TNR Disorders

Question 1

What are the four principles of TNR disorders and example.

Answer 1

1. Molecular characteristics and consequences of expansion differ
   - the harmful range for repeats is much lower when found in exons as compared to introns as opposed to 3’ UTR as opposed to 5’ UTR which can take the most repeats.
2. The tendency for repeat expansion depends on the gender of the parent transmitting it.
3. Individuals that fit an abnormal range of TNR but have almost no symptoms are said to carry “pre-mutations”
4. TNR disorders have genetic anticipation - the more repeats you have the more severe the symptoms and earlier the onset.

Question 2

Describe how TNR expansion in the coding region and the noncoding regions differ.

Answer 2

In the coding region are responsible for polyglutamine disorders like huntington which leads to proteins with excess polyglutamine residues. This leads to misfolded proteins.

In the noncoding region, there is diminished or absent proteins like in Fragile X. The transcript is not even being made.

Question 3

Describe Huntington’s Disease.

Answer 3

The primary symptoms are saccadic eye movements, ataxic gait, choreatic movements, cognitive impairment, and mood/behavioral disorders.
-so movement disorder and dementia.

Frequency is three to seven out of 100,000.

Typical onset is midlife and from there it lasts 15-20 years.

It is an autosomal dominant mutation. And it is due to expanded CAG repeats in the first exon of the huntington protein.

The huntington protein is more misfolded and prone to forming aggregates which is toxic for the neurons.
-aggregates modify transcription, induce proteolysis, interfere with axonal transport and disrupt synaptic transmission.
The ubiquiton-proteosome pathway is overwhelmed and this also sequesters important proteins.

Question 4

What are the molecular genetics of Huntington?

Answer 4

The normal range of CAG repeats is 6-26.

The intermediate range is 27-35. They aren’t really affected by carry a vulnerability to expansion

Premutation is 36-39 and its incomplete penetrance of Huntington.

Disease phenotype is over 39 CAG repeats and patient is always affected.

This transmission is paternal, repeat expansion occurs through spermatogenesis.

Question 5

Describe Fragile X molecularly.

Answer 5

It is X linked dominant inheritance and is the most common inherited cause of intellectual disability and autism spectral disorders.

The mutation is caused by CGG expansion in the promoter of the FMR1 gene.

Normal: 6-44 CGG repeats
Gray zone: 45-55
Premutation: 55-200 CGG repeats
Full mutation: 200 - 4000 CGG repeats

for premutation, when it is transmitted by the mother there is a high risk for expansion. (Expansion to full mutation only occurs in the oocyte.)

at full mutation the FMR1 gene is transcriptionally silence and there is absence of protein. Methylation of the FMR gene.

FMR protein is an RNA binding protein which regulates translation of target mRNAs.

Question 6

Fragile X syndrome: What are the symptoms of full mutation in males? What are the phenotypes of premutation?

Answer 6

In males: Cognitive disability with a low IQ. After puberty they have long narrow face, large everted ears.

Hypotonia, hyperextensible joints.

Macroorchidism - large testes in 90%

Premutation: 2 conditions

1. Fragile X associated Tremor-Ataxia Syndrome, the risk is greater in males than females, its a neurodegenerative disorder.
2. Primary Ovarian Insufficiency
   - cessation of menses before the age of 40
   - 20% of female with pre-mutation, 1% of population normally.

Question 7

Describe Friedreich’s Ataxia

Answer 7

Autosomal recessive.

ataxic gait initially followed by progressive weakness in the extremeties, cognitive function is largely preserved.

-caused by GAA expansion in the first intron of the frataxin gene (FRDA) which encodes a mitochondrial protein.

It is present in 50% of cases of hereditary ataxia.

Disease prevalence of 1 in 29,000 and a carrier rate of 1 to 90.

Normal: 7-34 repeats
Diseased 200-1200 repeats.

This results in mRNA transcript loss. (there is no splicing and the mRNA is quickly degraded)

The consequences are most severe in tissues with large amounts of mitochondria. (heart and spinal chord) because your mitochondria is dysfunctional.

cell loss in the dorsal root ganglion, cardiomyocytes, and pancreatic beta cells.

1. Neurologic dysfunction
2. Cardiomyopathy - heart failures
3. Diabetes mellitus (pancreatic problems, no insulin.

There is also genetic anticipation with this disease.

Question 8

Describe myotonic dystrophy.

Answer 8

It is autosomal dominant disorder and is caused by CTG repeats in the 3’ UTR of the DMPK gene.

Key features: adult onset muscular distrophy

• myotonia
• type 2 diabetes
• cardiomyopathy.

Incidence is 1 per 10,000.

Normal: 5-34 CTG
Premutation: 35-49 presents no symptoms 
Mild phenotype: 50-150 CTG repeats. 
Classic DM1 (150-1000) repeats 
Severe (congenital) >1000. 

Both parents transmit until 1000 repeats. Expansion stops in males, after that only females can expand farther.

Congenital MD (>2000) is always inherited from the mother.

The more repeats the larger the loop that forms at the 3’ UTR. This sequesters more and more RNA binding proteins especially those involved with splicing leading to RNA toxicity.