ABCMdb

ABCC7 p.Tyr563Val

ClinVar:	c.1687T>A , p.Tyr563Asn D , Pathogenic c.1687T>G , p.Tyr563Asp ? , not provided
CF databases:	c.1687T>C , p.Tyr563His (CFTR1) D , c.1687T>A , p.Tyr563Asn (CFTR1) ? , This mutation is found in a single family with 2 PS patients, but the mutation in the other chromosome is unknown. c.1687T>G , p.Tyr563Asp (CFTR1) ? , The Y563D mutation was detected on one African-American CF chromosome of 50 screened. It was not detected on any of 208 normal African-American chromosomes by ASO analysis. The patient is a 9 year old pancreatic insufficient male with mild lung disease. c.1688A>G , p.Tyr563Cys (CFTR1) ? , The above mutation was detected by SSCP and identified by direct sequencing. The mutation destroys an AccI site which was used for confirmation.
Predicted by SNAP2:	A: D (95%), C: D (95%), D: D (95%), E: D (95%), F: D (95%), G: D (95%), H: D (95%), I: D (95%), K: D (95%), L: D (91%), M: D (95%), N: D (75%), P: D (95%), Q: D (95%), R: D (95%), S: D (95%), T: D (95%), V: D (95%), W: D (95%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: 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,

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Publications
[hide] Requirements for efficient correction of DeltaF508... Cell. 2012 Jan 20;148(1-2):164-74. doi: 10.1016/j.cell.2011.11.023. Mendoza JL, Schmidt A, Li Q, Nuvaga E, Barrett T, Bridges RJ, Feranchak AP, Brautigam CA, Thomas PJ
Requirements for efficient correction of DeltaF508 CFTR revealed by analyses of evolved sequences.
Cell. 2012 Jan 20;148(1-2):164-74. doi: 10.1016/j.cell.2011.11.023., [PMID:22265409]

Abstract [show]
Misfolding of DeltaF508 cystic fibrosis (CF) transmembrane conductance regulator (CFTR) underlies pathology in most CF patients. F508 resides in the first nucleotide-binding domain (NBD1) of CFTR near a predicted interface with the fourth intracellular loop (ICL4). Efforts to identify small molecules that restore function by correcting the folding defect have revealed an apparent efficacy ceiling. To understand the mechanistic basis of this obstacle, positions statistically coupled to 508, in evolved sequences, were identified and assessed for their impact on both NBD1 and CFTR folding. The results indicate that both NBD1 folding and interaction with ICL4 are altered by the DeltaF508 mutation and that correction of either individual process is only partially effective. By contrast, combination of mutations that counteract both defects restores DeltaF508 maturation and function to wild-type levels. These results provide a mechanistic rationale for the limited efficacy of extant corrector compounds and suggest approaches for identifying compounds that correct both defective steps.

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Sentences [show]
No. Sentence Comment
115 Top 20 508-Coupled Positions within NBD1 Using Four Independent Statistical Methods ELSC McBASC OMES SCA 435 453 460 S466T S466T 468 470 472 473 473 474 474 L475Y L475Y L475Y F490L F490L W496V W496V W496V W496V 503 505 507 509 512 513 Y517I Y517I Y517I Y517I 520 520 521 C524A C524A C524A C524A L526A L526A L526A L526A D529F D529F D529F D529F D537F D537F 543 Y563V Y563V Y563V Y563V A566P A566P 569 569 S573E P574A P574A P574A F575T F575T 578 582 E583G E583G 587 591 595 598 602 604 604 604 H609T 617 630 630 640 The alignment of 493 sequences was used to calculate pairwise coupling scores using each method (ELSC, SCA, McBASC, and OMES). Login to comment
127 The surface view A B I539T G550E R553M R555K 3M WT F S466T L475Y F490L W496V Y517I C524A L526A D529F D537F Y563V A566P S573E P574A F575T E583G H609T 0 1 2 3 Relative Yield NBD1 ( -gal.) 25 30 35 40 45 0.0 0.5 1.0 Temperature (C ) Relative Turbitity 0 1 2 3 4 -5 0 5 10 WT F I539T I539T F S573E R555K D529F Relative Yield NBD1 ( -gal.) Tm Figure 3. Login to comment
166 B C A B 0 1 2 3 0 1 2 Relative Yield NBD1 (b2;-gal.) Relative Yield CFTR (ELISA) WT ࢞F WT ƊF S466T L475Y F490L W496V Y517I C524A L526A D529F D537F Y563V A566P S573E P574A F575T E583G H609T 0 1 2 Relative Yield CFTR (ELISA) I539T G550E R553M R555K 3M Figure 4. Login to comment