Richard C. Boucher

Aldosterone metabolism and transepithelial potential difference in normal and cystic fibrosis subjects.

ABSTRACT: The transepithelial potential difference (PD) is raised across cystic fibrosis (CF) respiratory epithelia. This raised voltage reflects active sodium absorption across a relatively chloride impermeable membrane. Because relatively little is known about the regulation of the rate of sodium absorption across mammalian airways, we assessed the possible contribution of aldosterone to the PD in normal and CF respiratory epithelia. Aldosterone excretion in five CF patients was 12.2 ± 0.9 μg/24 h, a mean value not different from normal control subjects (13.6 ± 1.5 μg/24 h, n = 5). Despite similar aldosterone excretion rates, nasal PD was more than 2-fold greater in the CF patients (-53.6 ± 6.4 mV) than normal subjects (-21.3 ± 1.4 mV). The effect of an aldosterone antagonist, spironolactone, on aldosterone excretion and nasal and rectal PD was evaluated in four CF patients and five normal subjects. During spironolactone administration, aldosterone excretion increased (2− to 4-fold) and rectal PD decreased in both groups. However, nasal PD was unchanged in each group (CF = −52.1 ± 4.3 mV pre, −53.6 ± 1.4 mV during; normal = −21.2 ± 3.1 mV pre, −21.6 ± 3.2 mV during). We conclude that neither increased aldosterone secretion rates nor organ sensitivity to aldosterone can account for the abnormally raised PD that characterizes the respiratory epithelium of subject with CF.

A CFTR mutation (D1152H) in a family with mild lung disease and normal sweat chlorides.

To the Editor: Over 1000 mutations in the cystic fibrosis transmembrane regulator (CFTR) gene have been reported to cause cystic fibrosis (CF); however, only a few are associated with mild disease (1, 2). We report a novel mutation (D1152H) in three siblings with unusually mild CF, surviving past age 64 with pancreatic exocrine sufficiency, normal sweat chloride (Cl) concentrations, and reduced CFTR-mediated Cl conductance across the nasal epithelium. Direct sequencing of a positive heteroduplex band (3) in exon 18 of the propositus revealed a heterozygous G-to-C base change at base number 3586 of the CFTR cDNA sequence. This nucleotide change results in an aspartic acid to histidine substitution at position 1152 of the mature protein (D1152H). The clinical characteristics of the three siblings with the clinical syndrome of CF are summarized in Table 1. The study protocol was approved by the Institutional Review Board and informed consent was obtained. Although these patients had a relatively benign long-term clinical course and repeatedly normal sweat Cl values, each had a history of pulmonary symptoms, predominantly cough and intermittent episodes of ‘bronchitis’ dating from early childhood or adolescence; and later in life, there was evidence of airflow obstruction present on spirometric testing. Each had mucoid Pseudomonas aeruginosa cultured from sputum samples, and chest radiographs were compatible with CF with predominant upper lung zone bronchiectasis. Pancreatic exocrine function was preserved in the two subjects who were tested. Each male sibling with CF was infertile. One of the siblings had an episode of acute pancreatitis at age 64 that was of undefined etiology, despite extensive evaluation. All three had recurrent rhinosinus disease, either nasal polyps and/or recurrent sinusitis. Finally, the propositus had an open lung biopsy at age 54 (in 1978) that was compatible with pathologic features of CF lung disease. A fourth sibling died at age 25 (in 1948) with complications of a pulmonary/intestinal syndrome compatible with CF, but no DNA was available for mutation analysis. Medical records of her clinical disease have been destroyed, and the only information available was verbal recollection from family members and her family doctor and the death certificate. The three siblings with the clinical syndrome of CF were compound heterozygotes, D1152H/G542X. None of the six siblings, who were carriers or normal at each allele, had any symptomatology that was suggestive of CF, and each had a normal chest radiograph. Results of sweat gland and nasal potential difference (PD) measurements are summarized in Table 2. The sweat ductal PD measurement for the propositus was normal, which is consistent with normal concentrations of Cl in sweat. In contrast, neither of the two siblings tested secreted sweat in response to intradermal injection of isoproterenol (4). The nasal bioelectric properties of the two patients studied were also abnormal, consistent with those seen in mild CF patients (5, 6). Mutations with residual function are associated with milder disease presentations and have been classified as type IV mutations (7, 8). Recent work by Vankeerberghen et al. has demonstrated reduced whole cell Cl currents when a D1152H-bearing CFTR cDNA is expressed in Xenopus oocytes, confirming that D1152H is a type IV mutation (9). Since our initial report to the Cystic Fibrosis Gene Analysis Consortium (10, 11), D1152H has been detected frequently in men with congenital bilateral absence of vas deferens (CBAVD) from three continents (12–16). One large study found D1152H to be the fourth most common CFTR mutation in men with CBAVD (17). These men are commonly ascertained through infertility clinics and initially reported to have no Clin Genet 2005: 68: 88–90 Copyright # Blackwell Munksgaard 2005 Printed in Singapore. All rights reserved CLINICAL GENETICS doi: 10.1111/j.1399-0004.2005.00459.x