Abstract
BackgroundThe aims of this study were to characterize clinical features of a pediatric African-American cystic fibrosis (CF) patient heterozygous for F508del and a novel c.3623G > A mutation, and to identify the molecular defect(s) associated with c.3623G > A mutation.MethodsThe medical record of this patient was analyzed retrospectively. Western blotting and iodide efflux assay were used to study mutant CFTR protein expression level, maturation status, channel function, and the effects of CFTR modulation on these characteristics.ResultsThe encoding protein of c.3623G > A mutation, G1208D-CFTR, has a moderate processing defect and exhibits impaired channel function, which were partially rescued by using VX-809 or exposed to low temperature (28 °C). The patient has mild CF disease manifestations.ConclusionsOur biochemical findings correlate with the clinical phenotype and suggest that c.3623G > A is a CF-causing mutation. The study helps expand our knowledge of rare CFTR mutations in a minority population and may have important clinical implications for personalized therapeutic intervention.
Highlights
The aims of this study were to characterize clinical features of a pediatric African-American cystic fibrosis (CF) patient heterozygous for F508del and a novel c.3623G > A mutation, and to identify the molecular defect(s) associated with c.3623G > A mutation
Cystic fibrosis (CF) is an autosomal recessive genetic disease caused by the loss or dysfunction of the CF transmembrane conductance regulator (CFTR) channel activity resulting from mutations [1, 2]
Given that the two mutations this patient has, F508del and c.3623G > A, are both responsive to VX-809, we speculate that VX-809 and similar CFTR modulators could be beneficial for his therapy
Summary
The aims of this study were to characterize clinical features of a pediatric African-American cystic fibrosis (CF) patient heterozygous for F508del and a novel c.3623G > A mutation, and to identify the molecular defect(s) associated with c.3623G > A mutation. Cystic fibrosis (CF) is an autosomal recessive genetic disease caused by the loss or dysfunction of the CF transmembrane conductance regulator (CFTR) channel activity resulting from mutations [1, 2]. Chronic lung disease is the main cause of morbidity and mortality for CF patients. KalydecoTM ( known as ivacaftor or VX-770) was approved by U.S Food and Drug Administration (FDA) to treat CF patients age 2 or older with G551D and other nine class III and IV mutations [9]. FDA approved OrkambiTM (a combination of ivacaftor and lumacaftor ( known as VX-809)) to treat CF patients age 12 or older with two copies of F508del [9]
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