ABCMdb

ABCC7 p.Thr1246Val

ClinVar:	c.3737C>T , p.Thr1246Ile ? , not provided
CF databases:	c.3737C>T , p.Thr1246Ile (CFTR1) ? , A novel mutation was identified by DGGE and direct sequencing; the nucleotide change C->T at position 3869leads to T1246I in exon 20. This mutation was identified on a CF chromosome of an Irish patient, in collaboration with Dr. Watson. This was also discovered by Malone, Haworth, and Schwarz. The mutation was identified by direct DNA sequencing. It is the substitution of a single base (C to T) at position 3869, which results in the replacement of a threonine residue by an isoleucine residue at codon 1246. The patient's other CF mutation is [delta]F508, but we have yet been unable to show that it is on his other CF chromosome. We note that there are a number of other isoleucine substitutions (two with threonine: at 1059 and at 1220) which have been classified as polymorphins, and for this reason we are uncertain of the status of T1246I. We have seen this sequence change once in approximately 60 non-[delta]F508 CF chromosomes so far analysed.
Predicted by SNAP2:	A: D (91%), 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 (95%), M: D (95%), N: D (95%), P: D (95%), Q: D (95%), R: D (95%), S: D (95%), V: D (95%), W: D (95%), Y: 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, V: D, W: D, Y: D,

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Publications
[hide] Timing of CFTR Pore Opening and Structure of Its T... Cell. 2015 Oct 22;163(3):724-33. doi: 10.1016/j.cell.2015.09.052. Epub 2015 Oct 22. Sorum B, Czege D, Csanady L
Timing of CFTR Pore Opening and Structure of Its Transition State.
Cell. 2015 Oct 22;163(3):724-33. doi: 10.1016/j.cell.2015.09.052. Epub 2015 Oct 22., [PMID:26496611]

Abstract [show]
In CFTR, the chloride ion channel mutated in cystic fibrosis (CF) patients, pore opening is coupled to ATP-binding-induced dimerization of two cytosolic nucleotide binding domains (NBDs) and closure to dimer disruption following ATP hydrolysis. CFTR opening rate, unusually slow because of its high-energy transition state, is further slowed by CF mutation DeltaF508. Here, we exploit equilibrium gating of hydrolysis-deficient CFTR mutant D1370N and apply rate-equilibrium free-energy relationship analysis to estimate relative timing of opening movements in distinct protein regions. We find clear directionality of motion along the longitudinal protein axis and identify an opening transition-state structure with the NBD dimer formed but the pore still closed. Thus, strain at the NBD/pore-domain interface, the DeltaF508 mutation locus, underlies the energetic barrier for opening. Our findings suggest a therapeutic opportunity to stabilize this transition-state structure pharmacologically in DeltaF508-CFTR to correct its opening defect, an essential step toward restoring CFTR function.

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56 Timing of Motion at Position 1246 of the NBD1-NBD2 Interface (A) Inward single-channel currents of the cut-DR(D1370N) CFTR background construct (top trace) and of channels bearing mutations T1246V, T1246P, T1246C, T1246N, and T1246A, respectively, in the same background. Login to comment