BIOL1008 Lecture Notes - Lecture 31: Premature Ovarian Failure, Intron, Frataxin
Trinucleotide Repeat Disorders
Trinucleotide Repeat Disorders
Huntington Disease- a closer look
oNormal= 6-39 repeats
oAffected= 36-180 repeats
oAge of onset decreases as number of repeats increases
oSpontaneous expansion may occur in males with 35+ repeats (“transmitter
males”)
oFurther amplification passed on by males only (“anticipation”)
oMutant protein is called “Huntingtin”
oInsoluble and doesn’t break down
oAccumulates in brain cells inhibiting function
oTraps other proteins
Replicative slippage model
oWhen you have a repeat, the polymerase can slip and
move down to form a loop
oOne strand has more copies
oMutation is repaired by inserting more bases in the
non-mutated strand
oOccurs on strands containing short tandem repeats
(STR’s)
oResults in lengthening or shortening of sequence
oSTR’s become hotspots for mutation
Trinucleotide repeat disorders
oCaused by amplification of a pre-existing 3bp repeat in coding or noncoding
regions of genome
oOccurs through replicative slippage
oImplicated in 14+ diseases in humans
Fragile X syndrome
oFMR-1 gene- 38kb, 17 exons
oCGG repeat in noncoding region
oNormal= 6-55 repeats with AGG interspersed (stabilising)
oUnaffected carriers= 60-200 repeats (premutation)
oAffected= 230+ repeats- turns off gene
oInvolved in learning and memory
oHas function in synaptic development and weeding out
oComplex pattern of expression- very specific sites (not encouraging for
treatment)
oViral-mediated gene therapy being attempted on mice
oProtein level reduced or absent
oSeverity increases as number of repeats increases
oAmplification from premutation only occurs in females (CF, Huntingtons)
oMosaics exist- premutation and full mutation
oMore often seen in males
oOnly becomes active when it is passed through a woman
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