ABCC8 p.His125Gln
| Predicted by SNAP2: | A: D (53%), C: D (53%), D: D (71%), E: D (59%), F: D (53%), G: N (57%), I: D (59%), K: D (71%), L: D (59%), M: D (63%), N: N (61%), P: D (80%), Q: D (53%), R: D (63%), S: N (61%), T: N (57%), V: D (53%), W: D (71%), Y: D (53%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: 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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[hide] Insight in eukaryotic ABC transporter function by ... FEBS Lett. 2006 Feb 13;580(4):1064-84. Epub 2006 Jan 19. Frelet A, Klein M
Insight in eukaryotic ABC transporter function by mutation analysis.
FEBS Lett. 2006 Feb 13;580(4):1064-84. Epub 2006 Jan 19., 2006-02-13 [PMID:16442101]
Abstract [show]
With regard to structure-function relations of ATP-binding cassette (ABC) transporters several intriguing questions are in the spotlight of active research: Why do functional ABC transporters possess two ATP binding and hydrolysis domains together with two ABC signatures and to what extent are the individual nucleotide-binding domains independent or interacting? Where is the substrate-binding site and how is ATP hydrolysis functionally coupled to the transport process itself? Although much progress has been made in the elucidation of the three-dimensional structures of ABC transporters in the last years by several crystallographic studies including novel models for the nucleotide hydrolysis and translocation catalysis, site-directed mutagenesis as well as the identification of natural mutations is still a major tool to evaluate effects of individual amino acids on the overall function of ABC transporters. Apart from alterations in characteristic sequence such as Walker A, Walker B and the ABC signature other parts of ABC proteins were subject to detailed mutagenesis studies including the substrate-binding site or the regulatory domain of CFTR. In this review, we will give a detailed overview of the mutation analysis reported for selected ABC transporters of the ABCB and ABCC subfamilies, namely HsCFTR/ABCC7, HsSUR/ABCC8,9, HsMRP1/ABCC1, HsMRP2/ABCC2, ScYCF1 and P-glycoprotein (Pgp)/MDR1/ABCB1 and their effects on the function of each protein.
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No. Sentence Comment
426 Shyng et al. [204] have reported that H125Q, N188S, F591L, T1139M, R1215Q and G1382S generated functional channels in the absence of ATP, indicating that the lack or reduction of KATP channel sensitivity to MgADP is a common molecular defect associated with the disease.
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ABCC8 p.His125Gln 16442101:426:38
status: NEW[hide] Functional analyses of novel mutations in the sulf... Diabetes. 1998 Jul;47(7):1145-51. Shyng SL, Ferrigni T, Shepard JB, Nestorowicz A, Glaser B, Permutt MA, Nichols CG
Functional analyses of novel mutations in the sulfonylurea receptor 1 associated with persistent hyperinsulinemic hypoglycemia of infancy.
Diabetes. 1998 Jul;47(7):1145-51., [PMID:9648840]
Abstract [show]
The ATP-sensitive potassium channel, K(ATP) channel, a functional complex of the sulfonylurea receptor 1, SUR1, and an inward rectifier potassium channel subunit, Kir6.2, regulates insulin secretion in the pancreas. Mutations in both the Kir6.2 and SUR1 genes are associated with persistent hyperinsulinemic hypoglycemia of infancy (PHHI), a disorder of pancreatic beta-cell function characterized by excess insulin secretion and hypoglycemia. We have studied the functional properties of novel SUR1 mutations identified in PHHI patients, including H125Q, N188S, F591L, T1139M, R1215Q, G1382S, and R1394H. R1394H and deltaF1388 SUR1, a previously identified PHHI mutation, resulted in no functional channels when coexpressed with Kir6.2 in COS cells, while H125Q, N188S, F591L, T1139M, R1215Q, and G1382S SUR1 generated functional channels in the absence of ATP. With the exception of N188S and H125Q, all mutants had reduced response to stimulation by MgADP. These results indicate that lack of, or reduction of, K(ATP) channel sensitivity to MgADP is a common molecular defect associated with the disease. The mutant channels also showed varied response to activation by the potassium channel opener diazoxide. Because these mutations are distributed throughout the molecule, our data have new implications for structure-function relationships of the K(ATP) channel, suggesting that structural elements in SUR1 outside of the two nucleotide-binding folds are also important in regulating channel activity.
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No. Sentence Comment
2 We have studied the functional properties of novel SUR1 mutations identified in PHHI patients, including H125Q, N188S, F591L, T1139M, R1215Q, G1382S, and R1394H.
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ABCC8 p.His125Gln 9648840:2:105
status: NEW3 R1394H and F1388 SUR1, a previously identified PHHI mutation, resulted in no functional channels when coexpressed with Kir6.2 in COS cells, while H125Q, N188S, F591L, T1139M, R1215Q, and G1382S SUR1 generated functional channels in the absence of ATP.
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ABCC8 p.His125Gln 9648840:3:146
status: NEW4 With the exception of N188S and H125Q, all mutants had reduced response to stimulation by MgADP.
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ABCC8 p.His125Gln 9648840:4:32
status: NEW75 The positions of the seven newly identified SUR1 mutations that are associated with the disease PHHI are shown in Fig. 1, including H125Q, N188S, F591L, T1139M, R1215Q, G1382S, and R1394H on both SUR1 topology models.
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ABCC8 p.His125Gln 9648840:75:132
status: NEW90 The level of activity of other channels follows the order of WT ~N188S ~T1139M > G1382S > H125Q > F591L > R1215Q.
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ABCC8 p.His125Gln 9648840:90:90
status: NEW112 Compared with wild-type channels, H125Q had a slightlygreater response to diazoxide (P < 0.1, ANOVA), N188S hada response that is similar to the wild-type channel (NS, ANOVA), T1139M and G1382S mutant channels had slightly reduced responses, while F591L and R1215Q channels had severely reduced responses (P < 0.005 and 0.025, respectively, ANOVA) (Fig. 6).
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ABCC8 p.His125Gln 9648840:112:34
status: NEW131 Another patient, compound heterozygous for the H125Q mutation and the F1388 mutation, had clinically mild disease.
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ABCC8 p.His125Gln 9648840:131:47
status: NEW132 The mild disease is consistent with the functional data of the H125Q mutation.
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ABCC8 p.His125Gln 9648840:132:63
status: NEW156 With the exception of N188S and H125Q, which formed channels that were indistinguishable from the wild-type in terms of regulation of the channel by nucleotides and diazoxide, all other mutants caused defects of various severity in the resulting channels.
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ABCC8 p.His125Gln 9648840:156:32
status: NEW162 Although for some mutations ( F1388, H125Q, R1215Q, R1394H) the in vitro findings correlate well with the clinical observations, in other mutations there seems to be a discrepancy between in vitro and clinical observations.
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ABCC8 p.His125Gln 9648840:162:37
status: NEW175 Five others (H125Q, N188S, F591L, T1139M, and R1215Q) are outside of the predicted nucleotide-binding folds.
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ABCC8 p.His125Gln 9648840:175:13
status: NEW176 However, except for N188S and H125Q, these mutations all show some defects in regulation of the channel by MgADP or by diazoxide.
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ABCC8 p.His125Gln 9648840:176:30
status: NEW185 Pancreatectomy BV N188S 3992-3 c-to-g <1 week Severe No Pancreatectomy CB H125Q F1388 1 year Mild No Pancreatectomy Q R1215Q 3992-9 g-to-a <1 week Severe Inadequate Pancreatectomy AO R1394H 3992-9 g-to-a < week Severe No Pancreatectomy BI F591L - <1 week Mild Yes Diazoxide BU G1382S - <1 week Severe ??
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ABCC8 p.His125Gln 9648840:185:74
status: NEW[hide] Genetic heterogeneity in familial hyperinsulinism. Hum Mol Genet. 1998 Jul;7(7):1119-28. Nestorowicz A, Glaser B, Wilson BA, Shyng SL, Nichols CG, Stanley CA, Thornton PS, Permutt MA
Genetic heterogeneity in familial hyperinsulinism.
Hum Mol Genet. 1998 Jul;7(7):1119-28., [PMID:9618169]
Abstract [show]
Familial hyperinsulinism (HI) is a disorder characterized by dysregulation of insulin secretion and profound hypoglycemia. Mutations in both the Kir6.2 and sulfonylurea receptor (SUR1) genes have been associated with the autosomal recessive form of this disorder. In this study, the spectrum and frequency of SUR1 mutations in HI and their significance to clinical manifestations of the disease were investigated by screening 45 HI probands of various ethnic origins for mutations in the SUR1 gene. Single-strand conformation polymorphism (SSCP) and nucleotide sequence analyses of genomic DNA revealed a total of 17 novel and three previously described mutations in SUR1 . The novel mutations comprised one nonsense and 10 missense mutations, two deletions, three mutations in consensus splice-site sequences and an in-frame insertion of six nucleotides. One mutation occurred in the first nucleotide binding domain (NBF-1) of the SUR1 molecule and another eight mutations were located in the second nucleotide binding domain (NBF-2), including two at highly conserved amino acid residues within the Walker A sequence motif. The majority of the remaining mutations was distributed throughout the three putative transmembrane domains of the SUR1 protein. With the exception of the 3993-9G-->A mutation, which was detected on 4.5% (4/88) disease chromosomes, allelic frequencies for the identified mutations varied between 1.1 and 2.3% for HI chromosomes, indicating that each mutation was rare within the patient cohort. The clinical manifestations of HI in those patients homozygous for mutations in the SUR1 gene are described. In contrast with the allelic homogeneity of HI previously described in Ashkenazi Jewish patients, these findings suggest that a large degree of allelic heterogeneity at the SUR1 locus exists in non-Ashkenazi HI patients. These data have important implications for genetic counseling and prenatal diagnosis of HI, and also provide a basis to further elucidate the molecular mechanisms underlying the pathophysiology of this disease.
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No. Sentence Comment
63 Mutations within the SUR1 gene Patient Exon or intron Nucleotide changea Codona predicted effect Domainb Restriction site change Frequency (%) HI chromosomes (n = 88) Segregation demonstrated Frequency 200 normal chromosomes A1 exon 2 221G→A R74Q Tm PstI 1 (1.1%) NA 0 B2d exon3 375C→G H125Q Tm DdeIc 1 (1.1%) NA 0 C3e exon 4 563A→G N188S Tm TspRI 1 (1.1%) yes 0 D4 exon 6 949delC 317fs/ter Tm Bsp1286I 1 (1.1%) yes 0 E5 exon 8 1216A→G N406D Tm XcmI 1 (1.1%) NA 0 F6f intron 10 1630+1G→T aberrant splicing Tm BsrI 2 (2.3%) yes 0 G7 exon 12 1773C→G F591L Tm BsoF1 1 (1.1%) no 0 H8 exon 13 1893delT 631fs/ter Tm BstNI 1 (1.1%) yes 0 F6f intron 15 2117-1G→A aberrant splicing NBF-1 PstI 1 (1.1%) yes 0 I9 exon 24 2860C→T Q954X - BstNI 1 (1.1%) yes 0 J10g exon 28 3416C→Th T1139M Tm NlaIII 1 (1.1%) yes 0 K11 exon 29 3644G→A R1215Q Tm NciI 1 (1.1%) yes 0 J10g intron 32 3992-9G→Ai aberrant splicing NBF-2 NciI 4 (4.5%) yes 0 C3e intron 32 3992-3C→G aberrant splicing NBF-2 AvaI 1 (1.1%) yes 0 L12 exon 34 4135G→C G1379R NBF-2 EagI 1 (1.1%) yes 0 M13 exon 34 4144G→A G1382S NBF-2 BglI 1 (1.1%) yes 0 B2d exon 34 4162delTTCi,j delF 1388 NBF-2 BseRI 1 (1.1%) yes 0 J10g exon 34 4181G→Ah R1394H NBF-2 DraIII 1 (1.1%) yes 0 N14 exon 35 4310G→Ai aberrant splicing NBF-2 MspI 1 (1.1%) yes 0 O15 exon 37 4525insCGGCTT insertion of AlaSer ft d 1508 NBF-2 PvuIIk 1 (1.1%) yes 0 after codon 1508 aNucleotide and codon positions are according to the full-length human SUR1 cDNA sequence incorporating the alternative splicedform of exon 17 (GenBank accession nos L78208 and L78216).
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ABCC8 p.His125Gln 9618169:63:300
status: NEW200 A model for SUR1 (29) predicts that the remaining seven missense mutations (Arg74Gln, His125Gln, Asn188Ser, Asn406Asp, Phe591Leu, Thr1139Met, Arg1215Gln) are located either within transmembrane segments or are present on the extracellular or cytoplasmic loops connecting adjacent trans- membranehelices.Theidentificationofthesemissensemutations in HI patients provides a basis for further studies to elucidate the functions of these transmembrane domains in SUR1 and KATP channel activity.
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ABCC8 p.His125Gln 9618169:200:86
status: NEW201 We have found that the His125Gln, Phe591Leu, Thr1139Met and Arg1215Gln mutations result in various reductions in the sensitivity of KATP channels to stimulation by MgADP in vitro (S.-L.Shyng et al., unpublished data).
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ABCC8 p.His125Gln 9618169:201:23
status: NEW233 To detect the His125Gln mutation, which did not alter a restriction enzyme site, PCR-directed site-specific mutagenesis was used to incorporate a DdeI restriction site into products derived from wild-type alleles.
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ABCC8 p.His125Gln 9618169:233:14
status: NEW