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Woe is the child who tastes salty from a kiss on
the brow,for he is cursed, and soon must die.
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Statistics

• Cystic fibrosis affects 1 out of every 2500
  newborn Caucasians and it is suspected that 1 in
  25 Caucasians are carriers of the disease
• In the United States, approximately 30,000 people
  have cystic fibrosis and it is thought that 1 in
  31 Americans is a carrier of CF
• Most CF patients do not live beyond their 30s

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CF

• Characterized by pulmonary disease and infection,
  insufficient pancreatic function causing
  malabsorption of nutrients, an elevation in sweat
  chloride levels, and sterility in males
• Caused by mutation of CFTR protein
• Affects epithelial cells lining passageways of
  the lungs, liver, pancreas, intestines,
  reproductive tract, and skin

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• Autosomal recessive genetic disease
• Disease identified in 1950s
• 1985 gene identified and mapped

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CF Gene

• Chromosome 7
• q31.2
• 250 000 base pairs long
• 27 exons
• mRNA transcript 6129 base pairs
• 4443 bp code for amino acid sequence of CFTR
  protein

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Cystic Fibrosis Transmembrane Conductance
Regulator

• Class ABC proteins or ATPase
• Nucleotide-Binding Domain (NBD or NBF)
• Membrane-Spanning Domain (MSD)
• Trans-Membrane Domain (TMD)
• Regulatory Domain (R domain)

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Normal CFTR mechanism

• Stimulus
• Adenylate Cyclase produces cAMP
• cAMP activates Protein Kinase A
• In the presence of ATP, PKA phosphorylates R
  domain
• ATP hydrolyses or binds to NBD1 and NBD2
• Chloride ion passes through channel

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Multi-functional Protein

• CFTR regulates Outwardly Rectifying Chloride
  Channels (ORCC)
• Regulates Epithelial Sodium Channels (ENaC)
• Regulates Inwardly Rectifying Potassium Channels
  (ROMK)
• Regulates ATP release

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Mutations

• Over 800 known mutations to CFTR protein causes
  CF
• Most common, accounting for 70 of CF cases, is
  caused by the ?F508 mutation
• Mutations affect the efficiency of chloride
  transport and reabsorption in the CFTR protein

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?F508

• ?F508 causes the deletion of three nucleotides
• Occurs on NBD1
• Results in the deletion of phenylalanine

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Theoretical Model of NBD1
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Effects of mutation

• Mutant proteins never reach the plasma membrane
• Retained by endoplasmic reticulum to be degraded
• Trafficking defect
• Mutant proteins that do reach the membrane do not
  respond to cAMP
• Functional defect

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Effects of mutations
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Mutated CFTR protein mechanism
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Effects of mutated CFTR protein

• Pulmonary disease and infection
• Insufficient pancreatic function causing
  malabsorption of nutrients
• An elevation in sweat chloride levels
• Sterility in males (CBAVD)

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Treatment

• Pilocarpine Sweat Test
• Potentially- genetic therapy
• Enzymatic supplements
• Diet
• Antibiotics

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