ABCMdb

ABCC7 p.Met150Val

Predicted by SNAP2:	A: D (66%), C: D (59%), D: D (91%), E: D (85%), F: D (75%), G: D (80%), H: D (80%), I: D (63%), K: D (91%), L: D (63%), N: D (80%), P: D (91%), Q: D (66%), R: D (85%), S: D (80%), T: D (75%), V: N (66%), W: D (85%), Y: D (75%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: N, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D,

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[hide] Deletion of CFTR translation start site reveals fu... Cell Physiol Biochem. 2009;24(5-6):335-46. Epub 2009 Nov 4. Ramalho AS, Lewandowska MA, Farinha CM, Mendes F, Goncalves J, Barreto C, Harris A, Amaral MD
Deletion of CFTR translation start site reveals functional isoforms of the protein in CF patients.
Cell Physiol Biochem. 2009;24(5-6):335-46. Epub 2009 Nov 4., [PMID:19910674]

Abstract [show]
BACKGROUND/AIMS: Mutations in the CFTR gene cause Cystic Fibrosis (CF) the most common life-threatening autosomal recessive disease affecting Caucasians. We identified a CFTR mutation (c.120del23) abolishing the normal translation initiation codon, which occurs in two Portuguese CF patients. This study aims at functionally characterizing the effect of this novel mutation. METHODS: RNA and protein techniques were applied to both native tissues from CF patients and recombinant cells expressing CFTR constructs to determine whether c.120del23 allows CFTR protein production through usage of alternative internal codons, and to characterize the putative truncated CFTR form(s). RESULTS: Our data show that two shorter forms of CFTR protein are produced when the initiation translation codon is deleted indicating usage of internal initiation codons. The N-truncated CFTR generated by this mutation has decreased stability, very low processing efficiency, and drastically reduced function. Analysis of mutants of four methionine codons downstream to M1 (M82, M150, M152, M156) revealed that each of the codons M150/M152/M156 (exon 4) can mediate CFTR alternative translation. CONCLUSIONS: The CFTR N-terminus has an important role in avoiding CFTR turnover and in rendering effective its plasma membrane traffic. These data correlate well with the severe clinical phenotype of CF patients bearing the c.120del23 mutation.

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126 jointly mutated into valines and the respective stable cells wereanalysedbyimmunoblotforCFTR.ResultsinFig.5A reveal the presence of two proteins (D and E) for single mutants of M82V, M150V, M152V and M156V (lanes 36, respectively) and also for the double mutants M150V/ M152, M150V/M156V and M152V/M156V (lanes 7-9). Login to comment
130 Individual and double mutations of M82V, M150V and M152V (lanes 5-8) did not cause loss of either protein species D or E, consistent with the corresponding constructs in the in vivo assay. Login to comment
131 The mutant M82V/M150V/M152V (lane 4) does not alter the production of proteins D and E either. Login to comment
140 Lanes 3-10 correspond to the proteins produced by the methionines mutants all in the c.120del23-CFTR pNUT background: lane 3, M82V; lane 4, M150V; lane 5 M152V; lane 6, M156V; lane 7, M150V/M152V; lane 8, M150V/M156V; lane 9, M152V/M156V; lane 10, M150V/M152V/M156V. Login to comment
144 Lanes 2-8 all in pSP73: 2, CFTR exons 2-24; 3, M82V/ M150V/M152V/M156V; 4, M82V/M150V/M152V; 5, M82/M152V; 6, M82V/M150V;7, M150; 8, M82V. Login to comment
148 However, when the triple mutant (M150V/M152V/M156V) was analysed (lane 10, Fig.5A), only the lower form (E ~128 kDa) could be detected. Login to comment

[hide] CFTR: domains, structure, and function. J Bioenerg Biomembr. 1997 Oct;29(5):443-51. Devidas S, Guggino WB
CFTR: domains, structure, and function.
J Bioenerg Biomembr. 1997 Oct;29(5):443-51., [PMID:9511929]

Abstract [show]
Mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) cause cystic fibrosis (CF) (Collins, 1992). Over 500 naturally occurring mutations have been identified in CF gene which are located in all of the domains of the protein (Kerem et al., 1990; Mercier et al., 1993; Ghanem et al., 1994; Fanen et al., 1992; Ferec et al., 1992; Cutting et al., 1990). Early studies by several investigators characterized CFTR as a chloride channel (Anderson et al.; 1991b,c; Bear et al., 1991). The complex secondary structure of the protein suggested that CFTR might possess other functions in addition to being a chloride channel. Studies have established that the CFTR functions not only as a chloride channel but is indeed a regulator of sodium channels (Stutts et al., 1995), outwardly rectifying chloride channels (ORCC) (Gray et al., 1989; Garber et al., 1992; Egan et al., 1992; Hwang et al., 1989; Schwiebert et al., 1995) and also the transport of ATP (Schwiebert et al., 1995; Reisin et al., 1994). This mini-review deals with the studies which elucidate the functions of the various domains of CFTR, namely the transmembrane domains, TMD1 and TMD2, the two cytoplasmic nucleotide binding domains, NBD1 and NBD2, and the regulatory, R, domain.

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54 A119CFTR (the first 118 amino acids were deleted creating the next functional methionine at Met150 ), and MIV-M150V (both methionines at positions 1and 150 were Table I. Single Channel Characteristics of CFTR Channelsin Oocytes PS WT R117H 9.3 ±0.4(4) 6.5 ±0.5(4)* Po 0.65 ±0.02(7) 0.49±0.01(7)* Selectivity Br > Cl > I(4:3) Br > Cl > 1(5:4) * Denotes significantly different from wild type (WT). Login to comment
70 Generation of Cl- currents by the double mutant (MIV-M150V) suggests that methionines beyond amino acid 150may also be able to initiate translation initiation of CFTR. Login to comment