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The cystic fibrosis gene: a molecular genetic perspective.

ABSTRACT: The positional cloning of the gene responsible for cystic fibrosis (CF) was the important first step in understanding the basic defect and pathophysiology of the disease. This study aims to provide a historical account of key developments as well as factors that contributed to the cystic fibrosis transmembrane conductance regulator (CFTR) gene identification work. A redefined gene structure based on the full sequence of the gene derived from the Human Genome Project is presented, along with brief reviews of the transcription regulatory sequences for the CFTR gene, the role of mRNA splicing in gene regulation and CF disease, and, various related sequences in the human genome and other species. Because CF mutations and genotype-phenotype correlations are covered by our colleagues (Ferec C, Cutting GR. 2012. Assessing the disease-liability of mutations in CFTR. Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a009480), we only attempt to provide an introduction of the CF mutation database here for reference purposes.

SUBMITTER: Tsui LC

PROVIDER: S-EPMC3552342 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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The cystic fibrosis gene: a molecular genetic perspective.

Tsui Lap-Chee LC Dorfman Ruslan R

Cold Spring Harbor perspectives in medicine 20130201 2

The positional cloning of the gene responsible for cystic fibrosis (CF) was the important first step in understanding the basic defect and pathophysiology of the disease. This study aims to provide a historical account of key developments as well as factors that contributed to the cystic fibrosis transmembrane conductance regulator (CFTR) gene identification work. A redefined gene structure based on the full sequence of the gene derived from the Human Genome Project is presented, along with brie ...[more]

PMID: 23378595

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Project description:Gene therapy holds promise for the treatment of a range of inherited diseases, such as cystic fibrosis. However, efficient delivery and expression of the therapeutic transgene at levels sufficient to result in phenotypic correction of cystic fibrosis pulmonary disease has proved elusive. There are many reasons for this lack of progress, both macroscopically in terms of airway defence mechanisms and at the molecular level with regard to effective cDNA delivery. This review of approaches to cystic fibrosis gene therapy covers these areas in detail and highlights recent progress in the field. For gene therapy to be effective in patients with cystic fibrosis, the cDNA encoding the cystic fibrosis transmembrane conductance regulator protein must be delivered effectively to the nucleus of the epithelial cells lining the bronchial tree within the lungs. Expression of the transgene must be maintained at adequate levels for the lifetime of the patient, either by repeat dosage of the vector or by targeting airway stem cells. Clinical trials of gene therapy for cystic fibrosis have demonstrated proof of principle, but gene expression has been limited to 30 days at best. Results suggest that viral vectors such as adenovirus and adeno-associated virus are unsuited to repeat dosing, as the immune response reduces the effectiveness of each subsequent dose. Nonviral approaches, such as cationic liposomes, appear more suited to repeat dosing, but have been less effective. Current work regarding non-viral gene delivery is now focused on understanding the mechanisms involved in cell entry, endosomal escape and nuclear import of the transgene. There is now increasing evidence to suggest that additional ligands that facilitate endosomal escape or contain a nuclear localization signal may enhance liposome-mediated gene delivery. Much progress in this area has been informed by advances in our understanding of the mechanisms by which viruses deliver their genomes to the nuclei of host cells.

Dataset Information

The cystic fibrosis gene: a molecular genetic perspective.

Publications

The cystic fibrosis gene: a molecular genetic perspective.

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