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What are repeat expansion disorders?

REDs are diseases that are caused by the expansion of repetitive sequences of DNA in genes.


What were the diseases that were originally discovered to be REDs?

These diseases are triplet repeat/trinucleotide repeat expansions.

- FXS (Fragile X Syndromes).

- SBMA (spinal and bulbar muscular atrophy).

- DM (myotonic dystrophy).

- Huntinton's disease.


How are most REDs thought to work?

Through a gain-of-function mechanism. The repeat causes the protein of RNA produced by that gene to obtain disease-causing properties. The toxicity can arise at either the RNA or the protein level.

There are, however, some loss-of-function diseases.


What is FXS?

Fragile X Syndrome.

This is an X-linked condition that is fully penetrant (people that carry the mutation will show the phenotype) and only 50% penetrant in females.

FXS results in a long face, protruding ears, low muscle tone and macroochidism (abnormally large testicles). There are also a range of learning disabilities.


What is FXTAS?

Fragile X-Associated Tremor/Ataxia Syndrome.

This is an adult-onset condition that is caused by shorted expansions in the same gene that causes FXS.


What is FXS caused by?

A loss of FMRP (fragile X mental retardation protein).

FMRP is an RNA-binding protein associated with polyribosomes and mRNA granules. It functions as a translational repressor until the protein is required.

This process is important in LTP, learning and memory.


What is FXTAS caused by?

55-200 CGG repeats in FMR1.


What are the pathological symptoms of FXTAS?

- White matter lesions in the middle cerebellar peduncle.

- Ubiquitinated inclusions (protein aggregates).


What are polyglutamine disorders? Give examples.

CAG triplet repeat expansion disorders.

- Spinobulbar muscular atrophy (SBMA).
- HD
- DRPLA (Dentatorubral-pallidoluysian atrophy; Japanese HD).
- Spinocerebellar ataxia (SCA) types 1, 2, 3, 6, 7, and 17.


What are the common features of polyglutamine diseases?

- Autosomal dominant inheritance (with the exception of SBMA which is X-linked recessive).

- Genetic anticipation i.e. age of onset gets progressively earlier over successive generations. This is associated with paternal transmission.

- Inverse relationship between the CAG repeat lengths and age of onset.

- Works by a toxic 'gain of function' mechanism.

- Causes protein accumulation in nucleus and aggregation.


Describe the pathology of HD.

Severe atrophy of the striatum, cortical atrophy, reduction in brain size and thickness of the cortex.

Areas that have lost neurons show astrogliosis (abnormal increase in the number of astrocytes due to the destruction of nearby neurons).


Describe the different categories of HD with regards to repeat lengths.

- 27-35 repeats long means you yourself are not likely to develop the disease yourself, but your offspring are.

- 36-39 repeats means you have the allele but may never develop HD, there is not 100% penetrance.

- 40 or more repeats means that the person will develop the disease with all the symptoms.


Describe protein aggregation in HD.

Protein aggregates are not restricted to areas that are affected by HD i.e. there is no direct correlation between aggregation and pathology.

Furthermore, only the N-terminus of the Huntington protein appears to be in these aggregates.


What is protein sequestration?

The selective interaction of a protein with specific molecules in the cytoplasm. This interaction inhibits its transport into other areas of the cell.


What proteins form polyglutamine aggregates and how?

Proteins that have long non-pathological polyglutamine tracts can be sequestered into mutant polyglutamine aggregates.


What is CRB and how does it regulate gene transcription?

CREB-Binding Protein.

It regulates gene transcription by possessing histone acetyltransferase (HAT) activity.

HATs open up chromatin making DNA more accessible to transcription factors.


What is happening to gene transcription in HD and how can this be treated?

There are very low levels of CRB in Huntington's brains. This means that there is a decreased histone acetylation and a global dysregulation of transcription.

One way to treat this is by using HDAC (histone deacetylase) inhibitors. These drugs are in early stage clinical trials.


What is SBMA?

Spinal and Bulbar Muscular Atrophy.

This is an adult-onset neuromuscular disease that is characterised by muscle weakness and wasting especially in the limbs, face and throat. This causes speech and swallowing difficulties and muscle cramps.


What is the pathology of SBMA?

The degeneration of spinal and bulbar neurons.


What is SBMA caused by?

CAG repeat expansions in the androgen receptor. Mutations are X-linked recessive.


What did SBMA studies in transgenic mice show?

Male mice were getting sick a lot earlier than females. They also had a large amount of protein aggregates in their cell nuclei.

When the male mice were castrated (an attempt to decrease the amount of testosterone) they saw much less sickness and protein aggregation.

When exogenous testosterone was given to female mice, it caused the nuclear accumulation that was found in the males.


What is the obligate step in the pathogenesis of SBMA?

Testosterone drives the nuclear translocation of the androgen receptor. Once the mutant androgen receptor is in the nucleus it starts to accumulate and aggregate.


What are examples of neurodegenerative and neuromuscular disorders that are caused by non-coding repeat expansions?

- Myotonic dystrophy.


- Spinocerebellar ataxia 8, 10, 12, 31 &36.

- ALS (this is the most common genetic cause of motor neuron disease that we know of).

Expansions that are causing these diseases tend to be longer than coding repeat expansions.


What is myotonic dystrophy?

This is an autosomal dominant neuromuscular disease. It is multisystemic affecting muscle, heart, cognitive function, behaviour, eyes and causes endocrine symptoms.


What are the two different types of DM?

1) DM1 CTG expansion in 3’-UTR of DMPK (dystrophia myotonica protein kinase).

2) DM2 CTG expansion in 1st intron of CNBP/ZNF9 (zinc finger domain).

DM1 is more common than DM2 and shows genetic anticipation mainly in maternal transmission.


What are the three methods of non-coding repeat toxicity?

- RNA foci/protein sequestration. These aggregates are not as stable and insoluble as protein aggregates, but there are suggestions that they can sequester various proteins and interfere with their functions.

- Repeat-associated non-AUG translation (RANT). This is where proteins are translated without the start codon AUG.

- Haploinsufficiency.


What is one way in which MD is potentially working?

RNA foci sequester Muscleblind-like proteins (MBNL1-3) and CUG-binding protein/Elav-like family member 1 (CELF1).

When MBNL is sequestered it is unable to carry out its normal function. When CELF1 is sequestered, it becomes phosphorylated and stabilised which leads to upregulation.


GGGGCC repeats are subjected to what? Where are they found?

RANT (they can be translated without a start codon AUG).

These repeats are found in cases of ALS/FTD that are caused by C9ORF72. d


What is unusual about C9ORF72 cases of ALS?

One of the key pathological features of ALS is ubiquinitated inclusions that you can detect using anti-p62 antibodies. In ALS caused by C9ORF72, you see the inclusions in the cerebellum which is unique to this form of ALS.


What happens if RAN translation occurs in a different reading frame? Where does this occur?

The proteins that are translated are a completely foreign string of amino acids.

This occurs in HD.