Am. J. Respir. Crit. Care Med., Volume 162, Number 5, November 2000, 1919-1924

Lung Disease Associated with the IVS8 5T Allele of the CFTR Gene

PEADAR G. NOONE, CHARLES A. PUE, ZHAOQING ZHOU, KENNETH J. FRIEDMAN, EMMA L. WAKELING, MUTTIAH GANESHANANTHAN, RICHARD H. SIMON, LAWRENCE M. SILVERMAN, and MICHAEL R. KNOWLES

Cystic Fibrosis/Pulmonary Research and Treatment Center, Departments of Medicine, and Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Institute of Child Health, University of London, London, United Kingdom; Pinnacle Health at Polyclinic Hospital, Harrisburg, Pennsylvania; and University of Michigan, Ann Arbor, Michigan

Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene. The 5T allele in intron 8 (IVS8) causes abnormal splicing in the CFTR gene, and is associated with lung disease when it occurs in cis with a missense mutation in the CFTR gene, R117H. However, the 5T variant alone has not been reported to cause lung disease. We describe two adult female patients with CF-like lung disease associated with the 5T allele. One patient's genotype is 5T-TG12-M470V/5T-TG12-M470V, and the other is F508/5T-TG12-M470V; full sequencing of the CFTR gene revealed no other mutation on the same allele as the 5T variant. The levels of full-length CFTR mRNA in respiratory epithelia were very low in these patients (11 and 6%, respectively, of total CFTR mRNA expression). Both patients had defective CFTR-mediated chloride conductance in the sweat ductal and/or acinar epithelia (sweat chloride, mmol/L, mean ± SEM: 40.0 ± 5.0 [n = 8 samples] and 80.0 ± 3.5 [n = 6 samples]) and airway epithelia (mV, mean ± SEM CFTR-mediated Cl conductance of 1.2 ± 2.2 [n = 5 studies] and 6.75 ± 8.1 [n = 4 studies]). These data suggest that the 5T polythymidine tract sequence on specific haplotype backgrounds (TG12 and M470V) may cause a low level of full-length functional CFTR protein and CF-like lung disease.

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