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CRRAB II- Week 6 > Scott: Cystic Fibrosis > Flashcards

Scott: Cystic Fibrosis Flashcards

1
Q

What type of genetic disease is CF?

A

Autosomal RECESSIVE

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2
Q

What causes CF?

A

INACTIVATING MUTATIONS in CF transmembrane CFTR gene

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3
Q

What is the second most frequent life-shortening genetic disease in hte US?

A

CF

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4
Q

What is CFTR?

A

chloride ion channel

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5
Q

Where is CFTR found?

A

on the apical surface of epithelial cells lining:

AIRWAYS
PANCREATIC DUCTS
INTESTINES

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6
Q

What are the most serious consequences and common COD from CF?

A

Pulmonary

Progressive lung disease causes death in 90% of pts

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7
Q

What are the clinical consequences of CF?

A
  1. Pulmonary
  2. GI- exocrine pancreas, diabetes, intestine
  3. Male infertility
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8
Q

Where is the CFTR gene found?

A

long arm of chromosome 7

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9
Q

What ethnic group is most commonly affected by CF?

A

Caucasians
Hispanics
African americans
Asian americans

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10
Q

What is a class I CFTR mutation?

A

NO PROTEIN PRODUCED

Nonsense mutation creates stop codon, Often mRNA is degraded

G542X, 5% of CF alleles

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11
Q

What is a class 2 CFTR mutation?

A

DEFECTIVE PROTEIN FOLDING

Activates ER quality control,
degradation of protein

F508del, 70% of CF alleles

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12
Q

What is a class 3 CFTR mutation?

A

DEFECTIVE GATING OR REGULATION OF CHANNEL OPENING

G551D, 4% of CF alleles

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13
Q

What is a class 4 CFTR mutation?

A

defective in ion transport

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14
Q

What is a class 5 mutation?

A

Normal CFTR produced but decreased amounts

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15
Q

What are more severe mutations? Less severe?

A

More severe- 1-3

Less severe- 4 and 5

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16
Q

What characterizes severe CFTR mutations?

A 
≤ 1% CFTR activity remaining
Diagnosed in FIRST YEAR
Median survival 37.4 y
Pancreatic INSUFFICIENT
At risk for CF-related diabetes, liver disease
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17
Q

What characterizes LESS severe CFTR mutations?

A

~5% CFTR activity remaining

May have LATE presentation
Survival to 50 not uncommon
Pancreatic SUFFICIENT

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18
Q

5 mutations occur in > 1% of US CF patients- F508Δ, G542X, G551D, W1282X,
N1303K. What category are they in?

A

SEVERE

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19
Q

What is the structure of the CFTR chloride ion channel?

A

The MSD forms a PORE for the chloride ion channel.

Nucleotide binding domains NBD and R domain provide REGULATORY SITES that promote opening of channel.

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20
Q

What do the NPD and R domains do?

A

NBD binds ATP

R has phosphorylation site for PKA

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21
Q

What is the F508del folding defect?

A

Principle folding defect

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22
Q

Where is the CFTR protein complex synthesized and what does it require?

A

ER

INTRA domain folding and INTER domain interactions

chaperones

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23
Q

What causes the F508del defect?

A

Incorrect folding of the NBD1 domain

Incorrect interaction of NBD1 with other domains

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24
Q

What happens when there is incorrect folding?

A

Altered interaction w/ chaperones

  1. RETENTION in ER and activation of quality control pathways
  2. DEGRADATION by the proteasome
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25
Q

Which mutations cause the most severe disease?

A

Mutations that result in little or NO functional protein

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26
Q

What outcomes are commonly associated w/ SEVERE mutations?

A
  1. Defect in pancreatic duct> pancreatic enzyme insufficiency
  2. Worse pulmonary disease
  3. Diabetes and Liver disease (severe mutations necessary to cause these but not all do)
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27
Q

What are the most frequent CF mutations in the US?

A

G542X
G551D
F508del

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28
Q

What is the G542X mutation?

A

Mutation creates stop codon at amino acid 542–>

Decreased mRNA/ non-functional protein

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29
Q

What is G551D?

A

Mutation makes ion channel unable to respond to ATP opening signal> greatly increase time in CLOSED conformation

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30
Q

What the F508del mutation?

A

Most common CFTR mutation

Almost complete LOSS of functional protein

  • Folding defect–> degradation of most protein
  • small fraction of protein at cell surface is defective in gating
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31
Q

What happens when the CFTR is functioning normally?

A

When the channel is OPEN ion channels flow through it “downhill” in the direction of the EC gradient>
EC gradient across the airway epithelial apical cell membrane favors flow of Cl ions OUT of the cell and into the EXTRACELLULAR space>
Increased concentration of Cl ions OUTSIDE the cell>
Creates osmotic conditions for flow of water out of the cell

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32
Q

What does the opening and closing of CFTR channel control?

A

Movement of water to apical surface of epithelial cells

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33
Q

What happens if the CFTR is NOT function or not regulated correctly?

A

Insufficient water is delivered to the cell surface

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34
Q

What is required to open the chloride channel?

A

Two signals:

  1. Phorsphorylation of R domain by PKA (sets conditions for opening making it possible for ATP to communicate w/ channel). PKA is activated by cAMP
  2. Binding of ATP to two NBD domains–> conformational change
35
Q

What determines the balance of water between the cell surface and the cell interior?

A

How long the CFTR stays open

36
Q

What closes channels?

A

Absence of environmental signals>

dephosphorylation of R domain

Hydrolyzation of ATP

37
Q

Why is CFTR chloride ion channel essential for respiratory function?

A

Airway surface liquid volume (ASL) is dependent on CFTR

38
Q

What is ASL?

A

A layer of liquid about 7 um thick overlying airway epithelium that is essential for the clearance of mucus (activity of cilia and hydration of mucus)

39
Q

What happens to ASL if CFTR is defective?

A

ASL layer is NOT maintained

40
Q

What happens if there is a decreased ASL layer?

A

Chronic infection–> permanent damage

41
Q

What are the 2 ways that a decreased ASL layer can lead to chronic infection?

A
  1. Build up of viscous mucous> failure to clear bacteria

2. Persistent colonization and desicated mucus> inflammation

42
Q

What are characteristic CF bacterial infections?

A

Stapholococcus aureus,

Pseudomonas aeruginosa, Burkholderia cepacia

43
Q

What are the 2 ways that a decreased ASL can lead to permanent damage?

A
  1. Infection, inflammation and mucus plugging> long term structural damage (bronchioletasis, bronchiectasis)
  2. Unless stopped ultimate outcome is respiratory failure
44
Q

What is the major COD for most individuals w/ CF?

A

Pulmonary failure d/t airway infection

45
Q

What are the major organisms that infect the airways of pts w/ CF?

A 
Haemophilus influenzae
Staphylococccus  aureus
Pseudomonas aeruginosa (pediatric pts)
Burkholderia cepacia
Aspergillus fummigatus

*these pathogens are usually NOT found in non-CF population

46
Q

What is the goal of treatment for pt’s w/ pulmonary related CF problems?

A

LIMIT mucus buildup

PREVENT/TREAT infections

47
Q

What is the mainstay tx for pulmonary sxs of CF?

A

Chest physiotherapy to improve drainage

Aggressive treatment of infection- antibiotics

48
Q

What is additional tx for pulmonary sxs of CF?

A

Hypertonic saline and Dnase aerosols to make MUCUS LESS VISCUS

Anti-inflammatories

49
Q

Where is CFTR located in the pancreas?

A

Epithelial cells lining PANCREATIC DUCT express CFTR

Base of the duct secretes high concentration of proteins, especially proteolyctic enzymes

50
Q

What do the CFTR expressing cells of the pancreas secrete?

A

HCO3

51
Q

What does the secretion of HCO3 in the pancreas do?

A

recruits luminal water and neutralizes secretions

prevents formation of protein plugs

52
Q

What happens in the pancreas if the CFTR lose function?

A

BLOCKAGE OF DUCT by secreted protein plugs>
damage to cells>
leakage of proteolytic enzymes>
destruction of tissue

53
Q

What is the pancreatic phenotype of CFTR dependent on?

A

severity of the genetic mutation

54
Q

Where is CFTR expressed in the intestine?

A

Crypts of intestinal epithelium

55
Q

What happens if the intestinal CFTR lose function?

A

fail to secrete water>

dehydration of the lumen and viscus mucus

56
Q

What are the consequences of loss of function of CFTR in the intestine?

A
  1. Obstruction (Meconium illeus-infants, and DIOS-older)
  2. Inability to absorb protein/fats
  3. Susceptibility to GI cancers
57
Q

How does CF affect male fertility?

A

Vas deferens is ABSENT

Becomes OBSTRUCTED in the fetus/infancy and is REABSORBED

58
Q

How does CFTR act in sweat glands?

A

Promotes uptake of Cl ions from extracellular space w/ Na following

59
Q

How does CF affect sweat glands?

A

Decreased ability to absorb Cl and Na> increased NaCl in sweat

NO TISSUE DAMAGE–> other ion channels compensate

60
Q

What is a definitive diagnostic test for CF?

A

Sweat test

61
Q

How does CF affect the pancreas?

A
  1. Pancreatic exocrine insufficiency

2. CF related diabetes

62
Q

What is pancreatic exocrine insufficiency? How does his affect individuals w/ two “severe” alleles?

A

Malabsorption of lipids
Malabsorption of fat based vitamins

All individuals with two “Severe” alleles are pancreatic insufficient and require pancreatic enzyme replacement therapy to maintain nutrition

63
Q

What is CF related diabetes and who does it affect??

A

Only occurs in homozygous for “severe” alleles but not all

64
Q

What are characteristics of both T1D and T2D associated w/ CF related diabetes?

A

Loss of pancreatic cell mass
AND
insulin resistance

65
Q

How id molecular genetic knowledge used for better testing and treatment?

A
  1. widespread screening

2. new txs to correct specific mut defects

66
Q

Why is screening for CF feasible?

A

Molecular genetics!

CFTR gene mutation is KNOWN

DNA seq of most muts is KNOWN

67
Q

What is the ACOG recommendation for genetic carrier screening?

A

Offer to ALL individuals planning a pregnancy or seeking prenatal care

68
Q

When do you offer prenatal testing for CF?

A

When 25% chance of CF

Both parents are carriers or they have a previous child w/ CF

69
Q

Do we screen newborns for CF?

A

YES

required in ALL st

70
Q

What is the value of carrier screening?

A

Allows parents to know which group they fall into

Two carriers: 1/4
1 carrier: 1/1000
Neither: 1/250,000

71
Q

What is the carrier frequency for individuals of northern european caucasian ethnic background?

A

1/25

72
Q

How is prenatal testing for CF conducted?

A

Chorionic villus sampling 10-12 weeks for DNA mutation testing
Amniotic fluid 16-17 weeks for DNA mutation testing
Also ultrasound for echogenic bowel

73
Q

Why does newborn screening for CF and early detection make a difference?

A

Nutrition- pancreatic enzyme replacement

Pulmonary function- aggressive tx to prevent obstruction, infection

74
Q

What is the typical protocol for newborn screening of CF?

A
  1. IRT immunoreactive trypsin- test of pancreatic function. Part of panel done on heel stick blood sample.
    (screening step 1)
  2. DNA mutation analysis based on panel representing vast majority of disease causing mutations
    (screening step 2)
  3. sweat test
    test of CFTR function
    (diagnostic)
75
Q

What is the definitive test for CF?

A

Sweat test

Induce sweat w/ chemical treatment>
sweat released over 30 min is absorbed>
Cl content measured

76
Q

Is DNA testing for CF done?

A

Yes , b/c of new treatments that are mutation specific

77
Q

How do we treat CF?

A

Aggressive, meticulous treatment of all possible manifestations

78
Q

What are the major objectives when treating CF?

A
  1. Lung- clear secretions, control infections
  2. Maintain nutrition
  3. Prevent intestinal obstruction
79
Q

What is a curative intervention for pulmonary sxs from CF?

A

lung transplant

80
Q

What are the two new strategies to treat CF?

A
  1. Lung transplant- 60% survival after 2 years

2. Drugs to target specific deficiencies of CFTR mutations

81
Q

What drug targets G551D (represents 4% of CFTR mutations and is a defect in ATP regulation of gating)?

A

IVACAFTOR (Kalydeco)-
corrector for G551D
keeps channel in open conformation for higher percent of time, even without ATP gating

IMPROVES FEV1 BY 10%

FDA approved Jan. 2012

82
Q

What drug targets F508 mutation (70% of alleles, Defect in folding leads to degradation before reaching cell surface
Small percent that reaches surface is defective in gating)?

A

IVACAFTOR + LUMACAFTOR

Lumacaftor is a corrector for F508 and promtes traffic to cell surface instead of degradation

Combination of the two–> 4-7% improvement of FEV1

83
Q

What drug targets G542X (Premature stop codon, 5% of alleles)?

A

ATALUREN

corrector for premature stop codon mutations

causes ribosome to be less sensitive to stop codons

phase 3 clinical trials show some improvement, but not statistically significant

CRRAB II- Week 6 (4 decks)

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