Personalized medicine in cystic fibrosis: genistein supplementation as a treatment option for patients with a rare S1045Y-CFTR mutation.
Cystic fibrosis (CF) is a life-shortening disease caused by the mutations that generate nonfunctional CF transmembrane conductance regulator (CFTR) protein. A rare serine-to-tyrosine (S1045Y) CFTR mutation was earlier reported to result in CF-associated fatality. We identified an African-American patient with the S1045Y mutation in CFTR, as well as a stop-codon mutation, who has a mild CF phenotype. The underlying mechanism of CF caused by S1045Y-CFTR has not been elucidated. In this study, we determined that S1045Y-CFTR exhibits twofold attenuated function compared with wild-type (WT)-CFTR. We report that serine-to-tyrosine mutation leads to increased tyrosine phosphorylation of S1045Y-CFTR, followed by recruitment and binding of E3-ubiquitin ligase c-cbl, resulting in enhanced ubiquitination and passage of S1045Y-CFTR in the endosome/lysosome degradative compartments. We demonstrate that inhibition of tyrosine phosphorylation partially rescues S1045Y-CFTR surface expression and function. Based on our findings, it could be suggested that consuming genistein (a tyrosine phosphorylation inhibitor) would likely ameliorate CF symptoms in individuals with S1045Y-CFTR, providing a unique personalized therapy for this rare CF mutation.
Division of Pulmonary Medicine, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;
Kavisha
K
Arora
Division of Pulmonary Medicine, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;
Sunitha
S
Yarlagadda
Department of Physiology, University of Tennessee Health Science Center and University of Tennessee CF Care and Research Center at Le Bonheur Children's Hospital, Memphis, Tennessee; Department of Pediatrics, University of Tennessee Health Science Center and University of Tennessee CF Care and Research Center at Le Bonheur Children's Hospital, Memphis, Tennessee; and.
Weiqiang
W
Zhang
Division of Pulmonary Medicine, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;
ChangSuk
C
Moon
Division of Pulmonary Medicine, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;
Erin
E
Bouquet
Department of Physiology, University of Tennessee Health Science Center and University of Tennessee CF Care and Research Center at Le Bonheur Children's Hospital, Memphis, Tennessee; Department of Pediatrics, University of Tennessee Health Science Center and University of Tennessee CF Care and Research Center at Le Bonheur Children's Hospital, Memphis, Tennessee; and.
Saumini
S
Srinivasan
School of Medicine, Wayne State University, Detroit, Michigan.
Chunying
C
Li
Department of Physiology, University of Tennessee Health Science Center and University of Tennessee CF Care and Research Center at Le Bonheur Children's Hospital, Memphis, Tennessee; Department of Pediatrics, University of Tennessee Health Science Center and University of Tennessee CF Care and Research Center at Le Bonheur Children's Hospital, Memphis, Tennessee; and.
Dennis C
DC
Stokes
Division of Pulmonary Medicine, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; anaren@cchmc.org.
Anjaparavanda P
AP
Naren
D002675:Child, Preschool; D003550:Cystic Fibrosis / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000235:genetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D004353:Drug Evaluation, Preclinical; D019833:Genistein / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010766:Phosphorylation; D057285:Precision Medicine; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism
C505032:CFTR protein, human; D047428:Protein Kinase Inhibitors; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D019833:Genistein; D050721:Proto-Oncogene Proteins c-cbl; C067419:CBL protein, human
cystic fibrosis transmembrane conductance regulator; rare cystic fibrosis mutations