ABCMdb

ABCC7 p.Arg248Glu

ClinVar:	c.743G>C , p.Arg248Thr ? , not provided
CF databases:	c.743G>C , p.Arg248Thr (CFTR1) ? , The mutation was detected by DGGE and identified by direct sequencing of a CBAVD patient with [delta]F508 on the other chromosome. The mutation was not observed in 100 other CFTR alleles from 50 unrelated individuals without CF history. The mutation may affect mRNA splicing.
Predicted by SNAP2:	A: D (80%), C: D (80%), D: D (91%), E: D (91%), F: D (85%), G: D (91%), H: D (85%), I: D (85%), K: D (66%), L: D (85%), M: D (85%), N: D (75%), P: D (91%), Q: D (80%), S: D (71%), T: D (80%), V: D (85%), W: D (80%), Y: D (85%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: N, F: D, G: D, H: N, I: D, K: N, L: D, M: N, N: N, P: D, Q: N, S: N, T: D, V: D, W: D, Y: D,

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Publications
[hide] Topogenesis of cystic fibrosis transmembrane condu... Biochemistry. 1999 Apr 27;38(17):5471-7. Chen M, Zhang JT
Topogenesis of cystic fibrosis transmembrane conductance regulator (CFTR): regulation by the amino terminal transmembrane sequences.
Biochemistry. 1999 Apr 27;38(17):5471-7., 1999-04-27 [PMID:10220334]

Abstract [show]
Cystic fibrosis transmembrane conductance regulator (CFTR) is a member of the ATP-binding cassette (ABC) transport superfamily. CFTR folding and assembly appear to involve several events occurred in the cytosol and ER. Misfolding of CFTR causes cystic fibrosis, and thus, understanding the folding mechanism of CFTR is extremely important. Recently, detailed study of membrane insertion process suggests that the first two transmembrane (TM) segments of CFTR have two distinct but independent mechanisms to ensure the correct membrane folding of its amino terminal end [Lu, Y., Xiong, X., Helm, A., Kimani, K., Bragin, A., Skach, W. R. (1998) J. Biol. Chem. 273, 568-576]. To understand how other TM segments are ensured to insert into membranes correctly, we investigated the topogenesis of TM3 and TM4 of CFTR in a cell-free expression system. We found that the correct membrane insertion of TM3 and TM4 of CFTR was ensured by their flanking amino acid sequences and controlled by the correct membrane insertion of their preceding TM1 and TM2. Thus, correct membrane insertion and folding of TM1 and TM2 play an essential role in the membrane insertion and folding of the subsequent TM segments of CFTR.

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No. Sentence Comment
47 Primers carrying various mutations are 5'-AATCTGGAGGTTGTTAAAGGCGTC-3' (E217R/Q220K), 5'-CATCATTTCCCCTAGCCC-3' (R242E), 5'-CT- GATCTTCGTAATTCATCATCAT-3' (K246N/R248E), and 5'-TCCCAGCTTCCTGATCT-3' (R251E). Login to comment
49 The resulting constructs were named CFTR-N4R(E217R/Q220K), CFTR-N4R(R242E), CFTR-N4R(K246N/R248E), CFTR-N4R(R251E), CFTR-N4R(-8), and CFTR-N4R(-5). Login to comment
53 The final DNA clones were named CF-TM3,4R, CF-TM3,4R(E217R/Q220K), CF-TM3,4R(-8), and CF-TM3,4R(-5), respectively. To engineer R242E and K246N/R248E mutations into CF-TM3,4R, an EcoRI-EcoNI fragment encoding TM3 and part of TM4 was released from CF-TM3,4R and used to replace the amino terminal-encoding sequence in CFTR-N4R(R242E) and CFTR-N4R(K246N/R248E). Login to comment
54 The resulting constructs were named CF-TM3,4R(R242E) and CF-TM3,4R(K246N/R248E), respectively. To replace TM1 and TM2 of CFTR with that of Pgp, CFTR-N4R(-8) was linearized with XbaI, treated with Klenow DNA polymerase supplemented with dNTP in the absence of dGTP to avoid filling at the G position, and then digested with HindIII. The XbaI-HindIII fragment from CFTR-N4R(-8) and an EcoRI-NciI fragment encoding TM1 and TM2 of Pgp from pGPGP-N3 (12) were ligated into a pGEM-4z vector digested with EcoRI and HindIII. The resulting construct was named P1,2CF3,4R(-8). Login to comment
72 The mutant molecules used were CF-TM3,4R(E217R/ Q220K), CF-TM3,4R(R242E), and CF-TM3,4R(K246N/ R248E). Login to comment