A MUTATION IN THE CYSTIC-FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATORGENE ASSOCIATED WITH ELEVATED SWEAT CHLORIDE CONCENTRATIONS IN THE ABSENCE OF CYSTIC-FIBROSIS
Je. Mickle et al., A MUTATION IN THE CYSTIC-FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATORGENE ASSOCIATED WITH ELEVATED SWEAT CHLORIDE CONCENTRATIONS IN THE ABSENCE OF CYSTIC-FIBROSIS, Human molecular genetics, 7(4), 1998, pp. 729-735
Mutations in the cystic fibrosis transmembrane conductance regulator (
CFTR) have been shown to cause cystic fibrosis (CF) and male infertili
ty due to congenital bilateral absence of the vas deferens, We report
the identification of a 6.8 kb deletion (del14a) and a nonsense mutati
on (S1455X) in the CFTR genes of a mother and her youngest daughter wi
th isolated elevated sweat chloride concentrations, Detailed clinical
evaluation of both individuals found no evidence of pulmonary or pancr
eatic disease characteristic of CF, A second child in this family with
classic CF was homozygous for the del14a mutation, indicating that th
is mutation caused severe CFTR dysfunction, CFTR mRNA transcripts bear
ing the S1455X mutation were stable in vivo, implying that this allele
encoded a truncated version of CFTR missing the last 26 amino acids,
Loss of this region did not affect processing of transiently expressed
S1455X-CFTR compared with wild-type CFTR, When expressed in CF airway
cells, this mutant generated cAMP-activated whole-cell chloride curre
nts similar to wild-type CFTR. Preservation of chloride channel functi
on of S1455X-CFTR was consistent with normal lung and pancreatic funct
ion in the mother and her daughter. These data indicate that mutations
in CFTR can be associated with elevated sweat chloride concentrations
in the absence of the CF phenotype, and suggest a previously unrecogn
ized functional role in the sweat gland for the C-terminus of CFTR.