Ex2 L7 - Syndromes of Telomere Shortening

Question 1

What happens when telomeres are too long?

Answer 1

cells activate a clipping mechanism that makes them too short

Question 2

The telomerase enzyme complex is needed for…

Answer 2

allowing stem cells and gametes to survive/replicate, but can also cause cancer

Question 3

What are the two essential components of the telomerase enzyme complex?

Answer 3

telomerase reverse transcriptase (hTERT)- catalytic subunit

telomerase RNA component (hTR or hTERC) - provides RNA template

Question 4

What is the Dyskerin complex?

Answer 4

consists of dyskerin protein and three others

Question 5

The telomerase enzyme complex has —– components

Answer 5

6 ribonucleotide components

Question 6

Telomere syndromes are associated with mutations in…

Answer 6

5/6 of the telomerase enzyme components

Question 7

Telomere syndromes cause…

Answer 7

critical shortening of telomeres to the extent that they produce a phenotype and cause health issues

Question 8

What are the telomere cap proteins?

Answer 8

The Shelterin complex:
- protects ends of telomeres from DNA repair (cutting of the overhanging end) until telomerase gets there
- regulates telomerase activity by acting as a docking station

Question 9

People with telomere syndromes have telomeres in the — percentile

Answer 9

1st %

Question 10

Telomere syndromes are —– conditions.

Answer 10

inherited

Question 11

What is genetic anticipation?

Answer 11

• with every generation, telomeres get shorter and the telomere syndrome gets more severe
• since telomeres are needed for gamete formation, every generation has even shorter telomeres than the one before (they start off even worse)

Question 12

What is a hematologic manifestation in relation to telomere syndromes?

Answer 12

• most common is that people with telomere syndromes die from aplastic anemia (no blood cell division)
• stem cells (including hematopoietic stem cells) senesce as a result of short telomeres
• blood cells have rapid turnover, so if they can’t be replaced, this is where we will see problems first
• causes low oxygenation, clotting, immune response, etc. which ends up being the cause of death

Question 13

Describe (simply) why maternal stress leads to infants having shorter telomeres

Answer 13

maternal stress activates the HPA axis, produces cortisol, cortisol crosses the placenta, causes inflammation/cytokine release, which affects the baby and shortens telomeres

Question 14

Describe Dyskeratosis Congenita (DC)

Answer 14

• rare telomere syndrome, results from mutations in Dyskerin (hTR, hTERT, DKC1) or Shelterin complex genes
• autosomal recessive and/or X linked
• Triad of cutaneous abnormalities/presnetations: oral leukoplakia, skin hyperpigmentation, and nail dystrophy/ridging
• Bodily effects: bone marrow failure, aplastic anemia, and premature aging

Question 15

Describe Hoyeraal-Hreiderasson Syndrome (HHS)

Answer 15

• very rare telomere syndrome, homozygous hTERT or DKC1 mutations
• happens more often in small populations where there is inbreeding
• severe, multisystem presentation (impaired prenatal and postnatal growth, progressive aplastic anemia, severe immunodeficiency, cerebellar hypoplasia)
• usually diagnosed months after birth, and patients die by age 4

Question 16

Describe Idiopathic Pulmonary Fibrosis (IPF)

Answer 16

• progressive lung scarring leading to respiratory failure as a result of impaired elastic capacity and gas exchange
• hTERT and hTR mutations identified in many patients
• short telomeres identified even in patients without the mutations