DM1 1 and 2 Flashcards
What is DM1 stand for?
Myotonic dystrophy
What is myotonic dystrophy?
Multisystem NMD, characterized by muscle weakness, wasting, & myotonia, Microsatellite repeat expansion in DMPK 3’ UTR (DM1) or CNBP 1st intron (DM2)
What does the toxic gain of function cause?
Toxic gain-of-function causes widespread dysregulation of pre-mRNA splicing (spliceopathy)
What type of genetic mutation of DM?
autosomal dominant
If one parent has one affected allele what is the percentage kids will be affected?
50%
Prevalence of DM?
DM is second most common MD after DMD, most common adult MD, prevalence = ~1/8,000
What % DM1 and its future?
98% of DM is DM1
• ~15% of DM1 is fetal-onset congenital DM1
• ~10% of DM1 is childhood-onset, beginning 1-10 yrs old
• ~75% of DM1 is adult-onset, with patients developing symptoms in 2nd, 3rd, 4th decade
where is DM highly prevalent?
High prevalence in PQ, particularly in Charlevoix and Saguenay–Lac St-Jean regions, ~1/600
Diagnosis of DM1?
- DM1 patients usually have characteristic thin, long face, hollow temples and, in men, early frontal balding
- DM causes muscle weakness and wasting, usually beginning in face, neck, and distal limbs
- Myotonia = delayed relaxation (prolonged contraction)
- Myotonic myopathy includes action (grip & release) and percussion myotonia
- When clinical signs point to DM1, genetic testing definitive
- Histological evidence of central nuclei, fiber size variability
What causes DM1?
- DM1 caused by CTG repeat expansion in the 3’ UTR of the DMPK gene
- Mutation causes formation of CUG)n in DMPK transcripts, nuclear aggregation of DMPK mRNA (foci), sequestration of RNA binding proteins = DMPK mRNA toxic gain-of-function
- DMPK protein reduced, however this loss-of-function mechanism does not cause DM1
at DNA level what is expanded?
CTG expansion in 3 pime uTR area of DMPK gene
at mRNA level?
CUG is added
In healthy individuals how many CTG repeats do we have? And what is the threshold
5 is most common, ranges from 5-28, largest number of repeats in healthy individual is 37
Do carries of pre-mutation present symptoms?
No or at least very mild sympotoms such as cateracts
Explain correlation b/w repeats, severity and age of onset for DM1
INCREASED repeats = increase servierty and early onset
Important aspects of DM1 pathobiology:
anticipation and instability
Repeat instability
• Variations in CTG)n lengths between tissues can occur during multiple stages of development
• Against expectations, CTG)n more unstable in nondividing cells of muscle, heart, brain, than in proliferating blood cells
• In skeletal muscle, DM1 expansion typically grows to >2,000 repeats by 20 yrs old, and in patients over 40, average repeat length in muscle >4,000, 3- to 25-fold larger than in blood
• Thus, CTG)n expansion size depends on tissue sampled
& age
Genetic anticipation
Genetic anticipation a phenomenon in which disease severity increases and/or age of disease onset decreases from one generation to the next
• In DM1, anticipation often occurs from generation to next, with larger CTG expansions, younger onset, & more severe symptoms in each subsequent
generation
• CTG)n increases >200 repeats per generation
• Anticipation not inevitable, occasionally CTG)n undergoes intergenerational contraction
What do the CUG expansions on mRNA DMPK do?
CUG expansions form nuclear foci caused by folding of CUG)n into double-stranded hairpin structures that sequester muscleblind (MBNL1) & upregulate CELF1 (aka CUGBP1) RNABPs
Microsatellite expansion within DMPK 3’ UTR sequesters MBNL1, what does MBNL1 do?
mitigates MBNL1- dependent splicing, as well as promotes nuclear retention of DMPK mRNA (nuclear foci)
what does PKC activation by expanded CUG do?
induces CUGBP1 (CELF1) hyperphosphorylation, which stabilizes protein & enhances alternative splicing, stability, translation of CUGBP1 targets
In spinal cord sections of DM1 patients (A and B), FISH and IF analyses demonstrates:
nuclear (blue) foci of CUG)n mRNA (red) in ChAT-positive (green) α-motoneurons of anterior horn, in DM1 patients, muscle blind and cug foci are centrally located (seeing how it traps MBNL-1
Fluorescence in situ hybridization (FISH) and immunofluorescence of tibialis anterior muscle section shows:
myonuclear (blue) colocalization of CUG)n mRNA foci (red) with MBNL1 protein (green) in DM1 patients
Pathogenic model of DM1
- Decreased MBNL1 and increased CUGBP1 activity alter splicing of transcripts involved in DM1 pathology, e.g., RNAs encoding chloride channel (CLCN1) and insulin receptor α subunit (IRα)
- Genes responsible for some clinical features, such as cataracts, not yet been identified
