The CF is the most common lethal autosomal recessive hereditary
disorder, worst in the European origin populations, affecting an average one
out of 2500 live births (= q2), i.e., one out of 25 (= 2pq) individuals is a
carrier of this disease. However, this frequency varies according to geographic
and ethnic origin of the patients.
CFTR gene, which is responsible for this disorder, contains
27 exons spreading over 250 kb of chromosome 7 (7q31) and encodes an mRNA of
The early hypotheses regarding the function of CFTR protein
revolved around two possibilities. The first postulated that the CFTR protein
is a Cl- channel. This hypothesis was compatible with the defect in permeability
of Cl- ions at the CF epithelial apical membranes. The other proposed that the
CFTR protein is not an ionic channel but it plays a role in the regulation of
Cl- channel either by associating with them, or by transporting a regulatory
factor for Cl- channels in or out of the cell. The later results determined
the function of CFTR protein as a Cl- channel.
The discoverers of CFTR gene termed it the ütransmembrane
conductance regulatorè. In fact, the CFTR protein regulates other channels also,
the outwardly rectifying chloride channel (ORCC), epithelial Na+ channel (ENaC)
and at least two inwardly rectifying K+ channels ROMK1 and ROMK2. Besides being
a channel regulator, it also plays a role in transport of ATP, modifying the
phenomenon of exocytosis/endocytosis, regulation of pH of intracellular organelles.
The molecular anomalies have variable effects on the CFTR
protein and its functions. Welsh and Smith have proposed a classification of
these anomalies in relation to the Cl- channel function (Welsh & Smith 1993)
Mutations altering the
production of the protein. These mutations result in the total or partial
absence of the protein. This class includes the nonsense mutations and those
that produce a premature stop codon (anomalies of splicing and frameshift
mutations). In certain cases the mutated mRNA is unstable and doesnèt produce
the protein. In other cases, the abnormal protein produced will probably
be unstable and degrade rapidly. This is what produces the truncated protein
or the protein containing the aberrant sequence (anomalies of splicing or
the frame shift). Functionally, these mutants are characterized by a loss
of conductance of Cl- channel in the affected epithelia.
Mutations altering the
cellular maturation of the protein. A number of mutations alter the maturation
of the protein and thus the transport of these proteins to the plasma membrane.
In this way, the protein is either absent from the plasma membrane or present
in a very small quantity. The mutations of this class represent the majority
of CF alleles (DF508).
the regulation of Cl- channel. These mutations are frequently situated in
the ATP binding domain (NBF1 and 2).
the conduction of Cl- channel. Certain segments of membrane spanning domains
participate in the formation of an ionic pore. The missense mutations situated
in these regions produce a correctly positioned protein that has a cAMP
dependant Cl- channel activity. But the characteristic of these channels
is different from those of endogenous CFTR channel with a diminution of
ion flux and a modified selectivity.
Mutations altering the stability of mRNA.
Mutations altering the stability of mature CFTR protein.
Fanen P, Hasnain A
Atlas of Genetics and Cytogenetics in Oncology and Haematology 2001-09-01
Cystic Fibrosis and CFTR Gene
Online version: http://atlasgeneticsoncology.org/teaching/30032/cystic-fibrosis-and-cftr-gene