Lecture - CF As A Genetic Disorder Flashcards
1
Q
Cystic fibrosis clinical features
A
- chronic obstructive lung disease
- pancreatic exocrine deficiency
- male infertility due to CBAVD
- meconium ileaus
- biliary cirrhosis
2
Q
Cystic fibrosis genetics
A
- autosomal recessive disorder
- affects 1/2500 caucasian
- 1 in 25 are healthy carriers
- unaffected siblings carrier is 2/3
- child of carrier is 1/2 for carrier risk
- siblings of parents carrier risk is 1/2
- incidence varies with ethnic origin: asian is 1/90.000 (1/150)
- carrier frequency: 2xsqrt(incidence)
3
Q
IDentification of the CF gene
A
- positional cloning
- CFTR was the first autosomal gene isolated by positional cloning
- gene locus on chromocome identified by linkage analysis
- CF localised to chromosome 7q31
- gene has 27 exons, predicting 1480 aa protein
- p.F508del mutation detected
- gene transcript expressed in sweat glands, lungs and pancreas
4
Q
CFTR protein function
A
- ABC transporter family sited in apical membrane of epithelial cells
- functions as a chloride channel
- cAMP activated
- different mutations have different effects on function
- most common mutation is pF508del
5
Q
CF allelle mutation
A
- over 2000 different types of CF mutations, most are very rare
- F508 - 70% alleles
- G551D, G542X - 4, 3% alleles
- if not F508del, further mutation testing can be arranged: CF mutation panel
- remember - mutation depends on ethnic background
6
Q
- severe and mild mutations
A
- SevereL F508del, G551D, G542X, R553X, W1282X
- Mild: R117H, R234W, R347P, A455E, P574H
- Mild mutant alleles are dominant over severe and convey pancreatic sufficiency. Severe mutations correlate with pancreatic insufficency
7
Q
CFTR functional classifications
A
- class I: no protein synthesis
- Class II: block in processing: F508del
- Class III: defective regulation
- Class IV: alrtered conductance
- Class V: reduced synthesis
- Class VI: impaired conductance of other ions
8
Q
CF genotype:phenotype correlation
A
- severe with pancreatic insufficiency
- severe mutations do not correlate well with severity of pulmonary disease
- polymorphism variable effect
- intrafamilial variations in severity
9
Q
CF mutations alterations
A
- can be affected by other sequence variation (cis or trans)
- splicing variants
- results in different transcripts: normal amount of protein with R117H (reduced conductivity), reduced amount of CFTR protein, altered protein size…
10
Q
CBAVD
A
- accounts for 1-2% male infertility
- 97% of males with CF have CBAVD
- is a CFTR-related disorder
11
Q
Newborn screening
A
- reduced morbidity in first 2 yearrs of life
- improved nutrition in first 10 years
- improved lung function in first 10 years
- screen for IRT (caused by thick secretion blocking pancreatic ducts)
- false positives and false positives
- also sweat test
- 92% of CF babies detected
- 2% not detected but known high risk
- 6% missed
- prognosis varies
12
Q
Genetic counselling
A
- prenatal diagnosis with DNA analysis of Chorion villus sample - direct mutation analysis
- IVF
13
Q
Possible therapies for CF
A
- gene therapy: add functional CFTR gene to cells
- Pharmacotherapy: activating mutant CFTR in cells: CFTR correctors/potentiators
- Non CFTR approaches: Down regulate ENaC, increase Ca activated chloride channel
14
Q
Possible pharmacotherapy for class 1
A
- premature stop signal - do not produce protein
- ## Ataluren: Glycosides that read through stop signals
15
Q
Possible pharmacotherapy for class 2
A
- abnormal protein strucrture, degraded after translation
- chaperones: aid survival and placemen
- VX-809: Lumicaftor
