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Mutations in the Cystic Fibrosis Transmembrane Regulator Gene and In Vivo Transepithelial Potentials

Programs in Genetics and Genomic Biology, Population Health Sciences, and Integrative Biology, The Research Institute, Hospital for Sick Children, Toronto; Division of Respirology, St. Michael's Hospital, Toronto; Division of Urology, Mount Sinai Hospital, Toronto; Departments of Molecular and Medical Genetics, Pediatrics, Medicine, and Surgery, University of Toronto, Toronto, Canada; Hebrew University, and Pediatric Gastroenterology Unit, Hadassah Medical Organization, Jerusalem; and Department of Pediatrics, CF Center, Jerusalem, Israel

Correspondence and requests for reprints should be addressed to Peter Durie, M.D., F.R.C.P.C., The Hospital for Sick Children, 555 University Avenue, Toronto, ON, Canada, M5G 1X8. E-mail: peter.durie{at}sickkids.ca

Aim: To examine the relationship between cystic fibrosis transmembrane regulator gene mutations (CFTR) and in vivo transepithelial potentials.

Methods: We prospectively evaluated 162 men including 31 healthy subjects, 21 obligate heterozygotes, 60 with congenital bilateral absence of the vas deferens (CBAVD) and 50 with CF by extensive CFTR genotyping, sweat chloride and nasal potential difference testing.

Results: Six (10%) men with CBAVD carried no CFTR mutations, 18 (30%) carried one mutation, including the 5T variant, and 36 (60%) carried mutations on both alleles, for a significantly higher rate carrying one or more mutations than healthy controls (90% versus 19%, p < 0.001). There was an overlapping spectrum of ion channel measurements among the men with CBAVD, ranging from values in the control and obligate heterozygote range at one extreme, to values in the CF range at the other. All pancreatic-sufficient patients with CF and 34 of 36 patients with CBAVD with mutations on both alleles carried at least one mild mutation. However, the distribution of mild mutations in the two groups differed greatly. Genotyping, sweat chloride and nasal potential difference (alone or in combination) excluded CF in all CBAVD men with no mutations. CF was confirmed in 56% and 67% of CBAVD men carrying 1 and 2 CFTR mutations, respectively.

Conclusion: Abnormalities of CFTR transepithelial function correlate with the number and severity of CFTR gene mutations.

Key Words: CFTR mutations • congenital bilateral absence of the vas deferens • cystic fibrosis • nasal potential difference • sweat chloride

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