Complex alleles in monogenic disease pose a challenge for clinicians because they are often associated with uncommon diagnostic and clinical features. Here we report on the 30 year course of a basic defect and disease in an individual with cystic fibrosis (CF) who was compound heterozygous for the cystic fibrosis transmembrane conductance regulator (CFTR) mutations R553X1 and the complex allele F508del-R553Q.2

The amino acid substitution R553Q resides within the ABC signature motif of CFTR.3 R553Q has been shown in heterologous model systems to partially correct the defective processing and anomalous ion channel gating of mutant F508del CFTR.4 Hence R553Q has been classified as a disease reverting suppressor mutation. Investigation of the affected subject, however, revealed a more complex manifestation of the basic defect of anomalous epithelial chloride conductance.

The sweat test is still the gold standard to diagnose CF5 whereby elevated sweat chloride concentrations of more than 60 mmol/l are considered to be diagnostic of CF. The R553X/F508del-R5553Q index case showed a strong increase in sweat electrolytes from infancy to adulthood. Quantitative pilocarpine iontophoresis sweat tests yielded chloride concentrations below 30 mmol/l during infancy, 30–50 mmol/l by the age of 4–5 years, 60–65 mmol/l by the age of 7 years and 100–120 mmol/l by the age of 17–29 years. Nasal potential difference measurements6 revealed a typical CF phenotype of a high basal potential difference (−46 mV) and a large response of +30 mV on superfusion with the sodium channel blocker amiloride. No chloride diffusion potential (+3 mV) was induced by chloride free solution and isoprotenerol, indicating that CFTR mediated chloride conductance was absent in the patient’s upper respiratory epithelium. Intestinal current measurements in rectal biopsies7 uncovered a small transient chloride secretory response to carbachol, suggesting that some residual CFTR mediated chloride secretion within the typical CF range was operating in the patient’s intestinal epithelium.

Clinically, the female patient presented with typical manifestations of CF. Since birth she had been suffering from growth retardation, steatorrhoea, and chronic cough and wheezing. The parents’ persistent suspicion that their child was affected by CF was discarded by medical professionals because of repeated false negative sweat tests in early childhood. At the age of diagnosis, 7 years, the exocrine pancreatic insufficient girl was below the third percentile for height and weight. Symptomatic treatment achieved normal anthropometry and lung function during school age. Concurrent with the emergence of type III diabetes mellitus during adolescence, lung function was gradually deteriorating so that the patient needed to receive a lung transplant by the age of 27 years. She is now a full time working clerk.

DISCUSSION

Two major conclusions can be drawn from this singular case. Firstly, CF is a clinical diagnosis and should not be denied by apparently normal sweat electrolytes. Several disease causing CFTR mutations that are associated with sweat test values below 60 mmol/l are known,8 9 and correspondingly contemporary algorithms explicitly require thorough investigations for making a diagnosis in individuals with sweat test values within the borderline range of 30–60 mmol/l chloride.10 Secondly, the partial correction of the basic defect observed in transfected cells4 was only seen in the patient’s sweat glands, but not in her respiratory and intestinal epithelia. The clinical characteristics of the R553X/F508del-R553Q subject were similar to those of R553X/F508del compound heterozygotes.2 Moreover, even in the sweat gland, the basic defect was corrected only early in life, but faded over the years, indicating that aging mechanisms abolished the rescue by R553Q in the morphologically inconspicuous tissue.

In summary, R553Q rescued the molecular pathology of F508del CFTR in a cellular model, but it was not a disease reverting suppressor mutation in the affected individual.