Cystic fibrosis is a genetic disorder. It is characterized by chronic lung inflammation. The root cause of CF is a mutation in the CFTR gene. The product of this gene is a chloride ion channel. The most common mutation is ∆F508, a deletion of 3 base pairs at a specific point in the genome.
What is Cystic Fibrosis?
Cystic fibrosis is a genetic disorder commonly prevalent in Caucasians, and rare in Asians & Africans. It is a disease in which secretary glands function abnormally. It is characterized by a blockage of the airways of the lungs by mucus.
CFTR Gene And Its Function
The major turning points in understanding this heritable disorder have been achieved in recent years through gene isolation, followed by sequencing studies. CF researchers have found that the gene named Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) in CF patients is mutated. It resides on the long arm of chromosome 7.The product of this gene is a 1480 amino acid protein, localized in the apical membrane of the exocrine epithelial cells. It functions principally as a cAMP regulated chloride ion channel.
Affected individuals will have two mutated CFTR alleles, one inherited from each parent. Numerous CF mutations have been reported. The most common among them is ∆F508 mutation, frequently identified in Caucasians. ∆F508 is a 3bp deletion mutation in exon 10 of chromosome 7 making the protein short of phenylalanine at the 508th position.
According to the statistics compiled by the Cystic Fibrosis Genetic Analysis Consortium, 66% of the CF patients studied showed the presence of ∆F508 mutation. About 1000 different mutations have been found that lead to abnormalities in the biosynthesis or in the function of the CFTR protein. They have been classified into 5 classes:
Cystic Fibrosis Mutations
Cystic fibrosis research has revealed several genetic mutations;-
Class I:- No synthesis of CFTR protein: These are missense, nonsense or frameshift mutations making the cell devoid of CFTR protein. The phenotypic effects tend to be more severe.
Class II:- Defective processing of CFTR protein: Common to this class is ∆F508: This class of mutation is characterised by faulty processing and lack of transport of CFTR protein to the apical membrane.
Class III:- Defective Regulation: It is a type of missense mutation leading to the formation of nonfunctional CFTR at the apical membrane.
Class IV:- Defective Conductance: It targets the function of CFTR, reducing the conductance of the chloride ion channel.
Class V:- Reduced production of CFTR: Characterised by reduced expression of normal CFTR protein, hence mild phenotypes.
Such variable mutations lead to various clinical manifestations in different organs from mild CF to complex pathophysiological symptoms of lung CF.