Lecture 9: Repeat Expansion Disorders II Flashcards
Give an example of a RED caused by expansions resulting in gain of RNA function
DM (myotonic dystrophy)
What is the inheritance pattern of myotonic dystrophy (DM)?
Dominant
Give 5 clinical features of DM
- myotonia (impaired muscle relaxation)
- Muscle wasting
- Insulin resistance
- Cardiac conduction defects
- Cataracts
- cognitive dysfunction
What is the typical age of onset of myotonic dystrophy?
Typically adult onset with age being determined by the number of repeats
Severe cases that are congenital (onset at birth) have most number of repeats (>1000)
How many forms of DM are there?
2 (DM1 and DM2) –> caused by repeat expansions in two different genes resulting in the same clinical features/disorder
What causes DM1?
expansion of trinucleotide CTG repeats in the 3’ UTR of DMPK gene
What is the pre-mutation and pathogenic repeat length for DM1?
Premutation = 37-50
Pathogenic = 50-1000
Does DM1 have a maternal or paternal expansion bias?
Maternal
Why does DM particularly affect muscle tissue?
Because it shows extensive somatic instability in proliferative cells and since DMPK (in DM1) and ZNF9/CNBP (in DM2) are highly expressed in muscle tissue, the repeats continue to expand and contract
What is the cause of DM2?
expansion of tetranucleotide CCTG repeats in intron 1 of ZNF9/CNBP gene
What is the pre-mutation and pathogenic repeat length for DM2?
Pre-mutation = 31-74
Pathogenic = 75-11000
Why, in the case of DM, can two repeat sequences located in non-coding regions of different genes cause the same disease?
They share a common pathogenic mechanism by RNA gain of function.
- The transcribed repeat containing RNA accumulates in discrete nuclear foci (can be detected in the cell nucleus)
–> as long as the gene in which the repeat is located is highly expressed in the muscle tissue, the effects will give a similar disease.
How does disease result from RNA gain of function?
The transcribed expanded repeat containing RNA can form imperfect hairpin structures due to G=C base pairing.
1. Sequester splicing proteins such as MBNL1 (normally involved in RNA splicing, sequestering of which results in aberrant alternative splicing of mRNAs)
2. Activation of PKC, which phosphorylates and stabilises CUGBP1 leading to increased availability and affects downstream mechanisms involved in processing of mRNAs (E.g. alternative splicing, mRNA translation and mRNA decay)
How can aberrant splicing resulting from RNA gain of function lead to the clinical features of DM?
Aberrant splicing of genes involved in production of:
1. insulin receptor = insulin resistance
2. chloride channel = myotonia
3. cardiac troponin _ = cardiac abnormalities
Genes that are affected in cataracts have not yet been identified.
How many disorders can result from expansion of the CGG trinucleotide repeat in the FMR1 gene?
Three:
- Fragile X syndrome (FXS) = 200-4000 repeats (full FRAXA mutation - gene silences, no FMRP)
- Fragile X-associated tremor/ataxia syndrome (FXTAS) = 55-200 repeats (pre-mutation stage)
- Fragile X-associated Premature ovarian insufficiency (FXPOI) = 55-200 repeats (pre-mutation stage)
How does the pathogenic mechanism resulting in FXS and the pre-mutation associated disorders FXTAS and FXPOI differ?
FXS = full FRAXA mutation - silencing of FMR1 due to CpG methylation and histone modification prevents FMRP expression (gene loss of function)
FXTAS/FXPOI = FRAXA pre-mutation - increased transcription leading to more mRNA containing expanded repeat, form unusual hairpin structures, sequesters RNA binding proteins resulting in dysregulation of proteins whose expression is usually regulated by these RNA binding proteins (RNA gain of function)
