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CF and CFTR

         Cystic fibrosis (CF) is an autosomal-recessive disease, CFTR is a chloride channel that regulate the epithelial sodium channel.

  • involves both exocrine and endocrine gland dysfunction

  • involves multiple organ systems, especially the pancreas and lungs.


       CF occurs with a frequency of approximately 1:3600 live births in white population, ( so it is the most common inherited fatal disease in this group) whereas it is 1:29000 in black persons and 1:6500 in Hispanic persons, it is rare in Asian and native Americans. CF first described in 1938 with median survival was < 1 year but today it is estimated > 36 years in the US, which means that within a short period , the management of this disease has been greatly improved.

   Etiology


Mutation of the cystic fibrosis transmembrane-conductive  regulator (CFTR) gene causes a change in structure of the CFTR glycoprotein, and results in the development of CF. 

So, let’s take a look at CFTR and CFTR gene

      CFTR is a chloride channel that regulate the epithelial sodium channel , so that, CFTR mutations results in abnormal ion and water transport across epithelial membranes, especially in the lungs, pancreas, intestines, biliary tract, sweat glands, and vas deferens .
But it is not just a chloride channel, it is also regulates numerous other pathways, such as the transport of HCO3- , glutathione and thiocyanate, immune cells and metabolism of lipids, thus, it affects the PH balance in the surface fluid in the airway, and the mucociliary clearance as well as innate immunity, and this leads to chronic infection and inflammation. The respiratory disorder represents the major cause of morbidity and mortality of CF patients.
CFTR gene is a long gene located on the long arm of chromosome 7 , it was discovered 25 years ago and this discovery was of great importance :

  • - It was the basis for knowing the cellular and molecular changing of CF lung disease.

  • - The development of mutation-specific therapies that are now becoming available for some of CF patients.

  • - The generation of animal models to study in vivo pathogenesis.

More than 2000 mutations have been identified , the most common one is F508del (presents in a homozygous or heterozygous form in 80% of people with CF ). On the basis of CFTR functional abnormality , CFTR mutations have been grouped into 6 classes:

  • - Class 1 : no functional protein due to a premature stop codon in mRNA that leads to a truncated nonfunctional protein.

  • - Class 2 : unstable and/or misfolded protein that is improperly processed and degraded in proteasomes before reaching the cell membrane.

  • - Class 3 : defective regulation of gating but properly positioned.

  • - Class 4 : reduce chloride conductance but properly positioned.

  • - Class 5 : reduce synthesis of functional protein due to aberrant splicing.

  • - Class 6 : less stable functional protein with accelerated turnover.

  We can summarize the effect of mutations as following: CFTR gene mutation −→ Abnormal, dysfunctional or decreased CFTR protein −→ Defective ion transport −→ Deficient airway surface liquid −→ Defective mucociliary clearance ←−→ Trio of airway obstruction + chronic persistent infection + inflammation ←−→ Bronchiectasis −→ Respiratory failure. In other organ systems, aberrant ion transport leads to ductal obstruction that results in pancreatic insufficiency, and congenital absence of the vas deferens. 

CFTR mutations in the diagnosis of CF

     The diagnosis of CF requires:

  • - Either 2 positive sweat tests (the standard of reference).

  • - Or Genotype analysis revealing 2 CFTR mutations known to cause CF.

Plus 1 of the following:

  • - Chronic sinopulmonary disease

  • - Gastrointestinal or nutritional abnormality

  • - Salt loss syndrome

  • - Obstruction azoospermia in boys

  • - CF in a first degree relation.

CFTR in treatment of CF

       CF has no definitive cure, the aim of the treatment is to maintain good health, so that, it is necessary to choose the best and most appropriate drug combination for patients according to their symptoms.
The management includes basically nutritional therapies and pulmonary therapies. One of the newest and effective drugs is CFTR Modulators : This is a new class of drugs that recover CFTR function and hold the promise of substantial long term benefit.