Mutations in the cystic fibrosis transmembrane regulator gene and in vivo transepithelial potentials

Abstract

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.

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Figure 2.

The combined effects of sodium and chloride diffusion potential (ΔAmil + Cl⁻-free + Iso) are demonstrated. The values on the x axis represent the change in potential difference (ΔPD) from the basal measurement immediately before commencing perfusion with amiloride to the final plateau that is achieved after perfusion with the chloride-free solution and isoproterenol. The range and variability of each measurement and the relationship of each group with one another are shown as in Figure 1. The patient groups show a continuum of values, which appear to reflect the combined consequences of sodium and chloride transport. The reference range for the control subjects is based on 25 healthy men without identified CFTR gene mutations.

Figure 3.

Individual sweat chloride measurements are plotted against stimulated nasal chloride conductance (ΔCl⁻-free + Iso). The reference limits for both tests are illustrated to identify patients with: normal sweat chloride and nasal PD values (bottom left quadrant), abnormal sweat chloride and nasal PD (top right quadrant), normal sweat test but abnormal nasal PD (bottom right quadrant), and abnormal sweat test but normal nasal PD (top left quadrant). The incidental heterozygotes (I Hetero) are distinguished from the control subjects without identified CFTR gene mutations. See text for details.