title: A Genotypic-Oriented View of CFTR Genetics Highlights Specific Mutational Patterns Underlying Clinical Macrocategories of Cystic Fibrosis.
abstract: Cystic fibrosis (CF) is a monogenic disease caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The genotype-phenotype relationship in this disease is still unclear, and diagnostic, prognostic and therapeutic challenges persist. We enrolled 610 patients with different forms of CF and studied them from a clinical, biochemical, microbiological and genetic point of view. Overall, there were 125 different mutated alleles (11 with novel mutations and 10 with complex mutations) and 225 genotypes. A strong correlation between mutational patterns at the genotypic level and phenotypic macrocategories emerged. This specificity appears to largely depend on rare and individual mutations, as well as on the varying prevalence of common alleles in different clinical macrocategories. However, 19 genotypes appeared to underlie different clinical forms of the disease. The dissection of the pathway from the CFTR mutated genotype to the clinical phenotype allowed to identify at least two components of the variability usually found in the genotype-phenotype relationship. One component seems to depend on the genetic variation of CFTR, the other component on the cumulative effect of variations in other genes and cellular pathways independent from CFTR. The experimental dissection of the overall biological CFTR pathway appears to be a powerful approach for a better comprehension of the genotype-phenotype relationship. However, a change from an allele-oriented to a genotypic-oriented view of CFTR genetics is mandatory, as well as a better assessment of sources of variability within the CFTR pathway.
authors.affiliation: Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy.|Pasteur Institute, Cenci Bolognetti Foundation, Sapienza University of Rome, Rome, Italy.|Policlinico Umberto I Hospital, Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Lucarelli
authors.affiliation: Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy.
authors.forename: Sabina Maria
authors.initials: SM
authors.lastname: Bruno
authors.affiliation: Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy.|Pasteur Institute, Cenci Bolognetti Foundation, Sapienza University of Rome, Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Pierandrei
authors.affiliation: Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy.
authors.forename: Giampiero
authors.initials: G
authors.lastname: Ferraguti
authors.affiliation: Policlinico Umberto I Hospital, Rome, Italy.|Department of Pediatrics, Sapienza University of Rome, Rome, Italy.|Cystic Fibrosis Reference Center of Lazio Region, Rome, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Stamato
authors.affiliation: Policlinico Umberto I Hospital, Rome, Italy.|Department of Pediatrics, Sapienza University of Rome, Rome, Italy.|Cystic Fibrosis Reference Center of Lazio Region, Rome, Italy.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Narzi
authors.affiliation: Policlinico Umberto I Hospital, Rome, Italy.|Department of Pediatrics, Sapienza University of Rome, Rome, Italy.|Cystic Fibrosis Reference Center of Lazio Region, Rome, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Amato
authors.affiliation: Policlinico Umberto I Hospital, Rome, Italy.|Cystic Fibrosis Reference Center of Lazio Region, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cimino
authors.affiliation: Policlinico Umberto I Hospital, Rome, Italy.|Cystic Fibrosis Reference Center of Lazio Region, Rome, Italy.
authors.forename: Serenella
authors.initials: S
authors.lastname: Bertasi
authors.affiliation: Policlinico Umberto I Hospital, Rome, Italy.|Department of Pediatrics, Sapienza University of Rome, Rome, Italy.|Cystic Fibrosis Reference Center of Lazio Region, Rome, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Quattrucci
authors.affiliation: Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy.|Policlinico Umberto I Hospital, Rome, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Strom
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D003550:Cystic Fibrosis / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D005091:Exons; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D018740:Genetic Heterogeneity; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D010641:Phenotype; D015995:Prevalence; D055815:Young Adult
chemical_list: D019005:Cystic Fibrosis Transmembrane Conductance Regulator