A MUTATION IN THE CYSTIC-FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATORGENE ASSOCIATED WITH ELEVATED SWEAT CHLORIDE CONCENTRATIONS IN THE ABSENCE OF CYSTIC-FIBROSIS

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.