HIGH HETEROGENEITY FOR CYSTIC-FIBROSIS IN SPANISH FAMILIES - 75 MUTATIONS ACCOUNT FOR 90-PERCENT OF CHROMOSOMES

We have analyzed 640 Spanish cystic fibrosis (CF) families for mutatio ns in the CFTR gene by direct mutation analysis, microsatellite haplot ypes, denaturing gradient gel electrophoresis, single-strand conformat ion analysis and direct sequencing. Seventy-five mutations account for 90.2% of CF chromosomes. Among these we have detected seven novel CFT R mutations, including four missense (G85V, T582R, R851L and F1074L), two nonsense (E692X and Q1281X) and one splice site mutation (711+3A-- >T). Three variants, two in intronic regions (406-112A/T and 3850-129T /C) and one in the coding region (741C/T) were also identified. Mutati ons G85V, T582R, R851L, E692X and Q1281X are severe, with lung and pan creatic involvement; 711+3A-->T could be responsible for a pancreatic sufficiency/insufficiency variable phenotype; and F1074L was associate d with a mild phenotype. These data demonstrate the highest molecular het erogeneity reported so far in CE indicating that a wide mutation s creening is necessary to characterize 90% of the Spanish CF alleles.