Lack of correlation between pulmonary disease and cystic fibrosis transmembrane conductance regulator dysfunction in cystic fibrosis: a case report

Hara Levy,Andrew A Colin,Daniel Asher,Carolynn L Cannon,Christopher García,Michael R Knowles,Robert H Cleveland,Gerald B Pier

doi:10.1186/1752-1947-4-117

Abstract

IntroductionMutations in both alleles of the cystic fibrosis transmembrane conductance regulator gene result in the disease cystic fibrosis, which usually manifests as chronic sinopulmonary disease, pancreatic insufficiency, elevated sodium chloride loss in sweat, infertility among men due to agenesis of the vas deferens and other symptoms including liver disease.Case presentationWe describe a pair of African-American brothers, aged 21 and 27, with cystic fibrosis. They were homozygous for a rare frameshift mutation in the cystic fibrosis transmembrane conductance regulator 3791delC, which would be expected to cause significant morbidity. Although 80% of cystic fibrosis patients are colonized with Pseudomonas aeruginosa by eight years of age, the older brother had no serum opsonic antibody titer to P. aeruginosa by age 13 and therefore would have failed to mount an effective antibody response to the alginate (mucoid polysaccharide) capsule of P. aeruginosa. He was not colonized with P. aeruginosa until 24 years of age. Similarly, the younger brother was not colonized with P. aeruginosa until age 20 and had no significant lung disease.ConclusionDespite a prevailing idea in cystic fibrosis research that the amount of functional cystic fibrosis transmembrane conductance regulator predicts clinical status, our results indicated that respiratory disease severity in cystic fibrosis exhibits phenotypic heterogeneity. If this heterogeneity is, in part, genetic, it is most likely derived from genes outside the cystic fibrosis transmembrane conductance regulator locus.

Highlights

Mutations in both alleles of the cystic fibrosis transmembrane conductance regulator gene result in the disease cystic fibrosis, which usually manifests as chronic sinopulmonary disease, pancreatic insufficiency, elevated sodium chloride loss in sweat, infertility among men due to agenesis of the vas deferens and other symptoms including liver disease.Case presentation: We describe a pair of African-American brothers, aged 21 and 27, with cystic fibrosis
Despite a prevailing idea in cystic fibrosis research that the amount of functional cystic fibrosis transmembrane conductance regulator predicts clinical status, our results indicated that respiratory disease severity in cystic fibrosis exhibits phenotypic heterogeneity
In part, genetic, it is most likely derived from genes outside the cystic fibrosis transmembrane conductance regulator locus

Summary

Conclusion

A prevailing idea in CF research is that the amount of functional CFTR predicts clinical status; research focus on gene therapy and upregulation of CFTR is based on this premise. Besides the transport of substrates such as chloride and glutathione, CFTR has non-transport functions, as illustrated by its role as a Figure 1 Pulmonary Function (PFT) FEV1% predicted. The incongruously benign course that these siblings present despite the expectation that their 3791delC mutation produces little or no functional CFTR, implies that factors outside CFTR, likely modifier genes, have a potent compensatory effect, and can steer the course away from its predicted severity. Consent Both patients were lost to follow-up and efforts to trace them and their family have proved futile.

Introduction

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Discussion