Mutation + Single Gene Defects

Question 1

What is a mutation?

Answer 1

Heritable alteration or change in genetic material

Question 2

What is a polymorphism?

Answer 2

Non-pathogenic alteration in DNA which may alter protein function but not usually deleterious

Question 3

How do mutations occur

Answer 3

Errors in DNA replication/repair

Exposure to exogenous mutagens (smoke, radiation, chemicals)

Question 4

What is a point mutation? Distinguish transitions vs transversions

Answer 4

Substitution of one base for another

Transition = purine to purine (A to G), pyrimidine to pyrimidine (T to C)

Transversion = purine to pyrimidine (A to C/T)

Question 5

What is a synonymous vs non-synonymous point mutation? What are the two types of non-synonymous point mutation?

Answer 5

Synonymous = amino acid sequence unchanged due to redundancy of genetic code

Non-synonymous = does change aa sequence

— missense = replacement of one aa for another
— nonsense = replacement of one aa for stop codon

Question 6

What does R117H or Arg117His mean?

Answer 6

Arginine residue 117 replaced by histamine

Question 7

What does G542X or Gly542Stop mean?

Answer 7

Glycine residue 542 replaced by stop codon

Question 8

What is a frameshift deletion/insertion?

Answer 8

Where number of nucleotides removed/added is not a multiple of 3, causing a shift in reading frame

Question 9

What do frameshifts often cause?

Answer 9

Premature termination

Question 10

Duchenne Muscular Dystrophy caused by? Therefore inheritance is…?

Answer 10

Exon deletions in X chromosome

X-linked recessive

Question 11

What is anticipation, and what causes it?

Answer 11

More early onset of disease as you go down generations

Due to expansion of trinucleotide repeat sequences - become unstable during replication causing the replication of more repeats

The more repeats, the more protein function is affected

Question 12

Why are triplet repeats more likely to expand?

Answer 12

Slippage during transcription, where repeats slip out of position and more triplets are transcribed than were there originally in the template

Question 13

What triplet repeat causes Huntington’s disease?

Pathology and symptoms

Answer 13

> 35 repeats of CAG repeat in the huntingtin gene

Pathology = neuron degeneration in basal ganglia and cortical brain regions

Symptoms = unsteady gait and jerky movements, LATER they develop dementia

Question 14

What triplet repeat causes myotonic dystrophy 1?

Symptoms?

Answer 14

CTG repeat in untranslated region of Dystrophia Myotonica Protein Kinase

Symptoms - muscle pain, myotonia (hyper excitability of muscle) , cardiac arrhythmias

Question 15

Loss of function mutations tend to be dominant or recessive?

Answer 15

Recessive

Question 16

What is haploinsufficiency?

Answer 16

When 50% of a functional gene is not sufficient for normal function

Question 17

What is a dominant negative effect?

Answer 17

When a loss of function mutant protein is interfering with the function of the normal mutant

Question 18

What is the cause of achondraplasia?

Answer 18

Mutation in fibroblast growth factor receptor 3, which normally inhibits enodochondral bone growth

Mutation will make the receptor function in absence of ligand - gain of function

Question 19

Prader-Willi and Angelman syndromes are both examples of..?

Explain how each are caused

Answer 19

Imprinting diseases

Prader-willi when paternal (willys) SNRPN gene is abnormally methylated (switched off)
Angelman when maternal (angels) UBE3A gene is abnormally methylated (switched off)