A new approach for identifying non-pathogenic mutations. An analysis of the cystic fibrosis transmembrane regulator gene in normal individuals

Cristina Bombieri, Silvia Giorgi, Soukeyna Carles, Rafael De Cid, Francesca Belpinati, Caterina Tandoi, Nathalie Pallares-Ruiz, Conxi Lazaro, Bianca Maria Ciminelli, Marie Catherine Romey, Teresa Casals, Fiorenza Pompei, Giorgio Gandini, Mireille Claustres, Xavier Estivill, Pier Franco Pignatti, Guido Modiano

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Given q as the global frequency of the alleles causing a disease, any allele with a frequency higher than q minus the cumulative frequency of the previously known disease-causing mutations (threshold) cannot be the cause of that disease, This principle was applied to the analysis of cystic fibrosis transmembrane conductance regulator (CFTR) mutations in order to decide whether they are the cause of cystic fibrosis. A total of 191 DNA samples from random individuals from Italy, France, and Spain were investigated by DGGE (denaturing gradient gel electrophoresis) analysis of all the coding and proximal non-coding regions of the gene. The mutations detected by DGGE were identified by sequencing. The sample size was sufficient to select essentially all mutations with a frequency of at least 0.01. A total of 46 mutations was detected, 20 of which were missense mutations. Four new mutations were identified: 1341 + 28 C/T, 2082 C/T, L1096R, and I1131V. Thirteen mutations (125 G/C, 875 + 40 A/G, TTGAn, IVS8-6 5T, IVS8-6 9T, 1525-61 A/G, M470V, 2694 T/G, 3061-65 C/A, 4002 A/G, 4521 G/A, IVS8 TG10, IVS8 TG12) were classified as non-CF-causing alleles on the basis of their frequency. The remaining mutations have a cumulative frequency far exceeding q; therefore, most of them cannot be CF-causing mutations. This is the first random survey capable of detecting all the polymorphisms of the coding sequence of a gene.

Original languageEnglish
Pages (from-to)172-178
Number of pages7
JournalHuman Genetics
Volume106
Issue number2
DOIs
Publication statusPublished - 1 Jan 2000

    Fingerprint

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Bombieri, C., Giorgi, S., Carles, S., De Cid, R., Belpinati, F., Tandoi, C., Pallares-Ruiz, N., Lazaro, C., Ciminelli, B. M., Romey, M. C., Casals, T., Pompei, F., Gandini, G., Claustres, M., Estivill, X., Pignatti, P. F., & Modiano, G. (2000). A new approach for identifying non-pathogenic mutations. An analysis of the cystic fibrosis transmembrane regulator gene in normal individuals. Human Genetics, 106(2), 172-178. https://doi.org/10.1007/s004390051025