Molecular and functional characterization of CBAVD-causing mutations located in CFTR nucleotide-binding domains

• Type: Article in International Scientific Journal
• Date: 2008

Authors

Grangeia, A (Author) FMUP; Barro Soria, R (Author) Other; carvalho, f (Author) FMUP; Ana M Damas (Author) ICBAS; Mauricio, AC (Author) ICBAS; Kunzelmann, K (Author) Other; barros, a (Author) FMUP; sousa, m (Author) ICBAS

Journal

Title: Cellular Physiology and Biochemistry

Vol. 22 No. 1

Pages: 79-92

ISSN: 1015-8987

Publisher: Cell Physiol Biochem Press

Indexing

ISI Web of Knowledge - 8 Citations

Scopus - 9 Citations

Other information

Authenticus ID: P-004-2RD

DOI: 10.1159/000149785

Abstract (EN): Background: About 98% of male affected with cystic fibrosis (CF [MIM 219700]) are infertile due to bilateral absence of vas deferens (CBAVD [MIM 277180]), which makes up 1-2 % of all cases with male infertility. A previous screening of the entire coding region of the cystic fibrosis transmembrane conductance regulator gene (CFTR [MIM 602421]) in CBAVD patients identified three novel mutations: P439S is located in the first nucleotide binding domain (NBD1) of CFTR, whereas P1290S and E1401K are located in NBD2. Methods: We analysed the effects of these novel mutations on CFTR processing and chloride (Cl(-)) channel activity. Results: Although maturation patterns were not affected, total amounts of mature P439S-CFTR and P1290S-CFTR were reduced. Confocal microscopy showed correct membrane localisation of E1401K-CFTR, whereas P439S-CFTR and P1290S-CFTR mutants were located mainly in the cytoplasm. Iodide influx assay and whole-cell patch clamp demonstrated significantly reduced cAMP-dependent anion conductances for all three mutants. Conclusion: Dysfunction of CFTR is caused by either defective CFTR trafficking (P439S and P1290S) or/and Cl(-) channel function (P1290S and E1401K). Thus reduced Cl(-) conductance caused by the three CFTR mutations affects normal development of vas deferens and leads to CBAVD, but the remaining function is sufficient to prevent other typical CF symptoms. Copyright (C) 2008 S. Karger AG, Basel.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 14