Channelopathy Molecular basis of the disease

1. CYSTIC
FIBROSIS
MOLECULAR BASIS OF
THE DISEASE &
CHANNELS INVOLVED
COURSE NO. 629

2. INTRODUCTION
Cystic fibrosis is a chronic,
progressive, life threatening genetic
disorder of pediatrics.
It affect white population (1 in 3200 live births)
but is uncommon among Asian and African population.
It affects exocrine glands (mainly sweat glands)
and mucus gland present on the epithelial lining of
lungs, pancreas, intestine, and reproductive system.
CF is a defect in epithelial chloride
channel protein, causes membrane to
become impermeable to Chloride ion.

3. GENETICS OF THE
DISEASE:
CF is autosomal recessive
disease means:
Children who inherit two
abnormal alleles -one from
each parent- will have CF
Children who inherit only
one mutant gene will be
carrier of the disease

4. CF occurs due to the deletion of 3
nucleotides which code for the
phenylalanine from the CFTR
(cystic fibrosis transmembrane
conductance regulator) gene
located on chromosome no.7 at
position 508
This mutation is known as ΔF 508
IT’S IN THE GENES!

5. CFTR gene encode for the CFTR protein channel

6. STRUCTURE OF THE
CFTR PROTEIN:
CFTR protein is a cAMP induced
Channel made up of five domains:
Two membrane-spanning domain
(MSD1 & MSD2) that form Cl¯ ion
channel.
Two nucleotide binding domains
(NBD1 & NBD2) that bind and
hydrolyze ATP.
A regulatory R domain.

7. REGULATION OF CFTR PROTEINREGULATION OF CFTR PROTEIN
Several proteins bind with CFTR and regulate it’s activity.
Protein phosphatase 2A (PP2A), AMP kinase (AMPK),
syntaxin-1A (SYN1A), synaptosome associated protein 23kD
(SNAP23) ,mammalian uncoordinated 18a (Munc-18a) inhibit
channel activity and channel mediated transport
Na/H exchanger regulatory factor isoform-1 (NHERF-1),
receptor for activated C-kinase (RACK1), protein kinase C
(PKC), protein kinase A (PKA) and ezrin, radixin, moesin
binding domain (MBD), NBD, Phosphatidylinositol
bisphosphate, Rho and regulatory domain enhance the activity
of CFTR

8. ASSEMBLY OF PROTEINS WITH CFTR PROTEIN

9. ΔF508 mutations result
in the defected NBD1
domain due to which
protein is folded
incorrectly.
Recognized, marked and
degraded by the cell
quality control mechanism
when reaches to the ER
Protein does not reaches
to the apical membrane
of epithelium

10. PROGRESSION OF THE DISEASEPROGRESSION OF THE DISEASE
In Respiratory epithelium, function of CFTR is to secrete
chloride ion
Loss of CFTR function causes
Loss or reduction of Cl ion in luminal secretion
Followed by active luminal Na absorption through
ENaC
Increases passive water absorption from the lumen.
Impaired mucociliary action, accumulation of thick,
viscous, dehydrated mucus

11. Obstruction of air passage and recurrent pulmonary
infections

12. In pancreas, reduction in the luminal water content of the
secretion, thick mucus, will cause clogging of protein and
obstruction in ductules and acini of pancreas
Due to which digestive enzymes of pancreas will not
reach to the intestine.
Same is the condition in Liver, along with insufficient
secretion of bicarbonate ion. Thus bile is also not
reached to the intestine.
Digestive enzyme insufficiency will result poor absorption
of proteins, fats and fat soluble vitamins such as vitamin
A, D, E, and K.
Gastrointestinal abnormalities secondary to disease and
growth abnormalities.

13. In SWEAT GLANDS CFTR is responsible for reabsorbtion
of Cl ion along with Na ion through epithelial Na channel
(ENaC). Impaired function of CFTR cause the production
of hypertonic salty sweat, and ultimately dehydration.

16. References:
Robbins Basic Pathology, 9th edition.
Exploring Genes and Genetic Disorders
http://www.ornl.gov/sci/techresources/Human_Genome/posters/chromos
The Encyclopedia of Science
http://www.daviddarling.info/encyclopedia/ETEmain.html
Nature reviews Molecular Cell Biology
http://www.nature.com/nrm/index.html
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