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

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