ABCMdb

ABCC7 p.Gly550Asp

ClinVar:	c.1648G>T , p.Gly550* ? , not provided c.1648G>A , p.Gly550Arg ? , not provided
CF databases:	c.1648G>T , p.Gly550* D , CF-causing c.1648G>A , p.Gly550Arg (CFTR1) D , The above mutation was detected by DGGE and identified direct sequencing.
Predicted by SNAP2:	A: D (59%), C: D (80%), D: D (91%), E: D (85%), F: D (91%), H: D (91%), I: D (91%), K: D (95%), L: D (91%), M: D (91%), N: D (85%), P: D (91%), Q: D (85%), R: D (91%), S: D (80%), T: D (85%), V: D (71%), W: D (95%), Y: D (91%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D,

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Publications
[hide] Mutations in the nucleotide binding domain 1 signa... J Biol Chem. 2002 Sep 27;277(39):35896-905. Epub 2002 Jul 10. DeCarvalho AC, Gansheroff LJ, Teem JL
Mutations in the nucleotide binding domain 1 signature motif region rescue processing and functional defects of cystic fibrosis transmembrane conductance regulator delta f508.
J Biol Chem. 2002 Sep 27;277(39):35896-905. Epub 2002 Jul 10., 2002-09-27 [PMID:12110684]

Abstract [show]
The gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), an ATP binding cassette (ABC) transporter that functions as a phosphorylation- and nucleotide-regulated chloride channel, is mutated in cystic fibrosis (CF) patients. Deletion of a phenylalanine at amino acid position 508 (DeltaF508) in the first nucleotide binding domain (NBD1) is the most prevalent CF-causing mutation and results in defective protein processing and reduced CFTR function, leading to chloride impermeability in CF epithelia and heterologous systems. Using a STE6/CFTRDeltaF508 chimera system in yeast, we isolated two novel DeltaF508 revertant mutations, I539T and G550E, proximal to and within the conserved ABC signature motif of NBD1, respectively. Western blot and functional analysis in mammalian cells indicate that mutations I539T and G550E each partially rescue the CFTRDeltaF508 defect. Furthermore, a combination of both revertant mutations resulted in a 38-fold increase in CFTRDeltaF508-mediated chloride current, representing 29% of wild type channel activity. The G550E mutation increased the sensitivity of CFTRDeltaF508 and wild type CFTR to activation by cAMP agonists and blocked the enhancement of CFTRDeltaF508 channel activity by 2 mm 3-isobutyl-1-methylxanthine. The data show that the DeltaF508 defect can be significantly rescued by second-site mutations in the nucleotide binding domain 1 region, that includes the LSGGQ consensus motif.

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Sentences [show]
No. Sentence Comment
167 CFTR variant Isc n % of CFTR wt CFTR S549R 1.70 Ϯ 0.11 4 CFTR G551D 1.17 Ϯ 0.12 4 CFTR ⌬F508 0.76 Ϯ 0.07 17 CFTR ⌬F/G550E 9.30 Ϯ 0.55 14 (*) CFTR ⌬F/G550D 6.06 Ϯ 0.63 12 (*) CFTR ⌬F/G550H 4.17 Ϯ 0.40 8 (*) Mutations in the ABC Signature Motif Region Rescue CFTR⌬F50835900 CFTR⌬F/G550E relative to FRT-CFTR ⌬F508 (Fig. 4B), although the mature band C was barely detectable, and the steady-state levels of band B were decreased for the revertant (Fig. 4A). Login to comment
203 Because the G550E mutation replaces a Gly residue with the negatively charged Glu, we also constructed a CFTR⌬F/G550D variant to test whether the negative charge resulting from an aspartate substitution would have a similar effect on CFTR channel activation. Login to comment
208 CFTR⌬F/G550H and CFTR⌬F/G550D displayed 50 and 68% of CFTR⌬F/G550E Isc, respectively, demonstrating that these additional revertants were not as effective as G550E in suppressing the CFTR ⌬F508 defect. Login to comment
209 We tested the CFTR⌬F/G550D response to activation by low concentrations of forskolin (0.5 ␮M) as described in Fig. 3. Login to comment
210 However, unlike the results observed for CFTR⌬F/ G550E, suboptimal forskolin concentration failed to activate CFTR⌬F/G550D (not shown). Login to comment