ABCMdb

ABCC8 p.Phe591Leu

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Publications

PMID: 16442101 [PubMed] Frelet A et al: "Insight in eukaryotic ABC transporter function by mutation analysis."

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. Login to comment

PMID: 9648840 [PubMed] Shyng SL et al: "Functional analyses of novel mutations in the sulfonylurea receptor 1 associated with persistent hyperinsulinemic hypoglycemia of infancy."

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. Login to comment
3 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. Login to comment
75 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. Login to comment
90 The level of activity of other channels follows the order of WT ~N188S ~T1139M > G1382S > H125Q > F591L > R1215Q. Login to comment
102 Figure 5A illustrates the response ofmutant channels toMgADP.Inwild-type channels, MgADP stimulated channel activity in the presence of inhibitory ATP, and this stimulatory effect was reduced in mutant F591L, T1139M, R1215Q, and G1382S (Fig. 5B). Login to comment
112 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). Login to comment
124 Only F591L shows slightly increased ATP sensitivity (n = 3-8). Login to comment
141 The first had relatively mild disease andwas diazoxide-responsive even though the in vitro data on this mutation (F591L) might predict a more severe disease. Login to comment
158 F591L, T1139M, R1215Q, and G1382S all showed a reduced response to stimulation by MgADP. Login to comment
166 For two mutations, F591L and G1382S, it was not possible to correlate the in vitro and clinical characteristics, since the patients with these mutations were heterozygous with no mutation identified onthe second allele. Login to comment
175 Five others (H125Q, N188S, F591L, T1139M, and R1215Q) are outside of the predicted nucleotide-binding folds. Login to comment
185 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 ?? Login to comment

PMID: 9618169 [PubMed] Nestorowicz A et al: "Genetic heterogeneity in familial hyperinsulinism."

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). Login to comment
141 For proband G7, BsoF1 restriction enzyme analysis indicated that although the proband possessed a Phe591Leu mutation in the heterozygous state, this mutation was neither present in the proband`sparentsnorintwounaffectedsiblings(datanotshown). Login to comment
142 Nucleotide sequence analyses confirmed the absence of the Phe591Leu mutation in all first-degree relatives of proband G7. Login to comment
143 Since the results of extended haplotype analyses for kindred G were consistent with Mendelian inheritance for all offspring (data not shown), these data suggest that the Phe591Leu substitution occurred de novo in proband G7. Login to comment
144 With the exception of the Phe591Leu mutation, all other missense mutations examined co-segregated with the HI phenotype and displayed Mendelian inheritance (Fig. 4b and data not shown). Login to comment
200 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. Login to comment
201 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). Login to comment
202 Furthermore, increased sensitivity of KATP channel activity to inhibition by ATP was observed in channels containing the Phe591Leu mutation. Login to comment

PMID: 12110524 [PubMed] Huopio H et al: "K(ATP) channels and insulin secretion disorders."

No. Sentence Comment

76 Reduced sensitivity to stimulation by MgADP is a defect of channels generated by a number of HI-associated SUR1 mutations, including F591L, T1139M, R1215Q, G1382S, and E1506K (25, 59) (Fig. 1B). Login to comment
65 Reduced sensitivity to stimulation by MgADP is a defect of channels generated by a number of HI-associated SUR1 mutations, including F591L, T1139M, R1215Q, G1382S, and E1506K (25, 59) (Fig. 1B). Login to comment

PMID: 11867634 [PubMed] Taschenberger G et al: "Identification of a familial hyperinsulinism-causing mutation in the sulfonylurea receptor 1 that prevents normal trafficking and function of KATP channels."

No. Sentence Comment

222 Another mutation, F591L, which is also outside of the two NBFs, has similar detrimental effects on channel response to MgADP and diazoxide (20). Login to comment
221 Another mutation, F591L, which is also outside of the two NBFs, has similar detrimental effects on channel response to MgADP and diazoxide (20). Login to comment

PMID: 15807877 [PubMed] Ohkubo K et al: "Genotypes of the pancreatic beta-cell K-ATP channel and clinical phenotypes of Japanese patients with persistent hyperinsulinaemic hypoglycaemia of infancy."

No. Sentence Comment

130 For example, the patients having some kinds of missense mutations in the SUR1 gene such as F591L,13 R1420C, 20 R1506K 6 and K1385Q in this report showed mild hypoglycaemia, which is known to be responsive to drug therapy, and thus they do not need an operation. Login to comment

PMID: 24686051 [PubMed] Demirbilek H et al: "Clinical characteristics and phenotype-genotype analysis in Turkish patients with congenital hyperinsulinism; predominance of recessive KATP channel mutations."

No. Sentence Comment

67 The remaining six ABCC8 mutations, p.R168C, p.N188S, p.L533P, p.W232G, p.R842Q and p.F591L were each identified in a single patient. Login to comment
85 Gene Current age (year) Exon/intron DNA description Protein description Consequence Transmission Treatment Follow-up Developmental delay Comments Diazoxide responsive Octreotide responsive Pancreatectomy (histology) ABCC8 1 3.9 Exon 28 c.3554COA p.Ala1185Glu Missense Homozygous K C K Octreotide CCC Novel mutation 2 0.7 Exon 28 c.3554COA p.Ala1185Glu Missense Homozygous K C K Octreotide Novel mutation 3 9.1 Exon 28 c.3554COA p.Ala1185Glu Missense Homozygous K K K Irregular CCCC Novel mutation 4 0.7 Exon 28 c.3554COA p.Ala1185Glu Missense Homozygous K C K Octreotide C Novel mutation 5 0.2 Exon 28 c.3554COA p.Ala1185Glu Missense Homozygous K C K Octreotide Novel mutation 6 0.7 Exon 28 c.3512delT p.Leu1171fs Frameshift Homozygous K K C (diffuse) Remission 7 0.7 Exon 28 c.3512delT p.Leu1171fs Frameshift Homozygous K C C (diffuse) Octreotide 8 Died Exon 28 c.3512del p.Leu1171fs Frameshift Heterozygous paternal K K C (diffuse) Died 9 5.8 Exon 28 c.3512delT p.Leu1171fs Frameshift Homozygous K C K Octreotide CCC Ectodermal dysplasia 10 9.6 Exon 28 c.3512delT p.Leu1171fs Frameshift Homozygous K C K Octreotide CCC 11 0.7 Exon 4 c.502COT c.563AOG p.Arg168Cys/ p.Asn188Ser Missense Compound heterozygous K C C (diffuse) Octreotide K 12 Died Exon 10 c.1598TOC p.Leu533Pro Missense Homozygous K C K Died Novel mutation 13 10.6 Exon 5/ exon 21 c.694TOG/ c.2525GOA p.Trp232Gly/ p.Arg842Gln Missense/ Missense Compound heterozygous K C K Octreotide CC 14 5.5 Exon 12 c.1771TOC p.Phe591Leu Missense Heterozygous C K Diazoxide K KCNJ11 15 2.4 Exon 1 c.101GOA/ c.376GOA p.Arg34His/ p.Glu126Lys Missense/ Missense Compound heterozygous K C K Octreotide K 16 3.3 Exon 1 c.272GOA p.Trp91X Nonsense Homozygous K C C (diffuse) Octreotide CC 17 3.2 Exon 1 c.376GOA p.Glu126Lys Missense Homozygous K C C (diffuse) Octreotide CC HADH 18 4.4 Exon 6 c.706COT p.Arg236X Nonsense Homozygous C Diazoxide C Genotype-phenotype correlation " Comparison between KATP mutation-positive and KATP mutation-negative groups highlighted a statistically significant increased birth weight and younger age of presentation in KATP mutation-positive group as compared with KATP mutation-negative patients (Table 3). Login to comment