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Cystic Fibrosis and CFTR Gene

 

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I- Background

II- Incidence

III-Clinical Manifestations

IV- Diagnosis

V- CFTR gene and its mutations

V-1. Introduction
V-2. The DF508 mutation
V-3. Spectrum of CFTR gene mutations
V-4. Genotype-phenotype correlations

VI- CFTR protein and its functions

VI-1. Structure of CFTR protein
VI-2. Function of Cl- channel

VI-2.1. Function of Cl- channel
VI-2.2. The CFTR protein, a multi-functional protein

VI-3. Correlations of mutations of CFTR gene with the function of Cl-
channel

VI-3.1. Class 1: mutations altering the production of the protein.
VI-3.2. Class 2: mutations disturbing the process of cellular maturation cellular of the protein.
VI-3.3. Class 3: mutations disturbing the regulation of Cl- channel.
VI-3.4. Class 4: mutations altering the conduction of l Cl- channel.
VI-3. 4. Class 5: mutations altering the stability of mRNA,
VI-3. 4. Class 6: mutations altering the stability of mature protein.

VII- References

French




pdf version

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I- Background

 

II- Incidence

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.

 

III- Clinical manifestation

 

IV- Diagnosis

 

V- CFTR gene and its mutations

V-1. Introduction

CFTR gene, which is responsible for this disorder, contains 27 exons spreading over 250 kb of chromosome 7 (7q31) and encodes an mRNA of 6.5 kb.

 

V-2. The DF508 mutation

 

V-3. Spectrum of CFTR gene mutations

 

V-4. Genotype-phenotype correlations

Mutations. Editor.

 

 

VI- The CFTR protein and its functions

VI-1. Structure of the CFTR protein

Figure 1: proposed structure CFTR protein, by Riordan et al. 1989 - Pascale Fanen.

 

 

VI-2. Functions of the protein

VI-2.1. Cl- channel function

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.

 

VI-2.2. The CFTR protein, a multifunctional protein

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.

Figure 2: CFTR, a multi functional protein, by Schwiebert et al. 1999 - Pascale Fanen

 

VI-3. Correlation of CFTR gene mutations with the Cl- channel function

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) (figure 3).

Figure 3: Classification of mutations of CFTR gene, by Welsh & Smith, 1993 - Pascale Fanen

 

VI-3.1. Class 1: 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.

VI-3.2. Class 2: 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).

VI-3.3. Class 3: mutations disturbing the regulation of Cl- channel. These mutations are frequently situated in the ATP binding domain (NBF1 and 2).

VI-3. 4. Class 4: mutations altering 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.

VI-3. 4. Class 5: mutations altering the stability of mRNA.

VI-3. 4. Class 6: mutations altering the stability of mature CFTR protein.

 


Contributor(s)

Written2001-09Pascale Fanen, Afia Hasnain
Service de Biochimie-Génétique, Inserm U.654, Hôpital Henri Mondor, 94010 Créteil, France

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Tue Mar 14 13:57:22 CET 2017


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