Transcript Cystic Fibrosis

Cystic Fibrosis
Clinical Features
Cystic fibrosis is a heterogeneous recessive
genetic disorder with features that reflect
mutations in the cystic fibrosis
transmembrane conductance regulator
(CFTR) gene.
 Classic cystic fibrosis is characterized by
chronic bacterial infection of the airways and
sinuses, fat maldigestion due to pancreatic
exocrine insufficiency, infertility in males due
to obstructive azoospermia, and elevated
concentrations of chloride in sweat.
 Patients with nonclassic cystic fibrosis have
at least one copy of a mutant gene that
confers partial function of the CFTR protein,
and such patients usually have no overt
signs of maldigestion because some
pancreatic exocrine function is preserved.
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Genotype and Phenotype
Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance
regulator (CFTR) gene which encodes a protein expressed in the apical
membrane of exocrine epithelial cells.
 This genotypic variation provides a rationale for phenotypic effects of the specific
mutations. The extent to which various CFTR alleles contribute to clinical variation
in CF is evaluated by genotype-phenotype studies.
 The poor correlation between CFTR genotype and severity of lung disease
strongly suggests an influence of environmental and secondary genetic factors
(CF modifiers).
 Several candidate genes related to innate and adaptive immune response have
been implicated as pulmonary CF modifiers. In addition, the presence of a genetic
CF modifier for meconium ileus has been demonstrated on human chromosome
19q13.2.
 The phenotypic spectrum associated with mutations in the CFTR gene extends
beyond the classically defined CF. Besides patients with atypical CF, there are
large numbers of so-called monosymptomatic diseases such as various forms of
obstructive azoospermia, idiopathic pancreatitis or disseminated bronchiectasis
associated with CFTR mutations uncharacteristic for CF.
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Molecular Genetics and Gene Function
Locus: 7q31.2 - The CFTR gene is found in region
q31.2 on the long (q) arm of human chromosome 7.
 Gene Structure: The normal allelic variant for this
gene is about 250,000 bp long and contains 27
exons.
 mRNA: The intron-free mRNA transcript for the
CFTR gene is 6129 bp long.
 Coding Sequence (CDS): 4443 bp within the
mRNA code for the amino acid sequence of the
gene's protein product.
 Protein Size: The CFTR protein is 1480 amino
acids long and has a molecular weight of 168,173
Da.
 Protein Function: The normal CFTR protein
product is a chloride channel protein found in
membranes of cells that line passageways of the
lungs, liver, pancreas, intestines, reproductive tract,
and skin. CFTR is also involved in the regulation of
other transport pathways.
 Associated Disorders: Defective versions of this
protein, caused by CFTR gene mutations, can lead
to the development of cystic fibrosis (CF) and
congenital bilateral aplasia of the vas deferens
(CBAVD).
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Protein Function and
Biochemistry

CFTR controls
chloride ion
movement in
and out of the
cell.
Protein Function Continued
Protein Structure and Function
CFTR transports chloride ions (Cl-)
ions across the membranes of cells
in the lungs, liver, pancreas,
digestive tract, reproductive tract,
and skin.
 CFTR is made up of five domains:
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two membrane-spanning domains
(MSD1 and MSD2) that form the chloride
ion channel
two nucleotide-binding domains (NBD1
and NBD2) that bind and hydrolyze ATP
(adenosine triphosphate)
and a regulatory (R) domain.
Delta F508, the most common CFcausing mutation, occurs in the DNA
sequence that codes for the first
nucleotide-binding domain (NBD1).
Changes in Protein structure
CFTR functions principally as a cAMP-induced
chloride channel and appears capable of regulating
other ion channels.
 Besides the most common mutation, ΔF508,
accounting for about 70% of CF chromosomes
worldwide, more than 850 mutant alleles have been
reported to the CF Genetic Analysis Consortium.
 These mutations affect CFTR through a variety of
molecular mechanisms which can produce little or no
functional CFTR at the apical membrane.
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3D Image of Protein
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When a CFTR protein with the delta F508
mutation reaches the ER, the quality-control
mechanism of this cellular component
recognizes that the protein is folded
incorrectly and marks the defective protein
for degradation. As a result, delta F508 never
reaches the cell membrane.
People who are homozygous for delta F508
mutation tend to have the most severe
symptoms of cystic fibrosis due to critical loss
of chloride ion transport.
This upsets the sodium and chloride ion
balance needed to maintain the normal, thin
mucus layer that is easily removed by cilia
lining the lungs and other organs. The
sodium and chloride ion imbalance creates a
thick, sticky mucus layer that cannot be
removed by cilia and traps bacteria, resulting
in chronic infections.
Presentation of Disease
Mucous in the airways cannot be easily cleared from the lungs.
Presentation of Disease
Colon
Pancreas
Sticky mucus secretion
Ducts are filled with sticky mucus. Scaring of tissue.
Treatment
•The only way to cure CF would be to use gene therapy to replace the
defective gene or to give the patient the normal form of the protein before
symptoms cause permanent damage.
•The major goal in treating CF is to clear the abnormal and excess
secretions and control infections in the lungs, and to prevent obstruction in
the intestines.
•For patients with advanced stages of the disease, a lung transplant
operation may be necessary.
•Although treating the symptoms does not cure the disease, it can greatly
improve the quality of life for most patients and has, over the years,
increased the average life span of CF patients to 30 years.
Gastrointestinal Treatment
Modified diet
Due to pancreatic disorders, children with CF require a modified diet, including vitamin
supplements (vitamins A, D, E, and K) and pancreatic enzymes. Maintaining adequate
nutrition is essential. The diet calls for a high-caloric content (twice what is considered
normal for the child's age), which is typically low in fat and high in protein. Patients or
their caregivers should consult with their health care providers to determine the most
appropriate diet.
Gene Therapy
Gene therapy is the use of
normal DNA to "correct" for the
damaged genes that cause
disease.
 In the case of CF, gene
therapy involves inhaling a
spray that delivers normal
DNA to the lungs.
 The goal is to replace the
defective CF gene in the lungs
to cure CF or slow the
progression of the disease.
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