Trinucleotide Repeat Expansion

Question 1

fuck

Answer 1

you

Question 2

Why do TNR expand? %%%

Answer 2

Instability-can have expansion or contraction

Question 3

Principles of TNR

Answer 3

MOlecular characteristics and consequences differ

Tendency for repeat expansion depends on transmitting parent

Premutations

Genetic anticipation

Question 4

TNR expansion characteristics

Answer 4

Coding Region-excess misfolded protein
(HD)

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

Question 5

Premutation phenotype

Answer 5

Either normal, mildly affected, or clinical phenotype

Question 6

Genetic anticiaption

Answer 6

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

Through more generations-disease gets worst

Question 7

Huntingtons Chorea

Premutation Phenotype+clicical features

Location of TNR explansion and correlation to phenotype

Mode of inheritance/parental preference

How to diagnose?

Answer 7

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,

Question 8

Fragile X

Premutation Phenotype+clicical features

Location of TNR explansion and correlation to phenotype

Mode of inheritance/parental preference

How to diagnose?

Answer 8

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

Question 9

FMR1 gene

Answer 9

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

Question 10

Freidrichs ataxia

Premutation Phenotype+clicical features

Location of TNR explansion and correlation to phenotype

Mode of inheritance/parental preference

Answer 10

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

Question 11

FRDA

Answer 11

Frataxin-plays role in mito iron metabolism

Under lower Fe- make more ISC and Heme biosynth

Question 12

dysarthria

dysphagia

chorieform movement

Answer 12

unclear articulation of normal speech

trouble swallong

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

Question 13

Myotonic Dystrophy Type 1

Answer 13

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