Genetics Of Cystic Fibrosis

Question 1

CFTR protein

Answer 1

Primary protein affected by cystic fibrosis

This channel proteins function is to allow chloride ions to move in and out of the cell membrane and allow cillia move properly

• channel is open 40% of the time and closed 60% of the time
• dysfunctional protein leads to intracellular build up chloride ions and ultimately inhibits mucocillary movement due to dehydration of the mucus layer. (this leads to high levels of infection due to mucus buildup)

In order to have proper function:

• protein quantity needs to be high (channels on apical surface)
• protein needs to open 40% of the time and close 60% of the time
• must be able to respond to regulator molecules

Question 2

CFTR function is measured how?

Answer 2

(# of CFTR channels present) * ((channel opening probability (40%)) * (channel conductance))

Question 3

CFTR gene specifics

Answer 3

Located at 7q31.2

• chromosome 7
• long arm region 3
• long arm band 1
• long arm sub-band 2

There are 2,000 different known mutations with the must common being:
(P.Phe508 deletion)
- this is a 3 base deletion that results in a loss of phenylalanine (Phe) amino acid deletion

Question 4

CFTR gene defects classifications in cystic fibrosis

Answer 4

Class 1:

• mutations cause absence of synthesis of the protein altogether
• MOST SEVERE*

Class 2:
- mutations cause defective protein maturation and premature degradation

Class 3:
- mutations cause disordered gating and regulation

Class 4:
- mutations cause defective conductance through the ion channel pores

Class 5:
- mutations cause reduced number of CFTR transcripts produced due to promoter or splicing issues

Class 6:
- mutations cause accelerated turnover of mature proteins from the cell surface.

Question 5

What is the best method for determining mutations in CFTR?

Answer 5

Sanger sequencing

PCR is the next best if Sanger is not possible

Question 6

Cystic fibrosis

Answer 6

One of the most common single gene mutations in the US

• is inherited in autosomal recessive disorders
• can show compound heterozygous (where one person is a heterozygote with two different class of mutation in each allele, but will not present any of them)

Occurrence in Caucasian population is very high especially compared to other races
- 1:2,000 w/ 3-5% fo all Caucasians carrying the disease

• High rates in consanguinity*
• having sex with blood relatives

Question 7

Why is cystic fibrosis occurrence so high in Caucasian populations?

Answer 7

It originated in Western Europe which is the dependents of most Caucasians

Hypothesis is that being a heterozygote produce a protection against TB, cholera and/or Black Plague

• this is similar to how sickle cell heterozygous is used to protect against malaria
• very low evidence to support right now