title: Unusually common cystic fibrosis mutation in Portugal encodes a misprocessed protein.
abstract: A561E, a novel cystic fibrosis (CF) associated mutation in the first nucleotide binding domain of CFTR, is the second most common CF mutation in Portugal. Properties of the A561E-CFTR protein were studied by immunoblotting, pulse-chase, immunocytochemistry, and MQAE halide-efflux assay in stably transfected BHK cells. Altogether, results presented here suggest that A561E causes protein mislocalization in the endoplasmic reticulum where the mutant protein must be trapped by the quality control mechanism. We conclude that A561E originates a protein trafficking defect, thus belonging to class II of CFTR mutations. As it is the case for F508del-CFTR (the most common CF mutant), low temperature treatment partially rescues a functional A561E-CFTR channel, suggesting that substitution of glutamic acid for alanine at position 561 does not completely abolish CFTR function. Pharmacological strategies previously reported for treatment of CF patients with the F508del mutation could thus be also effective in CF patients bearing the A561E mutation.
authors: Centro de Genética Humana, Instituto Nacional de Saúde Dr Ricardo Jorge, Lisboa 1649-016, Portugal.
authors: Filipa
authors: F
authors: Mendes
authors: Mónica
authors: M
authors: Roxo Rosa
authors: Anca
authors: A
authors: Dragomir
authors: Carlos M
authors: CM
authors: Farinha
authors: Godfried M
authors: GM
authors: Roomans
authors: Margarida D
authors: MD
authors: Amaral
authors: Deborah
authors: D
authors: Penque
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D006224:Cricetinae; D003550:Cystic Fibrosis / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry* / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism; D017353:Gene Deletion; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D011174:Portugal; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D013696:Temperature; D013997:Time Factors; D014162:Transfection
chemical_list: C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator