ABCMdb

ABCC7 p.Gly551Glu

ClinVar:	c.1651G>A , p.Gly551Ser D , Pathogenic c.1652G>A , p.Gly551Asp D , Pathogenic
CF databases:	c.1652G>A , p.Gly551Asp D , CF-causing ; CFTR1: This mutation has been found in six Caucasian CF chromosomes out of 155 eamined for a frequency of 4 %. It has not been found on any Black CF chromosomes. This mutation appears to be associated with a particular ten site haplotype shown on the following pages. We have not detected this mutation on any normal Caucasian chromosomes with similar haplotypes or other haplotypes. c.1651G>A , p.Gly551Ser D , CF-causing ; CFTR1: This mutation can be detected using ASOs: normal 5' GAGTGGAGGTCAACG 3', mutant 5' GAGTGGAAGTCAACG 3' with a final wash at 42 degrees celsius in 40 mM NaHPO4, 1 mM EDTA, 0.5 % SDS for 15 minutes. Two patients were found to be homozygous for this mutation. Their parents are second cousins and each carries the G551S mutation. These patients are remarkable in that they have a mild disease without elevated Na+ levels. One patient had decreased lung function, Pseudomonas infections, chronic pancreatitis, clubbing, and is currently 49 years old. This mutation was not found in 363 non-[delta]F508 CF chromosomes, nor in over 700[delta]F508 chromosomes, nor in a small number of normal chromosomes.
Predicted by SNAP2:	A: D (95%), C: D (95%), D: D (71%), E: D (95%), F: D (95%), H: D (95%), I: D (95%), K: D (95%), L: D (95%), M: D (95%), N: D (95%), P: D (95%), Q: D (95%), R: D (95%), S: N (61%), T: D (95%), V: D (95%), W: D (95%), Y: D (95%),
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] Emergent properties of proteostasis in managing cy... Cold Spring Harb Perspect Biol. 2011 Feb 1;3(2). pii: a004499. doi: 10.1101/cshperspect.a004499. Balch WE, Roth DM, Hutt DM
Emergent properties of proteostasis in managing cystic fibrosis.
Cold Spring Harb Perspect Biol. 2011 Feb 1;3(2). pii: a004499. doi: 10.1101/cshperspect.a004499., [PMID:21421917]

Abstract [show]
Cystic fibrosis (CF) is a consequence of defective recognition of the multimembrane spanning protein cystic fibrosis conductance transmembrane regulator (CFTR) by the protein homeostasis or proteostasis network (PN) (Hutt and Balch (2010). Like many variant proteins triggering misfolding diseases, mutant CFTR has a complex folding and membrane trafficking itinerary that is managed by the PN to maintain proteome balance and this balance is disrupted in human disease. The biological pathways dictating the folding and function of CFTR in health and disease are being studied by numerous investigators, providing a unique opportunity to begin to understand and therapeutically address the role of the PN in disease onset, and its progression during aging. We discuss the general concept that therapeutic management of the emergent properties of the PN to control the energetics of CFTR folding biology may provide significant clinical benefit.

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No. Sentence Comment
47 The G551E and G1349D mutants (purple) are folded and traffic normally to cell surface. Login to comment
49 The G551E and G1349D vCFTR only require a potentiator to open the channel and restore function. Login to comment

[hide] A single amino acid substitution in CFTR converts ... J Gen Physiol. 2014 Oct;144(4):311-20. doi: 10.1085/jgp.201411247. Epub 2014 Sep 15. Lin WY, Jih KY, Hwang TC
A single amino acid substitution in CFTR converts ATP to an inhibitory ligand.
J Gen Physiol. 2014 Oct;144(4):311-20. doi: 10.1085/jgp.201411247. Epub 2014 Sep 15., [PMID:25225552]

Abstract [show]
Cystic fibrosis (CF), one of the most common lethal genetic diseases, is caused by loss-of-function mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a chloride channel that, when phosphorylated, is gated by ATP. The third most common pathogenic mutation, a glycine-to-aspartate mutation at position 551 or G551D, shows a significantly decreased open probability (Po) caused by failure of the mutant channel to respond to ATP. Recently, a CFTR-targeted drug, VX-770 (Ivacaftor), which potentiates G551D-CFTR function in vitro by boosting its Po, has been approved by the FDA to treat CF patients carrying this mutation. Here, we show that, in the presence of VX-770, G551D-CFTR becomes responsive to ATP, albeit with an unusual time course. In marked contrast to wild-type channels, which are stimulated by ATP, sudden removal of ATP in excised inside-out patches elicits an initial increase in macroscopic G551D-CFTR current followed by a slow decrease. Furthermore, decreasing [ATP] from 2 mM to 20 microM resulted in a paradoxical increase in G551D-CFTR current. These results suggest that the two ATP-binding sites in the G551D mutant mediate opposite effects on channel gating. We introduced mutations that specifically alter ATP-binding affinity in either nucleotide-binding domain (NBD1 or NBD2) into the G551D background and determined that this disease-associated mutation converts site 2, formed by the head subdomain of NBD2 and the tail subdomain of NBD1, into an inhibitory site, whereas site 1 remains stimulatory. G551E, but not G551K or G551S, exhibits a similar phenotype, indicating that electrostatic repulsion between the negatively charged side chain of aspartate and the gamma-phosphate of ATP accounts for the observed mutational effects. Understanding the molecular mechanism of this gating defect lays a foundation for rational drug design for the treatment of CF.

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21 G551E, but not G551K or G551S, exhibits a similar phenotype, indicating that electrostatic repulsion between the negatively charged side chain of aspartate and the &#e067;-phosphate of ATP accounts for the observed mutational effects. Login to comment
32 Because this inhibitory effect is observed also in G551E, but not in G551K or G551S, a basic chemical mechanism of an electrostatic repulsion between the negatively charged side chain of 551D/E and the &#e067;-phosphate of ATP in shaping the observed mutational effects is proposed. Login to comment
164 In contrast, G551E-CFTR channels behave just like G551D-CFTR (Fig. 6 C), suggesting that an anionic side chain at residue 551 is required to confer this inhibitory action to site 2. Login to comment
191 (A-C) Responses to ATP withdrawal in different G551 mutants: G551S (A), G551K (B), and G551E (C). Login to comment