The document summarizes cystic fibrosis, including: 1) It is caused by mutations in the CFTR gene which encodes a chloride channel protein, leading to thick mucus in organs like the lungs and pancreas. 2) The most common mutation is DeltaF508. Symptoms include salty skin, lung infections, and poor growth. 3) Treatments aim to clear mucus from the lungs and control infections, while enzymes and vitamins address digestive issues. Gene therapy aims to replace the defective CFTR gene.

1. CYSTIC FIBROSIS
TRANSMEMBRRANE RECEPTOR

2. Introduction
History
 This gene was discovered after year of intensive research by Rommens
JM, Iannuzzi MC, et al. identification of the cystic fibrosis gene :
chromosome walking & jumping Science 1989.
 In 1938 Dorothy Hansine Andersen published an article, "Cystic Fibrosis of
the Pancreas and Its Relation to Celiac Disease: a Clinical and Pathological
Study," in the American Journal of Diseases of Children.
 First to describe the characteristic cystic fibrosis of the pancreas and to
correlate it with the lung and intestinal disease prominent in CF.
 First hypothesized that CF was a recessive disease and first used pancreatic
enzyme replacement to treat affected children.

3. 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.
Associated Disorders: Defective versions of this
protein, caused by CFTR gene mutations, can lead to
the development of CF and congenital bilateral
aplasia of the vas deferens (CBAVD).

4. CFTR Role In Body fig1
CFTR
Follow osmotic
methodSweat
glands
lungs
Pancreas
Intestine
kidneys
Defect in gene encoding
CFTR Leading to reduction in
chloride transport
Absorptive epithelia use
similar transporter & channels

5. Fig 2 Classification of CFTR mutations. CFTR mutations are classified into six classes according to their effect on
CFTR function. Class I mutations inhibit biosynthesis, while Class II mutations affect protein processing. Milder
mutations such as Class III, IV, and VI impair CFTR channel function and Class V mutations affect gene
expression,adaptedfromAllen(1999).
Classification of CFTR mutations.

6. Presentation of Disease
Colon
Pancreas
Sticky mucus secretion
Ducts are filled with sticky mucus. Scaring of tissue.
Mucous in the airways cannot be easily
cleared from the lungs.

7. ABC Transporters
 These are responsible for transporting small foreign molecule
(like drugs & toxins) especially out of cells i.e. exsorption (&
thus called efflux pump) which make them clinically important.
 A classical e.g. of ABC is P-glycoprotein which is responsible
for pumping hydrophobic drug especially anticancer drugs out of
cells
 All presence of large quantity of these protein thus makes the
cells resistant to a verity of drugs used in cancer chemotherapy a
phenomenon is called multi drug resistance.

8. Structure & organization of ABC
 Basic unit of an ABC transport consists of four core domains.
 Protein consist of an aqueous pore , formed by the TMDs with
large opening at the extracellular face of the membrane
 NBDs (nucleotide binding domain) are at the cytoplasmic
face of the membrane are in close apposition to the TMDs &
possibly partly buried in the bilayer membrane
Lipid
bilayerLipid
bilayer
pore
TM

9. Mechanism of Transport
 PBP(Periplasmic binding proteins) substrate can be
considered as the PBP substrate interacting at the
extracellular face of the membrane
 Substrate get released from PBP-substrate
complex
 Conformational changes takes place in the TMD &
is transmitted to the NBDs to initiate the ATP
hydrolysis which further leads to the
conformational changes to NBDs.

10. Cystic Fibrosis Transmembrane
Conductance Regulator
 Cystic fibrosis transmembrane conductance
regulator (CFTR) is a protein that in humans is
encoded by the CFTR gene.
 CFTR is an ABC transporter-class ion
channel that
transports chloride and thiocyanate ions across
epithelial cell membranes. Mutations of the
CFTR gene affect functioning of the chloride ion
channels in these cell membranes, leading
to cystic fibrosis and congenital absence of the
vas deferens.

11. Molecular Genetics and Gene
Function
The gene that encodes the
CFTR protein is found on
the human chromosome
7, on the long arm at
position q31.2.from base
pair 116,907,253 to base
pair 117,095,955.

12. Protein Function and
Biochemistry
 CFTR controls
chloride ion
movement in
and out of the
cell.

13. Protein Function Continued

14. STRUCTURE OF CFTR GENE

15.  CFTR is a glycoprotein with 1480 amino acids.The
protein consists of five domains.There are two
transmembrane domains, each with six spans
of alpha helices.
 These are each connected to a nucleotide binding
domain (NBD) in the cytoplasm.The first NBD is
connected to the second transmembrane domain by
a regulatory "R" domain that is a unique feature of
CFTR, not present in other ABC transporters.
 The ion channel only opens when its R-domain has
been phosphorylated by PKA and ATP is bound at
the NBDs.The carboxyl terminal of the protein is
anchored to the cytoskeleton by a PDZ-interacting
domain.

16. LOCATION AND FUNCTION
 The CFTR is found in the epithelial cells of many organs
including
the lung, liver, pancreas, digestive tract, reproductive tract,
and skin and sweat glands.
 CFTR functions as a cAMP activated ATP -
gated anion channel, increasing the conductance for
certain anions (e.g. Cl–) to flow down their electrochemical
gradient. ATP-driven conformational changes in CFTR open
and close a gate to allow transmembrane flow of anions
down theirelectrochemical gradient.
 CFTR defects result in reduced transport of sodium
chloride and sodium thiocyanate in the reabsorptive duct
and saltier sweat.This was the basis of a clinica.lly
important sweat test for cystic fibrosis.

17. 3D Image of Protein
 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.

18. Regulation of CFTR
Two separate processes control the gating of CFTR:
1) Phosphorylation
2) Binding and hydrolysis of ATP
Phosphorylation is necessary for activation, but it is not sufficient.
After phosphorylation, gating between the closed and open states is
controlled by ATP hydrolysis

19. CYSTIC FIBROSIS
 Cystic fibrosis also known as mucoviscidosis,is an
autosomal recessive genetic disorder that affects
mainly the lungs ,and also the pancreas, liver, and
intestine.
 It is characterised by abnormal transport of chloride
and sodium across an epithelium leading to thick
viscous secretions.
 the name cystic fibrosis refers to the
characteristic scarring (fibrosis) and cyst formation
within the pancreas, first recognized in the Andersen
DH (1938)

20.  Difficulty breathing due to lung infections that are
treated with antibiotics and other medications.
 Salty tasting skin.
 poor growth and poor weight gain despite normal
food intake.
 accumulation of thick, sticky mucus, frequent chest
infections, and coughing or shortness of breath.
 Males can be infertile due to congenital absence of
the vas deferens.
 Symptoms often appear in infancy and
childhood, such as bowel obstruction due
to meconium ileus in newborn babies.
 Gastrointestinal malabsorption.

21.  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.
CLINICAL FEATURES

23. CAUSES
 CF is caused by a mutation in the gene for
the protein cystic fibrosis transmembrane
conductance regulator (CFTR).This protein is
required to regulate the components of
sweat, digestive fluids, and mucus.
 CFTR regulates the movement of chloride and
sodium ions across epithelial membranes, such as
the alveolar epithelia located in the lungs.
 Most people without CF have two working copies of
the CFTR gene, and both copies must be missing for
CF to develop, due to the disorder's recessive nature.
CF develops when neither copy works normally (as a
result of mutation) and therefore
has autosomal recessive inheritance.

24.  CF is caused by a mutation in the gene cystic
fibrosis transmembrane conductance
regulator (CFTR).The most common
mutation, ΔF508, is a deletion (Δ signifying
deletion) of three nucleotidesthat results in a
loss of the amino acid phenylalanine (F) at the
508th position on the protein.
 This mutation accounts for 2/3rd of cf cases
worldwide.

25. Pathophysiology of CF
 In cystic fibrosis a loss of functional CFTR chloride channels
leads to defective cAMP-stimulated chloride transport in
most epithelia this defect result in decreased chloride
secretion & increased absorption
 Defective electrolyte transport is thought to alter the
volume or composition of the fluid secreted by the
pancreas, hepatobiliary tree , reproductive tract sweat gland
& airways.

26.  LUNGS : Disease results from clogging of the
airways due to mucus build-
up, decreased mucociliary clearance, and
resulting inflammation causing injury and
stucrural changes.
 Staphylococcus aureus, Haemophilus
influenzae, and Pseudomonas aeruginosa are the
three most common organisms causing chronic
lung infections in CF patients.
 Other symptoms :
 coughing up blood (hemoptysis)
 high blood pressure in the lung (pulmonary
hypertension)

27.  Gastrointestinal : Prior to prenatal and newborn
screening, CF was often diagnosed when a newborn
infant failed to pass feces (meconium). Meconium may
completely block the intestines and cause serious illness.
This condition, called meconium ileus, occurs in 5–
10% of newborns with CF.
 The thick mucus seen in the lungs has a counterpart in
thickened secretions from the pancreas, an organ
responsible for providing digestive juices that help break
down food.These secretions block
the exocrine movement of the digestive enzymes into
the duodenum and result in irreversible damage to the
pancreas, often with painful inflammation (pancreatitis)
 The lack of digestive enzymes leads to difficulty
absorbing nutrients with their subsequent excretion in
the feces, a disorder known as malabsorption, leading to
loss of fat soluble vitamins A,D,E and K.

28. Endocrine :The pancreas contains the islets of
Langerhans, which are responsible for making
insulin, a hormone that helps regulate
blood glucose. Damage of the pancreas can lead to
loss of the islet cells, leading to a type of diabetes .
This cystic fibrosis-related diabetes (CFRD) shares
characteristics that can be found in type 1 and type
2 diabetics, and is one of the principal
nonpulmonary complications of CF.
Vitamin D is involved in calcium and phosphate
regulation . Poor uptake of vitamin D from the diet
because of malabsorption can lead to the bone
disease osteoporosis in which weakened bones are
more susceptible to fractures

29. In addition, people with
CF often
develop clubbing of
their fingers and toes
due to the effects of
chronic illness and low
oxygen in their tissues.
Fig : Clubbing in the
fingers of a person with
cystic fibrosis

30. DIAGNOSIS
 Individuals with cystic fibrosis can be diagnosed
before birth by genetic testing, or by a sweat
test in early childhood.
 The newborn screen initially measures for raised
blood concentration of immunoreactive
trypsinogen.
 Ultimately, lung transplantation is often
necessary as CF worsens.

31. CURE
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 intestine.
 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.
•For patients with advanced stages of the disease, a lung
transplant operation may be necessary.

32. Treatment for cystic fibrosis
1. Gastrointestinal system
A. Pancreatic enzyme supplement
Cotazym
Creon
Ilozyme
Ku-zyme
Pancrease
ultraseMT12

33. Treatment for cystic fibrosis
B. Vitamin supplementation
Multivitamin tablets
C. Prevention & treatment of cirrhosis
Ursodeoxycholic acid

34. Treatment for cystic fibrosis
2. Cardiovascular system
Vasodilators Inotropic Diuretics
3. Pulmonary system
A. Anti obstructive therapy
0.9% sodium chloride solution is inhaled to liquefy pulmonary secretion
recombinant human dna has been approved for use in cf to reduces the
viscosity of CF sputum
Theophylline (bronchodilators)
B. Anti inflammatory therapy

35. C. Antibiotic therapy
1. Oral antibiotics
Trimethoprim-sulfamethoxazole Cephalexin
ciprofloxacin amoxicillin-clavulanic acid
2. Inhaled antibiotics
Colistin Gentamicin or tobramycin
Polymixin –B

36.  3. Parenteral antibiotics
Amikacin
Azlocillin
Aztreonam
Colistin
Imipenem
piperacillin

38. 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
defectiveCF gene in the lungs
to cure CF or slow the
progression of the disease.

39. Recent Drugs used for
Treatment of CF :
 The PulmonaryTherapies Committee of
Cystic Fibrosis Foundation recommends long-
term use of hypertonic saline for patients
with cystic fibrosis aged 6 years or older to
improve lung function and to reduce the
number of exacerbations.
 The cystic fibrosis transmembrane
conductance regulator (CFTR), Ivacaftor
(Kalydeco), was approved by the FDA in
January 2012.

40.  In March 2013, the FDA approved Tobramycin
inhalation powder for the treatment of CF
patients with P aeruginosa.The powder is
inhaled twice daily for 28 days; treatment is
then stopped for 28 days before resuming.