Bioinformatics in a Medical Context

Question 1

Inactive vs. active kinase form

Answer 1

Inactive: DFG is out and exposed to the solvent, the activation loop is closed
Active: DFG is in the cavity

Question 2

Acute myeloid leukemia (AML)

Answer 2

A disease that results in the super-production of lymphocytes, a lot of B cells are produced

Question 3

What are mutation hotspots?

Answer 3

Mutation hotspots are segments of DNA that are especially prone to genetic alteration.

Question 4

What are FLT3 and KIT?

Answer 4

• Mutation hotspots in AML
• They have 65% sequence similarity and the hotspot is very close to the binding site
• Gain of function mutations

Question 5

What is chronic myeloid leukaemia?

Answer 5

Leukemia where the bone marrow makes too many white blood cells. The kinase involved is BCR-ABL and comes from the reconstruction of the chromosomes. The kinase is constitutively

Question 6

Why did Imatinib resistance develop?

Answer 6

More than 100 point mutations inside the BCR-ABL kinase domain can reduce or even abrogate the interaction between Imatinib and the protein. Five amino acids are critical for Imatinib binding (T315, M318, E286, D381, I360). Except for T315, none of the remaining 4 residues have ever been the object of naturally occurring mutations in patients affected by CML.

Question 7

What is missense mutation?

Answer 7

A chance in one amino acid in a protein arising from a point mutation in a single nucleotide. It is a type of nonsynonymous substitution in a DNA sequence.

Question 8

Areas of DNA mutation

Answer 8

• wild-type
• core (most damaging)
• surface (could have an allosteric effect)
• interface

Question 9

What pathways do missense variants target?

Answer 9

• Proliferative, cancer-associated pathways
• Metabolic pathways
• Sensory, immune, and metabolic pathways

Question 10

What is titin?

Answer 10

• A protein expressed from 364-exon TTN gene
• 34350 aa in length
• Composed of self-folding domains and elastic elements
• So large that all individuals will carry several rare variants by chance
  The majority of genetic variation is yet to be characterised

Question 11

Molecular ruler

Answer 11

Determines sarcomere length

Question 12

Molecular spring

Answer 12

Prevents overextension on muscle relaxation and passive force on contraction

Question 13

Molecular scaffold

Answer 13

Multiple binding sites acting as signalling hubs, regulates signalling cascades, and greater cytoskeletal architecture

Question 14

Stress sensor

Answer 14

Measures and communicates changes in sarcomeric forces downstream

Question 15

Dynamic cellular components

Answer 15

PTMs and isoforms

Question 16

Diseases titin is involved in

Answer 16

• Tibial muscular dystrophy
• Hereditary myopathy with early respiratory failure
• Dilated cardiomyopathy

Question 17

Skeletal muscle and muscular dystrophy

Answer 17

• Congenital skeletal muscle diseases associated with titin variants are typically split into myopathies and dystrophies
• Myopathy is muscle weakness present from birth
• Dystrophy is progressive muscular degeneration

Question 18

Subtypes of cardiomyopathy

Answer 18

• Hypertrophic cardiomyopathy
• Dilated cardiomyopathy
• Restrictive cardiomyopathy
• Arrhythmogenic cardiomyopathy

Question 19

Hypertrophic cardiomyopathy (HCM)

Answer 19

The most common cardiomyopathy. It causes thickening of the heart muscle walls and thus constriction of the heart chambers.

Question 20

Dilated cardiomyopathy (DCM)

Answer 20

The cardiomyopathy most often associated with titin. It causes enlargement of the heart, the heart chambers expand and the muscle walls stretch.

Question 21

Restrictive cardiomyopathy (RCM)

Answer 21

Does not involve stretching or compressing of the heart muscle. A loss of elasticity and rigidity of the heart muscle walls restricts the cardiac cycle.

Question 22

Arrhythmogenic cardiomyopathy (ACM)

Answer 22

Characterised by arrhythmia. Typically diagnosed as arrhythmogenic right ventricular cardiomyopathy.