title: Lung disease associated with the IVS8 5T allele of the CFTR gene.
abstract: 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 DeltaF508/5T-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.
authors.affiliation: 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 27599-7248, USA.
authors.forename: P G
authors.initials: PG
authors.lastname: Noone
authors.forename: C A
authors.initials: CA
authors.lastname: Pue
authors.forename: Z
authors.initials: Z
authors.lastname: Zhou
authors.forename: K J
authors.initials: KJ
authors.lastname: Friedman
authors.forename: E L
authors.initials: EL
authors.lastname: Wakeling
authors.forename: M
authors.initials: M
authors.lastname: Ganeshananthan
authors.forename: R H
authors.initials: RH
authors.lastname: Simon
authors.forename: L M
authors.initials: LM
authors.lastname: Silverman
authors.forename: M R
authors.initials: MR
authors.lastname: Knowles
mesh_terms: D017668:Age of Onset; D000483:Alleles; D003550:Cystic Fibrosis / Q000235:genetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D004848:Epithelium / Q000378:metabolism; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007438:Introns; D017136:Ion Transport; D008171:Lung Diseases / Q000235:genetics*; D008875:Middle Aged; D020125:Mutation, Missense; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000032:analysis; D020545:Respiratory Mucosa / Q000378:metabolism; D013542:Sweat / Q000737:chemistry / Q000378:metabolism
chemical_list: C505032:CFTR protein, human; D012333:RNA, Messenger; D019005:Cystic Fibrosis Transmembrane Conductance Regulator