Mild Cystic Fibrosis in Pediatric Patient Found to Be Caused by Rare Gene Mutation

Researchers identified a novel, rare mutation causing cystic fibrosis (CF) in a pediatric African-American patient. The mutation, however, was found to be responsive to the CFTR corrector VX-809, therefore identifying potential personalized therapeutics. The study, “c.3623G > A mutation encodes a CFTR protein with impaired channel function,” was published in the journal Respiratory Research.

CF is caused by the loss or dysfunction of the CF transmembrane conductance regulator (CFTR) channel activity as a result of mutations in the CFTR gene. More than 2,000 CFTR mutations have been identified, with F508del established as one of the most prevalent CFTR mutations. However, only a relatively low number of mutations have been studied in detail at both the molecular level and in terms of specific disease manifestations.

Now, a group of researchers presented a clinical case of a pediatric African-American CF patient, who was heterogeneous for F508del but presented a novel missense mutation, c.3623G > A, that had never been characterized.

Researchers investigated the effects of the mutation at the molecular level with the goal of identifying a novel mutation-specific therapy. To this end, researchers reviewed retrospectively the medical record of this patient who received treatment at the the University of Tennessee Cystic Fibrosis Research and Care Center at LeBonheur Children’s Hospital in Memphis. They performed western blotting and iodide efflux assays to study the mutant CFTR protein expression level maturation status and channel function.

The research team found that the mutated protein, called G1208D-CFTR, is characterized by impaired CFTR protein maturation culminating with retention of only 33 percent of normal CFTR function, resulting in a defective channel function. These evidences correlated with the mild disease phenotype presented by the patient.

Interestingly, researchers were able to partially rescue the phenotype by exposure to low temperature (28° C) or using the CFTR corrector VX-809 (Lumacaftor, Vertex Pharmaceuticals). Lung damage, including the potential development of chronic sino-pulmonary infections (common in patients with residual CFTR channel function) was not assessed due to the patient’s young age.

In conclusion, researchers described a novel rare mutation in the CFTR gene, c.3623G > A, as a mild CF-causing mutation. Moreover, they showed that both mutations, F508del and c.3623G > A, are responsive to VX-809 treatment, therefore VX-809 and other similar CFTR modulators may represent a potential therapy for patients with this mutation.