F1099L-CFTR (c.3297C>G) has Impaired Channel Function and Associates with Mild Disease Phenotypes in Two Pediatric Patients

Life

YanhuiH. Zhang¹  AnjaparavandaP. Naren²  Saumini Srinivasan³  Weiqiang Zhang³  Aixia Ren³  JaspalS. Hothi³  DennisC. Stokes³  Xiaoying Zhang³  MichaelJ. Rock⁴ 

[1] Department of Bioscience Research, College of Dentistry, University of Tennessee Health Science Center, Memphis, TN 38163, USA;Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, R-4041, Cincinnati, OH 45229, USA;Department of Pediatrics, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USA;Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA;

关键词: protein channel;    cystic fibrosis (CF);    CFTR;    F1099L-CFTR;    CFTR modulators;    VX-809 (lumacaftor);   

DOI  :  10.3390/life11020131

来源: DOAJ

【 摘 要 】

(1) Background: many rare cystic fibrosistransmembrane conductance regulator (CFTR) mutations remain poorly characterized with regard to functional consequences of the mutation. We present the clinical features of two pediatric cystic fibrosis (CF) subjects who are heterozygous for F1099L (c.3297C>G), one with G551D (a class III mutation) and one with 3849 + 10kbC->T (a class V mutation). We also identified the molecular defect(s) that are associated with F1099L mutation to correlate with the clinical features that we observed; (2) Methods: clinical findings and history were extracted from the electronic medical record and de-identified. F1099L-CFTR protein expression level and maturation status, channel function, and the effects of CFTR modulation on these characteristics were investigated using western blotting and iodide efflux assay; (3) Results: these two subjects have mild CF phenotypes when F1099L is combined with two known disease-causing mutations. F1099L-CFTR has a moderate defect in processing and maturation, causing fewer CFTR channels at the cell surface and, therefore, impaired channel activities. These defects could be effectively corrected using VX-809 (lumacaftor); and, (4) Conclusions: our biochemical data correlate with the disease manifestations and suggest that F1099L is potentially a CF-causing mutation. The study expands our knowledge of rare CFTR mutations and may help in developing effective therapies for subjects with F1099L mutation.

【 授权许可】

Unknown