Misprocessing of the CFTR protein leads to mild cystic fibrosis phenotype.
Cystic fibrosis (CF) is mainly caused by mutations that interfere with the biosynthetic folding of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. The aim of this study was to determine the mechanism of dysfunction of a disease-causing mutation associated with variable phenotypes. In order to attain these objectives, we studied the effect of the p.L206W mutation on CFTR protein production and function, and we examined the genotype-phenotype correlation of [p.L206W]+[p.F508del] patients. We showed that p.L206W is a processing (class II) mutation since the CFTR biosynthetic pathway was severely impaired, whereas single-channel measurements indicated ion conductance similar to the wild-type protein. These data raise the larger question of the phenotypic variability of class II mutants, including p.F508del. Since multiple potential partners could modify the processing of the CFTR protein during its course to the cell surface, environmental and other genetic factors might contribute to this variability.
Clain
Jérôme
J
Institut National de la Santé et de la Recherche Médicale (INSERM) U. 468, Hôpital Henri Mondor, Créteil, France.
Lehmann-Che
Jacqueline
J
Duguépéroux
Ingrid
I
Arous
Nicole
N
Girodon
Emmanuelle
E
Legendre
Marie
M
Goossens
Michel
M
Edelman
Aleksander
A
de Braekeleer
Marc
M
Teulon
Jacques
J
Fanen
Pascale
P
D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002462:Cell Membrane / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D003550:Cystic Fibrosis / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D004594:Electrophysiology; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype
C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator