ABCC7 p.Arg170Leu
| ClinVar: |
c.509G>A
,
p.Arg170His
?
, Uncertain significance
|
| CF databases: |
c.509G>A
,
p.Arg170His
(CFTR1)
D
, This mutation was seen in a 48 year-old male being investigated for infertility whose other CF mutation is [delta]F508. We have seen this mutation only once in over 200 CF chromosomes screened.(Original Note 27March2001) Reported by Jennifer King (University of Iowa. 22/03/2002): It was also found in a 12 year old male patient who was seen for genetic evaluation following discovery of CBAVD (during a hydrocele repair operation). It turned out that he has a [delta]F508 mutation and a R170H mutation. His sweat test was normal.
c.508_510delC , p.Arg170del (CFTR1) ? , c.508C>G , p.Arg170Gly (CFTR1) ? , This mutation was detected by SSCP. It does not alter a restriction site. c.508C>T , p.Arg170Cys (CFTR1) ? , This mutation was identified on one French CF chromosome. |
| Predicted by SNAP2: | A: D (80%), C: D (91%), D: D (95%), E: D (91%), F: D (95%), G: D (91%), H: N (72%), I: D (91%), K: D (63%), L: D (91%), M: D (91%), N: D (91%), P: D (95%), Q: D (85%), S: D (80%), T: D (85%), V: D (91%), W: D (95%), Y: D (91%), |
| Predicted by PROVEAN: | A: N, C: D, D: N, E: N, F: D, G: D, H: N, I: D, K: N, L: D, M: N, N: N, P: N, Q: N, S: N, T: N, V: D, W: D, Y: D, |
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[hide] Mutational analysis of the P-glycoprotein first in... Biochemistry. 1998 Mar 10;37(10):3337-50. Kwan T, Gros P
Mutational analysis of the P-glycoprotein first intracellular loop and flanking transmembrane domains.
Biochemistry. 1998 Mar 10;37(10):3337-50., 1998-03-10 [PMID:9521654]
Abstract [show]
The role of individual intracellular (IC) loops linking transmembrane (TM) domains in P-glycoprotein (P-gp) function remains largely unknown. The high degree of sequence conservation of these regions in the P-gp family and other ABC transporters suggests an important role in a common mechanism of action of these proteins. To gain insight into this problem, we have randomly mutagenized a portion of TM2, the entire IC1 loop, TM3, the entire extracellular loop (EC2), and part of TM4, and analyzed the effect of such mutations on P-gp function. Random mutagenesis was carried out using Taq DNA polymerase and dITP under conditions of low polymerase fidelity, and the mutagenized segments were reintroduced in the full length mdr3 cDNA by homologous recombination in the yeast Saccharomyces cerevisiae strain JPY201. The biological activity of mutant P-gp variants was analyzed in yeast by their ability to confer cellular resistance to the antifungal drug FK506 and the peptide ionophore valinomycin, and by their ability to complement the yeast Ste6 gene and restore mating in a yeast strain bearing a null mutation [Raymond, M., et al. (1992) Science 256, 232-4] at this locus. The analysis of 782 independent yeast transformants allowed the identification of 49 independent mutants bearing single amino acid substitutions in the mutagenized segment resulting in an altered P-gp function. The mutants could be phenotypically classified into two major groups, those that resulted in partial or complete overall loss of function and those that seemed to affect substrate specificity. Several of the mutants affecting overall activity mapped in IC1; in particular we identified a segment of four consecutive mutation sensitive residues (TRLT, positions 169-172) with such a phenotype. On the other hand, we identified a cluster of mutants affecting substrate specificity within the short EC2 segment and in the adjacent portion of the neighboring TM4 domain. Expression and partial purification of a representative subset of these mutants showed that in all but two cases, loss of function was associated with loss of drug-induced ATPase activity of P-gp. Therefore, it appears that TM domains, IC and EC loops, are structurally and functionally tightly coupled in the process of drug stimulatable ATPase characteristic of P-gp.
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No. Sentence Comment
194 Such mutants showed near wild-type transport Table 1: Summary of Mutations Identifieda TM2 IC1 TM3 EC2 TM4 Q128H R138H F159I S176P G187E R206L L210I Q128R Q139H V161E K177I A192T W208G T211P L134P Q139P H162R N179S F200L K209E V213A A136V Q139R T169I E180G F204S I214L Q145H R170L G181R I214T F147L L171P G183D S224P F148S T172P D184N E155G D174G E155K S176F a Summary of the mutations identified in the current screen together with their position within the predicted secondary structure of P-glycoprotein, with respect to the second (TM2), third (TM3), and fourth (TM4) predicted transmembrane domains together with the first intracellular (IC1) and second extracellular loop (EC2).
X
ABCC7 p.Arg170Leu 9521654:194:275
status: NEW188 Group 1 comprised 17 mutants, including Q128R, L134P, F147L, F148S, F159I, V161E, H162R, T169I, R170L, L171P, T172P, G181R, G187E, W208G, K209E, I214L, and S224P.
X
ABCC7 p.Arg170Leu 9521654:188:96
status: NEW207 This was particularly important in the case of Mdr3 mutants such as Q128R, L134P, V161E, R170L, L171P, G181R, G187E, and S224P that show complete loss of function in the three assays conducted.
X
ABCC7 p.Arg170Leu 9521654:207:89
status: NEW297 The four mutations detected at these positions were nonconservative and involved elimination of a charged side chain (R170L), introduction of either a bulkier side chain (T169I) or of a helix breaker (L171P, T172P).
X
ABCC7 p.Arg170Leu 9521654:297:118
status: NEW[hide] Genomic landscape of non-small cell lung cancer in... Cell. 2012 Sep 14;150(6):1121-34. doi: 10.1016/j.cell.2012.08.024. Govindan R, Ding L, Griffith M, Subramanian J, Dees ND, Kanchi KL, Maher CA, Fulton R, Fulton L, Wallis J, Chen K, Walker J, McDonald S, Bose R, Ornitz D, Xiong D, You M, Dooling DJ, Watson M, Mardis ER, Wilson RK
Genomic landscape of non-small cell lung cancer in smokers and never-smokers.
Cell. 2012 Sep 14;150(6):1121-34. doi: 10.1016/j.cell.2012.08.024., [PMID:22980976]
Abstract [show]
We report the results of whole-genome and transcriptome sequencing of tumor and adjacent normal tissue samples from 17 patients with non-small cell lung carcinoma (NSCLC). We identified 3,726 point mutations and more than 90 indels in the coding sequence, with an average mutation frequency more than 10-fold higher in smokers than in never-smokers. Novel alterations in genes involved in chromatin modification and DNA repair pathways were identified, along with DACH1, CFTR, RELN, ABCB5, and HGF. Deep digital sequencing revealed diverse clonality patterns in both never-smokers and smokers. All validated EFGR and KRAS mutations were present in the founder clones, suggesting possible roles in cancer initiation. Analysis revealed 14 fusions, including ROS1 and ALK, as well as novel metabolic enzymes. Cell-cycle and JAK-STAT pathways are significantly altered in lung cancer, along with perturbations in 54 genes that are potentially targetable with currently available drugs.
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No. Sentence Comment
76 We identified five point mutations involving the CFTR gene in four samples; these included four missense (LUC18: M82V, LUC9: R170L, F354I, and A309S from panel screening) and one nonsense (LUC18: S478*) mutations.
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ABCC7 p.Arg170Leu 22980976:76:125
status: NEW