HD 1

Question 1

intro to HD

Answer 1

neurodegen disorder, AD inheritance (kids have 50% chance inheriting it), occur worldwide

Question 2

HD clin onset

Answer 2

avg age ~37

range from infant - 80s

Question 3

HD clin features

Answer 3

poor work performance, memory, hard to multi-task, restless fidgeting, awkward clumsy movement, onset of chorea & motor incoord

Question 4

HD problems

Answer 4

emotional, cognitive, psychiatric probs. depression, suicide more common. muscle wasting, weight loss despite normal calorie intake. 15-20 yrs after onset, death due to complics of falls/aspiration pneumonia

Question 5

juvenile HD (onset <20 yrs)

Answer 5

frequently lack chorea, instead have decr spontaneous & voluntary movements (rigidity)

Question 6

genetic anticipation

Answer 6

clin features of hereditary disease develop at earlier age or w incr severity as it goes to next generation. occurs in fragile x syndrome, myotonic dystrophy, spinocerebellar ataxias. to some degree in HD, esp w paternal transmission, lead to juvenile HD

Question 7

HD gene linked to polymorphic dna marker…

Answer 7

which maps to human xsome 4… localization uses recomb dna tech, ID genetic defect

Question 8

later, HD gene is found in small segment…

Answer 8

at tip of short arm, flanked by dna marker D4S10 & telomere

Question 9

interesting transcript IT15 contains

Answer 9

polymorphic trinucleotide repeat that’s expanded, unstable on HD xsomes

Question 10

HD belongs to large family of

Answer 10

dna repeat expansion ‘dynamic mutations’. (CAG)n polyglutamine subgroup of unstable trinucleotide repeat disorders

Question 11

HD patient alleles

Answer 11

1 normal, other is expanded allele of 65 repeats

Question 12

HD gene location

Answer 12

xsome 4p16.3

Question 13

HD caused by

Answer 13

incr in # repetitions of 3 nucleic acids (CAG = codon for Q) in 1st exon of gene

Question 14

in normal HD gene, # CAG repeats is

Answer 14

polymorphic, ~range 10-26 repeat

Question 15

HD penetrance

Answer 15

100%. ppl w 40 or + repeats develop disease if live long enough

Question 16

repeats bw 36-30 are rare but assoc w

Answer 16

reduced penetrance where some ppl develop HD, others don’t

Question 17

repeats bw 27-35 in paternal transmission

Answer 17

meiotically unstable. kids of these men can get disease-assoc repeats of 40 or +

Question 18

meiotic repeat instability in paternal transmission

Answer 18

tendency toward larger expansion, acc for anticipation in HD

Question 19

maternal transmission see repeat expansions & contraction in

Answer 19

~equal numbers, & thesee are ~small like 1-3 repeats

Question 20

paternally transmitted repeats prone to large incr in size explains why

Answer 20

juvenile onset cases ~inherited thru M germline

Question 21

juvenile HD always occurs if

Answer 21

CAG repeats 70 or +

Question 22

stronger relationship bw repeat size & onset age

Answer 22

if 60+ repeats (young age onset)

Question 23

HD belongs to family of CAG repeats polyQ diseases including

Answer 23

spinocerebellar ataxia (diff types) & spinobulbar muscular atrophy

Question 24

how does polyQ expansion in huntingtin protein lead to HD neuropathology

Answer 24

mitochondrial dysfxn, alter ca influx, cytoskeleton abnormalities/ axon transpo defects, proteolytic cleavage, protein accum (quality control, UB-proteasome, chaperones, autophagy), transcrip dysreg

Question 25

where does HD start/affect

Answer 25

striatum - part of basal ganglia. include caudate & putamen. deep grey matter containing neuron cell bods

Question 26

WT huntingtin protein involved in

Answer 26

transcrip reg - interact w TFs , reg BDNF prod. vesicle trafficking - axonal transpo. downreg glutamate (NMDA & kainate) receptors thru interaction w PSD postsynaptic density proteins. anti-apoptotic fxns

Question 27

BOTH loss of normal fxn & gain of toxic fxn of mutated huntingtin contrib to pathogenesis of HD

Answer 27

not only due to haplosufficiency. rare ppl who get HD mutation from both parents (homozygous) have similar ages of clin onset to heterozygous ppl w equiv CAGn expansions (tho clin deterioration for homozygotes more rapid)

Question 28

haplosufficiency

Answer 28

genetic defect leading to prod of only 1/2 of normal protein needed for fxn.. HD not only due to this

Question 29

proteolytic cleavage of mutant huntingtin generates N-term frag containing

Answer 29

polyQ expanision (key step in pathogenesis)

Question 30

in transgenic mice expressing full length mutant huntingtin, behavioral/neuropathological HD phenotype prevented IF

Answer 30

caspase 6 proteolytic cleavage site in huntingtin is elim

Question 31

characteristic feature of CAG trinucleotide repeat diseases (including HD)

Answer 31

intra cytoplasmic & intra nuclear b-sheet/amyloid aggreg of polyQ proteins (b-sheet monomers/oligmoers ~toxic… turn into amyloid fibrils)

Question 32

QBP1 polyQ binding peptide 1

Answer 32

prevent toxic transition from native into b-sheet monomer inhib neurodegen

Question 33

mutant huntingtin protein & toxic gain of fxn in HD pathogenesis

Answer 33

transcrip dysreg (abnormal interact of mutant w TFs), decr BDNF prod, disrupt axonal transpo, synaptic dysfxn & excitotoxicity, mito dysfxn & gen ROS, impair protein recycling by UPS, apoptic neuron cell death

Question 34

HD overview

Answer 34

autosomal dominant. chorea - dance like movements, emotional/cognitive changes, death.

Question 35

HD mutation

Answer 35

unstable trinucleotide CAGn repeat expansion mutation in exon 1 of HD gene on short arm of xsome 4

Question 36

unstable trinucleotide CAGn repeat expansion leads to

Answer 36

abnormal incr in poly-Q AA sq near N terminus of encoded huntingtin protein

Question 37

expanded polyQ tract leads to

Answer 37

misfolding of huntingtin, lead to loss of normal + gain of toxic fxn

Question 38

HD effect in brain

Answer 38

selective degeneration of neuron subsets, esp in striatum (caudate & putamen) & in cerebral cortex