prominant jaw, large testicles (macroorchidism) Patho: abnormal dendritic spines in male neurons |
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Where is the fragile x site? and why does it occur?
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- site is near the end of the long arm of the X chromosome.
-NORMALLY: this site is late to replicate during S phase - this is a frequent breakage site when cells are grown in low folate environment or other conditions that decr. pools of dTTP - depletion of dTTP further slows replication of already late replcating region --> delay in chromatin condensation in this region. **Occurance of fragile site is variable! depends on repeat length and culture conditions. --> not accurate results; false neg and false positives. |
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Inheritance pattern?
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unusual. different from other X linked ones.
PENETRANCE is <100% in males. ~30% females show symptoms of dz Incidence of dz is higher in those kids of females born to transmitting fathers: SHERMAN PARADOX Transmitting father --> carrier daughter --> these children will be likely to have Dz COMPARED TO: transmitting males & his siblings --> less likely to have Dz. This is bc carriers have less repeats... as generations go on... repeats increase. ***pre-mutation in transmitting males (but not affected) are at 100 repeats |
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Premutation
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In Males can carry Dz gene w/o mental retardation
This eventually evolves to a full mutation in affected family members |
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Fragile X MUTATION - what/ where?
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CGG repeat expansion within the 5' UTR of FMR1 (frag. mental retardation gene)
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Diff #'s of CGG repeat expansions and its phenotype?
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CGG repeat polymorphic in NORMAL ppl = 6 - 55CGGs
>200 CGG repeats = full mutation --> affected FX pts 55 - 200 CGGs = premutation --> asymptomatic carriers |
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Can premutation alleles expand to longer premutations or full mutation?
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Yes. Premutation repeats are unstable and can expand to full mutation during meiosis --> Affected offsprings
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T or F. The longer the premutation alleles, the more likely it will expand to full mutation.
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T. more so than short premutation alleles.
80% instability increases with length of repeat for 60 - 65 repeats 55 - 59 repeats... 31% likely to increase in length |
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T or F. Expansion to full mutation occurs in both males and female lines.
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F. ONLY IN FEMALE GERMLINE!!!
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How does the CGG expansion cause disease?
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The expansion has seen to cause an INCR in methylation of CYTOSINES in CpG dinucleotides in the region encompassing exon 1 and 5' flanking DNA
** the promoter and 5'UTR of FMR1 gene has many GC sequences and CpG islands... so methylation of those will prevent access of DNA to TRXN factors and RNA polymerase --> SHUTS DOWN TRXN of FMR1 gene *** CGG repeat expansion => loss of FMR1 FUNCTION |
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Function of FMR protein?
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an RNA binding protein
1. transport RNA btw nucleus and cytoplasm 2. Regulates translation of specific mRNAs esp BRAIN mRNAs |
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CAG repeat expansion causes?
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GLUTAMINE repeats
Neurodegenerative Dz Ex: Huntington's Spinal and bulbar muscular atrophy Spinocerebellar ataxia DRPLA |
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Phenotype of Huntington's & what is the inheritance pattern?
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Hyperkinetic disorder:
1. chorea - rapid jerky movements 2. dementia 3. personality changes 4. death 15-20yrs after onset 5. onset occurs 4th/5th decade 6. 10/100,000 frequency INHERITED IN AN AUTOSOMAL DOMINAL (AD) FASHION |
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Anticipation in CAG repeat disease. what is the relationship btw age and onset and successive generations?
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Inverse relationship exist btw CAG repeats and age of neurological symptoms
ie. Shorter repeat = older age onset Decr in age of onset with successive generations = anticipation. [Huntington's is >39 repeats] ie. at 60 - 80 repeats... onset occurs in teen years Meiotic instability of expanded repeat alleles is favored |
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T or F. molecular pathways leading to pathogenesis is completely understood.
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F. NOT completely understood.
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Polyglutamine Dz leads to what on molecular level?
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1. Misfolding & accumulation.
2. presence of neuronal intranuclear inclusion (NII) --> may serve to sequester toxic protein species 3. Polyglut inefficiently degraded by proteasome --> may affect proteosome's function and ability to degrade other proteins. |
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Polyglutamine Dz leads to what kinds of alterations?
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1. altered gene expression
2. altered protein interaction 3. altered cellular function ---> synaptic function is impaired. Axonal transport impaired. *** NOT a loss of function... GAIN OF NOVEL TOXIC PROPERTY |
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What is Myotonic Dystrophy type I (DM1)?
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most common form of muscular dystrophy.
AUTOSOMAL DOMINANT Dz Phenotype: myotonia, cataracts, cardiac arrythmias, insulin resistance -- weakness of face, neck, extremities. |
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DM1 results in Congenital onset when...?
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When mother is affected with Dz. Kids will have it. --> most severe form of Dz.
Feeding difficulties at birth --> results in weakness and mental retardation |
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Characteristics of DM1
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Large variability: some indiv with minimal symptoms while others show full blown Dz.
Anticipation: decr age onset = incr severity with successive generations |
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Where is the mutation occuring in DM1 on molecular level?
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DM1 caused by CTG repeat in 3' UTR of gene that encodes protein kinase DMPK
Gene gets transcribed but NOT translated! CTG repeats incr w/ successive generations |
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T or F. There is an indirect correlation btw repeat length and age of disease onset in DM1
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T. INVERSE relationship.
Longer repeats = younger age onset |
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T or F. There is an INDIRECT correlation btw repeat length and severity of disease
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F. DIRECT relationship
Longer repeat = higher severity! |
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How does CTG repeat cause disease?
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Expansion affects the normal trafficking of RNA transcribed from this gene. Causes formation of nuclear foci w/ DM1 mRNA
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T or F. DM1 is due to a loss of DMPK function?
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F. Since levels of DMPK are not universally altered so it is NOT likely due to a loss of DMPK function. Plus, mutation in DMPK in mice does not cause DM1.
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What is SIX5 regarding DM1?
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SIX5 is the gene from the complementary DNA strand. Hence expansion of CTG may affect expression of SIX5 gene also. BUT NOT PRIMARY MECH for DM1
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CTG repeat expansion in transgenic mice within an UNRELATED gene causes DM1... what does this mean?
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Mutation leads to disease through a DOMINANT mechanism
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What is DM2?
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Another form of myotonic dystrophy. Caused by CCTG TETRAnucleotide repeat in NONcoding region of ZNF9 gene.
ZNF9 gene is transcribed into RNA but NOT translated into protein. Nuclear foci also observed in presence of large CCTG expansions. ---> non-coding expansions may be the cause resulted from nuclear accumulation of the mutant RNA. |
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T or F. Both forms of DM show accumulation of mutant expasion repeats of RNA in nucleus.
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YUP YUP TRUEEEE In two distinct genes.
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What is the central patho mech in DM?
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TOXIC gain of function due to accumulating DM RNA --> lead to downstream altered function of proteins that relate to DM symptoms (Muscleblind & CUG-BP1 proteins ---> both involved in Alt Splicing)
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Mbn11 and CUG-BP1 proteins involved in?
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Alternative Splicing.
Knock out model of Mbn11 and OVERexpression of CUG-BP1 (a CUG binding protein) result in many symptoms of DM. Causes altered trafficking and accumulation of expanded repeats in RNA --> sequesters and loss of function of Mbn11 and incr function of CUG-BP1 |
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T or F. Loss of DMPK function of ZNF9 causes DM?
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F. it does NOT cause DM.
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T or F. Loss of expression of neighboring genes of DMPK cause DM
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F. DOES NOT cause DM
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T or F. Repeat expansion of Coding region causes DM
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NOPE. NON-CODING
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CGG repeat expansion causes...?
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FRAGILE X SYND
within 5' UTR --> methylation incr --> blocks Trxn --> loss of FRM1 function |
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CAG causes?
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polyglutamate expansion! in CODING region. translated into glutamine.
has DOMINANT TOXIC EFFECT --> neurodeg. Dz |
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CTG causes?
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DM1 & 2
expansion in 3'UTR --> defect in RNA trafficking, DOMINANT toxic effect --> altered gene function of other proteins... some get sequestered in foci |
