High heterogeneity for cystic fibrosis in Spanish families: 75 mutations account for 90% of chromosomes

Abstract

We have analyzed 640 Spanish cystic fibrosis (CF) families for mutations in the CFTR gene by direct mutation analysis, microsatellite haplotypes, denaturing gradient gel electrophoresis, single-strand conformation analysis and direct sequencing. Seventy-five mutations account for 90.2% of CF chromosomes. Among these we have detected seven novel CFTR 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. Mutations G85V, T582R, R851L, E692X and Q1281X are severe, with lung and pancreatic involvement; 711+3A-->T could be responsible for a pancreatic sufficiency/insufficiency variable phenotype; and F1074L was associated with a mild phenotype. These data demonstrate the highest molecular heterogeneity reported so far in CF, indicating that a wide mutation screening is necessary to characterize 90% of the Spanish CF alleles.

The Phenotypic Consequences of CFTR Mutations

“…More than 95% of patients also fail to produce digestive enzymes in the pancreas, resulting in pancreatic insufficiency (PI). Population studies of CF patients suggest that most of the PI patients were descendants from a single mutational event at the CF locus, whereas the pancreatic sufficient (PS) phenotype resulted from multiple different mutations Estivill et al 1995;Casals et al 1997;Mateu, 2002 ). There is a high level of male infertility (>95%) caused by absence or obstruction of the vas deferens, and many females also suffer from reduced fertility, possibly due to altered cervical mucus properties.…”

CFTR allelic heterogeneity in Brazil: historical and geographical perspectives and implications for screening and counseling for cystic fibrosis in this country

“…8 In heterogeneous populations, the number of different mutations is very large. [9][10][11][12] A worldwide survey found that 28 493 of the 43 077 studied CF chromosomes (66%) carried the p.F508del mutation. 13 The frequency of the p.F508del mutation differs between populations, ranging from 26% in Algeria and Venezuela to 47% in one Brazilian study and 87% in Denmark; other mutations also vary widely depending on the ethnic composition of the studied groups.…”

Multimutational Analysis of Eleven Cystic Fibrosis Mutations Common in the Mediterranean Areas

“…A recent worldwide survey revealed great mutational heterogeneity for CF in the Mediterranean region (2 ). Spain may have the highest heterogeneity of CF mutations among Mediterranean countries, with more than 75 different mutations detected, representing 90.2% of the CF chromosomes (3 ). On the other hand, only 10 mutations had a frequency higher than 1%, and these accounted for 74.2% of the CF chromosomes studied.…”

“…2 Departamento de Bioquímica y Biología Molecular, Universidad de Granada, Granada, Spain; 3 Servicio de Inmunología, Hospital 12 de Octubre, Madrid, Spain; 4 Instituto de la Recerca Oncologica (IRO), Hospital Duran I Reynals, Barcelona, Spain; * address correspondence to this author at: Servicio de Bioquímica, Hospital Universitario San Cecilio, Avda. Dr. Oloriz s/n, Granada 18012, Spain; fax 34-958249015, e-mail efarez@ugr.es)…”

“…Because of the health risks associated with tobacco exposure, analysis of biomarkers of tobacco exposure has increased. Cotinine is the preferred serum biomarker for tobacco exposure (2)(3)(4)(5).…”