Cystic Fibrosis

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Cystic Fibrosis

• AHMG, Fall 2004
• Juniata College

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Introduction

• Term coined 1938 cystic fibrosis of the
  pancreas
• Symptoms of classical CF
• Chronic lung infections, inflammation (90 of
  patients)
• Pancreatic insufficiency (85 of patients)
• Increased electrolyte level in sweat
• Meconium ileus (obstruction of bowel in newborn)
• Diabetes Mellitus
• Liver cirrhosis
• CBAVD (congenital bilateral aplasia of the vas
  deferens) in 95 of males

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Primary defect

• Decreased chloride ion export and increased
  sodium ion absorbance leading to insufficient
  hydration of epithelial surfaces (lung, pancreas,
  sweat glands, etc.)
• Sticky mucus on epithelium that cant be cleared
  by cilia
• Bacteria such as S. aureus and Pseudomonas
  aeruginosa colonize the lungs

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CF genetics

• Autosomal recessive
• Mutations in CFTR (cystic fibrosis transmembrane
  conductance regulator), located on chromosome
  7p31.2
• CFTR is a chloride ion transporter that binds ATP
  and hydrolyzes it for energy to transport Cl-.
  (1480 a.a.)
• CFTR gene is 230 kb transcript is 6.5 kb

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Mutations in CFTR

• Over 700 have been noted.
• Over 2/3 of mutant alleles are ?F508 (in-frame
  deletion of phe at residue 508)
• Mutation is in the nucleotide binding fold
  domains (protein is full-length, -1 a.a.)
• Cant be folded properly, so doesnt get out of
  the Golgi apparatus
• If mutant is folded properly, it gets to the
  surface and works sufficiently, so this is a good
  therapy target
• Low temperatures promote proper folding of
  mutants
• Homozygotes almost always severe disease (i.e.
  pancreatic insufficiency)

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Other mutations

• Milder mutations, like R117H
• Protein gets to membrane, but doesnt respond
  well to ATP
• Many homozygotes dont have pancreatic
  insufficiency and have milder pulmonary findings
• 5T and TG repeats
• Genotype/phenotype correlations imperfect, so
  counseling is difficult

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Article

• http//trishul.sci.gu.edu.au/mark/dgge.html