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CYSTIC FIBROSIS
MOLECULAR BASIS OF THE DISEASE & CHANNELS INVOLVED
COURSE NO. 629
Presented By:
SARA SIDDIQUI
INTRODUCTIONCystic 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.
GENETICS OF THEDISEASE: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
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!
CFTR gene encode for the CFTR protein channel
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.
REGULATION OF CFTR PROTEINREGULATION OF CFTR PROTEINSeveral 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
ASSEMBLY OF PROTEINS WITH CFTR PROTEIN
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
PROGRESSION OF THE DISEASEPROGRESSION OF THE DISEASEIn Respiratory epithelium, function of CFTR is to secrete chloride ion
Loss of CFTR function causes
Loss or reduction of Cl ion in luminal secretionFollowed by active luminal Na absorption through ENaC
Increases passive water absorption from the lumen.Impaired mucociliary action, accumulation of thick, viscous, dehydrated mucus
Obstruction of air passage and recurrent pulmonary infections
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.
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.
References:Robbins Basic Pathology, 9th edition.
Exploring Genes and Genetic Disorders
http://www.ornl.gov/sci/techresources/Human_Genome/posters/chromosome/index.shtml
The Encyclopedia of Science
http://www.daviddarling.info/encyclopedia/ETEmain.html
Nature reviews Molecular Cell Biology
http://www.nature.com/nrm/index.html
THANK YOU