31. Mutation Case Studies

Question 1

What causes cystic fibrosis?

Answer 1

• Defect due to CFTR protein important for Cl- ion transport
• Mutation causes Cl- ion build up which in turn leads to accumulation of sticky mucus in the ducts of the exocrine, lungs and vas deferens

Question 2

What is the most common mutation that gives rise to cystic fibrosis?

Answer 2

The frame deletion of phenylalanine at position 508

Question 3

What are the differences in haemoglobin subunits for adults and fetal?

Answer 3

Adults have 2 alpha and 2 beta

Fetal has 2 alpha and 2 gamma

Question 4

What mutation gives rise to sickle cell anemia?

Answer 4

• One single base pair change in the beta haemoglobin leads to a missense mutation
• The sixth AA changes from glutamic acid to valine, which alters the charge at this site
• Affects haemoglobin structure at low oxygen where HbS clumps in small vessels

Question 5

What does the aggregation of sickle cells cause?

Answer 5

• Changes the shape of the RBC to sickle shape which can block capillaries
• Lifespan of RBCs in HbS is reduced from 120 to 20 days resulting in aenemia

Question 6

What is thalassaemia caused by?

Answer 6

• Mutations in alpha or beta thalassaemia lead to decreased synthesis or stability of either alpha or beta globin respectively
• Abnormal Hb may lead to excessive RBC loss and cause anaemia

Question 7

What are the specifics of alpha thalassaemia?

Answer 7

4 alpha genes in total, the severity of the disease depends on how many are mutated

Question 8

What are the different forms of beta thalassaemia?

Answer 8

There are 2 beta genes for which there are 4 severities

Question 9

What are the three phenotypes are severity for beta thalassaemia?

Answer 9

1. . Beta thalassaemia trait/minor (one gene)
2. Beta thalassaemia intermedia (two genes) reduced
3. Beta thalassaemia major (two genes)

Question 10

What are splice mutations for beta thalassaemia?

Answer 10

The single nucleotide changes may create new splice sites

- May destroy splice sites and activate cryptic ones

Question 11

What does a triplet repeat mutation mean?

Answer 11

Changes in phenotype due to the expansion of a triplet repeat (3 base sequence)

Question 12

What mutation causes Huntington’s disease?

Answer 12

• Autosomal dominant gain of function
• CAG repeats in exon 1 of 67 make the protein toxic causing death of brain neurons
• CAG expansion within the coding sequence

Question 13

How is the severity of Huntington’s disease diagnosed?

Answer 13

• The longer the repeat the earlier the onset of the disease
• Homozygous affects phenotype and disease progression ate
• The longer the repeat the earlier the onset

Question 14

What is the cause of the fragile X syndrome?

Answer 14

• There exists a fragile X mental retardation protein, a regulatory protein which binds mRNA in neuorns and dendrites -> needed for synaptic development
• CGG expansion in 5’UTR triggers methylation of promoter and block transcription causing loss of FMRP