ASSESSING THE POSSIBLE UTILIZATION OF CFTR-M470V GENOTYPING FOR CF RISK DETERMINATION
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- Starting date
- September 1, 2003
- Duration (months)
- Life and Reproduction Sciences
- Person in charge
- Pignatti Pier Franco
We wish to propose that one of the most common polymorphisms in the CFTR gene, M470V, may be used for this purpose. This polymorphism:
1) turned out to be associated with random CFTR gene mutations of all molecular types in a recent study on non-CF individuals (see next section “preliminary results”). More precisely, the combined frequency of all rare variants among the CFTR genes with the M allele was 3.5 fold that of the CFTR with the V allele (0.260 vs 0.074).
2) in CF patients, the M allele frequency has been reported to be 90% versus 50% in normal alleles, in a study on 200 unrelated normal and mutant CFTR genes (Cuppens et al., 1994). Mutations DF508, G542X, N1303K (Cuppens et al., 1994), W1282X, R117H, R334W, R553X (Dork et al., 1992) are all associated with allele M, while mutation R1162X is not (Dork et al., 1992);
3) also, an increased frequency of the M allele has been reported in CFTR-related diseases: in 146 chronic rhinosinusitis patients, 9/10 patients with a CF mutation had the M allele (Wang et al., 2000); in 12 Chronic Obstructive Pulmonary Disease (COPD) patients M allele frequency was 70.8% versus 35.7 % in 52 controls, and in 19 Disseminated Bronchiectasis (DBE) patients, 5/5 patients carrying CF mutations had the M allele, versus 8/14 (57%) patients not carrying CFTR mutations (Tzetis et al., 2001). In CFTR-related diseases, a wide variety of CFTR gene mutations has been found, therefore no particular mutation panel can be proposed for these diseases, similar to that in use for CF genotyping, and short of complete gene screening, M470V typing could represent a simple first screen method.
On the basis of all these data, we hypothesize that CFTR alleles with the M variant should have an increased risk over CFTR alleles with the V variant of carrying a CF-causing mutation. Therefore, the probability of being a CF at risk couple would increase with the increase of the number of M genes from 0 to 4 in the partners of the couple.
The genotyping for M470V might be useful in: (i) the analysis of CF patients, (ii) atypical CF cases, and (iii) CFTR-related diseases, in particular when no CFTR mutation can be identified with a panel of CF mutations, (iv) as a first, more economic and convenient approach to CF screening countries in which little is yet known on the spectrum of CF causing mutations, or whenever economic and practical considerations suggest a simpler approach involving the typing of only one polymorphism with a simple method instead of a panel of mutations with more complex methods.
In conclusion, we propose to determine the genotype at the M470V polymorphism in families with a CF child, and to compare the results with our previous data on the general population.
If the hypothesis will be verified, modified residual risk calculation tables after mutation analysis, and the inclusion of M470V polymorphism in the CF mutation panels for CF testing, may be proposed.
- Fondazione per la Ricerca sulla Fibrosi Cistica - Onlus
Funds: assigned and managed by the department
Syllabus: ENTI.RIC - Finanziamento da enti vari per la ricerca
- Guido Modiano
- Università Roma Tor Vergata
- Carlo Castellani
- Azienda Ospedaliera Verona
- Bianca Maria Ciminelli
- Università Roma Tor Vergata
Biology and Genetics Section