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Flashcards in Trinucleotide Repeat Expansion Deck (13):
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fuck

you

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Why do TNR expand? %%%

Instability-can have expansion or contraction

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Principles of TNR

MOlecular characteristics and consequences differ

Tendency for repeat expansion depends on transmitting parent

Premutations

Genetic anticipation

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TNR expansion characteristics

Coding Region-excess misfolded protein
(HD)

Noncoding region-disease caused by absent or diminished protein (freidrichs ate or fragile X)

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Premutation phenotype

Either normal, mildly affected, or clinical phenotype

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Genetic anticiaption

More severe the mutation, the early and more severe the phenotype

Through more generations-disease gets worst

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Huntingtons Chorea

Premutation Phenotype+clicical features

Location of TNR explansion and correlation to phenotype

Mode of inheritance/parental preference

How to diagnose?

Symptoms-Cognitive impairment, behavior disorders, inventory choreiform movements, chorea, dystonia with dysarthria, abnormal eye mvements

Auto dominatn

Mutation-increase in glutamine in first exon of huntington protein
-aggregation overwhlems ubi-proteasome system

Premutaiton-less than 40 CAG repeats

Paternal transmission-repeat expansion occurs during spermatogenesis

Diagnosed by PCR-will have larger band+ MRI shows important parts of brain shrink in size,

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Fragile X

Premutation Phenotype+clicical features

Location of TNR explansion and correlation to phenotype

Mode of inheritance/parental preference

How to diagnose?

X linked
-normal transmitting males
-30/50% of female carriers with full mutation are affected (selected x inactivation)

most common inherited cause of autism spectrum disorders/intellectual instability

Caused by unstable expansion of CGG in promoter of FMR1 gene-in 5' UTR

Cog disabiity, long narrow face with evertyed ears, Macroordisms-large testes

Full mutation is over 230 repeats

Transmitted by female-HIGH RISK FOR EXPANSION

Premutation-distinct phoptype
-Tremor Ataxia-higher risk in males, progressive neurodegen disorder
-Primary ovarian insufficiency-cessation of menses early, 20% of females with permutation

Anticipation

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FMR1 gene

highly conserved

6 to 55 CGG repeas

Premutation form-when transmitted by female-high risk for increase in repeats

Translationtional regulator of target mRNA

Immature, thinner, dendritic spines-immature stage of neuronal dev

Gene is methlayed when have full mutation

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Freidrichs ataxia

Premutation Phenotype+clicical features

Location of TNR explansion and correlation to phenotype

Mode of inheritance/parental preference

Auto rec

Unstable expansion of GAA in first INTRON of FRDA gene
-encodes mito protein
-results in mRNA transcript loss, GAA part will not be spliced-degraded
-Cell lose in mito rich tissues

Ataxic gait, progressive weakness of extremities, dysarthria and dysphasia
-cog disfuction

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FRDA

Frataxin-plays role in mito iron metabolism

Under lower Fe- make more ISC and Heme biosynth

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dysarthria

dysphagia

chorieform movement

unclear articulation of normal speech

trouble swallong

repetitive and rapid, jerky, involuntary movement that appears to be well-coordinated

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Myotonic Dystrophy Type 1

Auto dominant disorder
-3' UTR of DMPK gene
-too many alternative splice isoforms
-decreased RNA stability, dif protein, dif RNA distribtion
-RNA splicing proteins are sequesterd

Adult onset muscular ystrophy-only way to get
-myotonia, type 2 diabetes, cardiomyopathy

50 or more CTG repeats is disease, can be MANY MORE

Pronounced gene anicipation

Both parents transmit TNR expansion
-males won't transmit pass 1000
-females will

Congential MD is almost always from mom