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Published ahead of print on July 13, 2006, doi:10.1164/rccm.200509-1377OC

Am. J. Respir. Crit. Care Med., Volume 174, Number 7, October 2006, 787-794

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Submitted on September 5, 2005
Accepted on July 10, 2006

Mutations in Cystic Fibrosis Transmembrane Regulator Gene and in vivo Transepithelial Potentials

Michael Wilschanski1, Annie Dupuis2, Lynda Ellis2, Keith Jarvi3, Julian Zielenski2, Elizabeth Tullis4, Sheelagh Martin2, Mary Corey2, Lap-Chee Tsui2, and Peter Durie5*

1 Pediatric Gastroenterology Unit and CF Center, Department of Pediatrics, Hebrew University, Hadassah Medical Organization, Jerusalem, Israel, 2 Hospital for Sick Children, Programs in Genetics and Genomic Biology, Population Health Sciences and Integrative Biology, the Research Institute, Toronto, Ontario, Canada, 3 Division of Urology, Mount Sinai Hospital, Toronto, Ontario, Canada; Departments of Molecular and Medical Genetics, Pediatrics, Medicine and Surgery, University of Toronto, Toronto, Ontario, Canada, 4 Division of Respirology, St. Michael's Hospital, Toronto, Ontario, Canada; Departments of Molecular and Medical Genetics, Pediatrics, Medicine and Surgery, University of Toronto, Toronto, Ontario, Canada, 5 Hospital for Sick Children, Programs in Genetics and Genomic Biology, Population Health Sciences and Integrative Biology, the Research Institute, Toronto, Ontario, Canada; Departments of Molecular and Medical Genetics, Pediatrics, Medicine and Surgery, University of Toronto, Toronto, Ontario, Canada

* To whom correspondence should be addressed. 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 CF patients and 34/36 CBAVD patients 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, cystic fibrosis, sweat chloride, nasal potential difference,congenital bilateral absence of the vas deferens




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