Lecture 11

Question 1

Genetic Anticipation

Answer 1

• Documented in ~1950’s
• Dismissed as ascertainment bias
• Each generation has more severe symptoms
• Mostly dominant
• Mechanisms can be complex and include loss of function, RNA gain of function, and/or protein gain of function

Question 2

Expansion Mechanisms

Answer 2

-DNA Replication
(DNA poly slips when copying the sequence of repeats->forms stable hairpin loop->next replication cycle, hairpin is unwound and repeated sequence is lengthened)

-DNA repair

-Implications
(Germ line and somatic expansion, even in post-mitotic cells)
-Extreme instability in somatic tissues
(Repeat sequences can be of different lengths between cells)

Question 3

Levels of Repeat Expansions

Answer 3

o DNA->RNA->Protein
o DNA – Fragile X, Friedreich’s Ataxia
o RNA – Myotonic Dystrophy, C9ORF72/ALS/FTD, Huntington’s, Fragile X-associated Tremor/Ataxia Syndrome, Fuch’s Endolethial Corneal Dystrophy
o Protein – Huntington’s C9ORF72/ALS/FTD, some Spinocerebellar Ataxias

Question 4

Fragile X

Answer 4

o Affects ~1/3500 males, ~1/6000 females
o ID, Autism Spectrum Disorder, elongated faces, large ears, macroorchidism (large testicles after puberty)
o FXTAS – tremor, ataxia (males), primary ovarian insufficiency (females)

Question 5

FMRP Gene

Answer 5

-Normal Bp<55, Premutation 55hypermethylation of the FMRP 5’ UTR->Loss of FMRP protein->increased production of specific synaptic proteins (glutamate receptors) and loss of ability to regulate synaptic biology

Question 6

Myotonic Dystrophy Symptoms

Answer 6

Cataracts, intellectual impairment, bone anomalies, arrhythmias, cardiomyopathy, swallowing issues, poor nutrition, weight loss, muslce weakness, myotonia, pain, breathing difficulties, defects in neurons

Question 7

Myotonic Dystrophy

Answer 7

RNA-level

Repeat expression CTG (CCTG in DM2) ->repeat is sequestering MBNL->MBNL loses function and mis-splices hundreds of targets (like ClC1; chloride channel)->mis-splice of ClC1 causes loss of expression altogether->myotonia

Question 8

Huntington’s

Answer 8

Protein level

• Dramatic loss of striatal neurons in the brain
• age of onset correlates w/ CAG repeat length

Expanded CAG repeat in coding region-> transcribed and translated into polyglutamine repeats-> myriad of downstream consequences, protein aggregates, etc-> cell death

Question 9

Huntington’s Symptoms

Answer 9

o Motor – chorea of the face, trunk, and limbs; delayed and reduced velocity of volitional saccades; motor impersistence, dystonia, bradykinesia, and rigidity
o Cognitive – executive dysfunction-decision making and multitasking; early on little insight into changes; difficulty searching memory but unlike AD less impairment of memory
o Psychiatric – depressed mood, apathy, anxiety, irritability, obsessive compulsive disorder; increased risk for suicide in affected patients and at-risk family members

Question 10

C9ORF72/ALS/FTD

Answer 10

o Most common form of familial amyotrophic lateral sclerosis
• G4C2 & C4G2 are produced from the locus
o Transcripts form RNA foci (spot of RNA larger than it’s supposed to be)
• Repeat-associated non-AUG dependent translation (RAN translation)
o Translation begins spontaneously at spot where there isn’t an AUG
• Unknown whether toxic RNA or toxic protein or both contribute to disease

Unknown if RNA and/or protein level

Question 11

C9ORF72/ALS/FTD Symptoms

Answer 11

Dementia, personality change, weakness, spasticity, muscle weakness, sloow speech, jaw jerk reflex, facial weakness, dysarthria, etc