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American Journal of Respiratory Cell and Molecular Biology. Vol. 27, pp. 619-627, 2002
© 2002 American Thoracic Society
DOI: 10.1165/rcmb.2001-0004OC

Five Percent of Normal Cystic Fibrosis Transmembrane Conductance Regulator mRNA Ameliorates the Severity of Pulmonary Disease in Cystic Fibrosis

Anabela S. Ramalho*, Sebastian Beck*, Michelle Meyer, Deborah Penque, Garry R. Cutting and Margarida D. Amaral

Centro de Genética Humana, Instituto Nacional de Saúde, and Departmento de Química e Bioquímica, Faculdade de Ciências - Universidade de Lisboa, Lisboa, Portugal; and Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland

Address correspondence to: Margarida D. Amaral, Centro de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge, Av. Padre Cruz, P-1649-016 Lisboa, Portugal. E-mail: mdamaral{at}igc.gulbenkian.pt

Estimates of the level of transcripts from the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene required to develop a CF phenotype range from 4–20% of normal. Due to the importance of obtaining reliable data on this issue for therapeutic strategies, we developed a novel polymerase chain reaction–based method to quantify CFTR transcripts and applied it to the analysis of nasal epithelium RNA of five patients with CF and the 3272-26A>G/F508del genotype. We calculated that 8.2 ± 0.84% of the total CFTR RNA present in these five patients is normal full-length CFTR mRNA. We then demonstrated (in nasal samples from F508del carriers, n = 30) that the abundance of full-length F508del CFTR transcripts is reduced compared with wild-type transcripts, and estimated that the average ratio of F508del/wild-type transcripts is 0.87 ± 0.06. To determine the amount of full-length transcripts relative to levels found in normal individuals, we corrected for the lower abundance of the F508del transcripts and calculated that the five patients with CF have, on average, 4.7 ± 0.45% of the normal level of wild-type CFTR mRNA. Because these patients have mild CF compared with F508del homozygotes, this CFTR mRNA level appears to be sufficient to avoid the severe complications of the disease.

Abbreviations: base pairs, bp • cystic fibrosis, CF • CF transmembrane conductance regulator, CFTR • polymerase chain reaction, PCR • reverse transcription, RT




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